Aus der Klinik für Psychiatrie und Psychotherapie

der Universitätsmedizin Göttingen,

Georg-August-Universität Göttingen

Effect of prefrontal High Frequency repetitive Transcranial

Magnetic Stimulation (rTMS) on Psychopathology and Working

Memory in Patients with Schizophrenia and Healthy Controls

Inaugural - Dissertation

zur

Erlangung des Grades eines Doktors der Naturwissenschaften

in der

Fakultät für Psychologie

der

RUHR - UNIVERSITÄT BOCHUM

vorgelegt von:

Dipl.-Psych. Birgit Guse

Gedruckt mit Genehmigung der Fakultät für Psychologie der

RUHR-UNIVERSITÄT BOCHUM

Referent: Prof. Dr. Boris Suchan

Korreferent: PD Dr. Thomas Wobrock

Tag der mündlichen Prüfung: 18.06.2013

Contents

1 Introduction …………………………………………………………… 3

1.1 Schizophrenia ………………………………………………………………….. 3

1.1.1 Negative Symptoms and Cognition ………………………………...……… 5

1.1.2 Working Memory Deficits and Cerebral Correlates ………………......…… 6

1.2 Transcranial Magnetic Stimulation ……………………………………….….. 10

1.2.1 Physical and Physiological Principles ……………………………………. 10

1.2.2 Stimulation Parameters of Repetitive Transcranial Magnetic Stimulation . 11

1.2.3 Therapeutic Applications of rTMS ……………………………………….. 13

1.2.3.1 rTMS Effect on Psychopathology ………...………………………….. 14

1.2.3.2 rTMS Effect on Cognition ……………………………………………. 16

1.3 Functional Magnetic Resonance Imaging ………...………………………….. 18

1.3.1 Physical and Physiological Principles ……………………………………. 18

1.3.2 Imaging rTMS Effects ……………………………………………………. 20

1.4 Summary and Unresolved Issues ……………………………………………... 21

2 Publications ………………...………………………………………… 24

2.1 Repetitive transcranial magnetic stimulation for the treatment of negative

symptoms in residual schizophrenia: rationale and design of a sham-controlled,

randomized multicentre study ……...……………………………………….……. 25

2.2 Cognitive effects of high frequency repetitive transcranial magnetic stimulation

(rTMS) – a systematic review ………...………………………………………….. 35

2.3 The effect of long-term high frequency repetitive transcranial magnetic

stimulation on working memory in schizophrenia and healthy controls – a

randomized placebo-controlled, double-blind fMRI study ………………………. 54

3 Discussion …………………………………………………………...... 63

3.1 Does rTMS improve Psychopathology in Patients with Schizophrenia? …….. 64

3.2 Does rTMS influence Cognition? …………………………………………….. 66

3.3 Does rTMS improve WM Dysfunction in Patients with Schizophrenia? Does

rTMS alter Brain Activation within the WM Network? ………………..………… 67

3.4 General Limitations ………………...………………………………………… 71

- 1 -

3.5 Conclusion and Future Perspective ………………………..……………….… 74

4 References …………..………………………………………….…….. 75

Abbreviations ……………………………………………………………………….… 87

Acknowledgements ………………………...………………………………………… 88

Curriculum Vitae ……………...……………………………………………………… 89

List of Publications …...………………………………………………………………. 90

- 2 -

1. Introduction

1.1 Schizophrenia

According to the diagnostic guidelines of the International Statistical Classification

of Diseases and Related Health Problems (ICD-10) of the World Health Organization

(WHO) different symptoms can be clustered for the diagnosis of schizophrenia (for

details see the box below). The normal requirement for diagnosis is that a minimum of

one clear symptom (and usually two or more if less clear-cut) belonging to one of the

groups listed from (a) to (d) below, or symptoms from at least two of the groups from

(e) to (h), should clearly be present for most of the time during a period of 1 month or

more.

The ICD-10 encodes distinct subtypes of schizophrenia F20.0-F20.9, whereas the

paranoid subtype (F20.0) is most prominent with a prevalence of about 65%. The

clinical picture is dominated by relatively stable, often paranoid, delusions, usually

accompanied by hallucinations, particularly of the auditory variety, and perceptual

disturbances. These symptoms are commonly defined as positive or productive

symptoms as they occur in addition to “normal” behaviour (see box below, PANSS-

symptoms). Conversely, another symptom group is defined as negative symptoms and

encompasses clear behavioural deficits such as apathy, blunted affect or social and

emotional withdrawal (see box below, PANSS-symptoms; for details see chapter 1.1.1).

The course of paranoid schizophrenia may be episodic, with partial or complete

remissions, or chronic. In chronic cases, the florid symptoms persist over years and it is

difficult to distinguish discrete episodes.

A clear distinction of symptom clusters is essential for pharmacotherapeutic

intervention since positive symptoms may be associated with a hyper-aroused state that

usually responds well to antipsychotic medications, whereas negative symptoms consist

of deficit features that may represent a more stable component of the disease and are

often characterized by neuroleptic resistance (e.g. Kay et al., 1987). Depending on the

definition of treatment-resistant schizophrenia, about 10–30 % of patients have little or

no response to antipsychotic medication, and up to an additional 30% of patients have

only partial responses to treatment (Falkai et al. 2005, 2006). Even if a patient’s positive

symptoms remit with antipsychotic agents, persisting negative symptoms or cognitive

- 3 -

impairment often determine an unfavourable course of the illness leading to a reduction

of psychosocial functioning and quality of life. Second generation antipsychotics

(SGAs) provide some benefits in improving negative symptoms compared to

conventional neuroleptic treatment but there is still a considerable portion of patients

suffering from such symptoms (Falkai et al. 2005, 2006). Despite this clinical relevance

there are only few treatment strategies available. Therefore, insights into novel

techniques potentially modulating brain functions are promising for therapeutic

purposes.

ICD-10: Diagnostic Guidelines for Schizopnrenia, Symptom Clusters. (a) thought echo, thought insertion or withdrawal, and thought broadcasting; (b) delusions of control, influence, or passivity, clearly referred to body or limb movements or specific thoughts, actions, or sensations; delusional perception; (c) hallucinatory voices giving a running commentary on the patient's behaviour, or discussing the patient among themselves, or other types of hallucinatory voices coming from some part of the body; (d) persistent delusions of other kinds that are culturally inappropriate and completely impossible, such as religious or political identity, or superhuman powers and abilities (e.g. being able to control the weather, or being in communication with aliens from another world); (e) persistent hallucinations in any modality, when accompanied either by fleeting or half-formed delusions without clear affective content, or by persistent over-valued ideas, or when occurring every day for weeks or months on end; (f) breaks or interpolations in the train of thought, resulting in incoherence or irrelevant speech, or neologisms; (g) catatonic behaviour, such as excitement, posturing, or waxy flexibility, negativism, mutism, and stupor; (h) "negative" symptoms such as marked apathy, paucity of speech, and blunting or incongruity of emotional responses, usually resulting in social withdrawal and lowering of social performance; it must be clear that these are not due to depression or to neuroleptic medication; (i) a significant and consistent change in the overall quality of some aspects of personal behaviour, manifest as loss of interest, aimlessness, idleness, a self-absorbed attitude, and social withdrawal.

Positive and Negative Symptoms according to the Positive and Negative Syndrome Scale for Schizophrenia (PANSS, Kay et al., 1987): Positive Symptoms: Negative Symptoms:

Blunted affect Delusions Emotional withdrawal Conceptual disorganization Poor rapport Hallucinatory behaviour Passive/ apathic social withdrawal Excitement Difficulty in abstract thinking Grandiosity Lack of spontaneity Suspiciousness/ persecution Stereotyped thinking Hostility

- 4 -

1.1.1 Negative Symptoms and Cognition

According to the Positive and Negative Syndrome Scale (PANSS), developed and

standardized for the typological and dimensional assessment of schizophrenic

phenomena (Kay et al., 1987), the negative symptoms in schizophrenia are determined

by 7 different deficit features. (1.) Blunted affect describes the diminished emotional

responsiveness that is characterized by a reduction in facial expression, affective

modulation and communicative gestures. (2.) Emotional withdrawal is determined by

the lack of interest in, involvement with, and affective commitment to life’s events. (3.)

Poor rapport defines the lack of interpersonal empathy, the openness in conversation,

characterized by distancing and reduced verbal and non-verbal communication. (4.)

Social withdrawal describes a diminished interest and initiative in social interactions

due to passivity, apathy or avolition leading to neglect of daily activities. (5.) Difficulty

in abstract thinking implies the impairment in the use of the abstract-symbolic mode of

thinking, as evidenced by difficulty in classification, forming generalizations and

problem solving. (6.) Lack of spontaneity and flow of conversation describe the

reduction in the normal flow of communication associated with apathy, avolition,

defensiveness and cognitive deficit. This is manifested by diminished fluidity and

productivity of the verbal-interactional process. The last deficit feature describes (7.)

stereotyped thinking, the decreased fluidity, spontaneity and flexibility of thinking. That

is, rigid, repetitious or barren thought content. Taken together, the negative syndrome is

characterized by a range of interpersonal or social deficits as well as affective emotional

impairment that is connected to cognitive restraint.

A quantitative review of Heinrichs & Zakzanis (1998) indicates a reliable

neurocognitive deficit in schizophrenia compared to healthy controls. In the reviewed

literature, global verbal and nonverbal memory, attention and word fluency tests yielded

the highest proportion of significant test score differences between patients and

controls. More recently, Reichenberg (2010) reviewed meta-analytic studies in

consideration of neuropsychological functioning in schizophrenia. Results indicate

cognitive impairment in a broad range of domains reflecting a substantial impairment in

schizophrenia (Figure 1, Reichenberg et al., 2010). Importantly, there is some

consistency in documenting an association between negative symptoms and the severity

of cognitive impairment, particularly in executive functions (Green et al., 2000; Henry

- 5 -

& Crawford, 2005; Johnson-Selfridge & Zalewski, 2001; for a review see Reichenberg

et al. 2010). Conversely, relative inconsistency is reported with regard to the association

of positive symptoms and the severity of cognitive deficits (Aleman et al., 1999;

Johnson-Selfridge & Zalewski, 2001; for a review see Reichenberg et al., 2010).

Figure 1: Neuropsychological performance profile of schizophrenia. Summary of meta-analytic studies presented in effect size units (in Reichenberg et al., 2010).

Lesioning and neuroimaging studies have linked schizophrenia negative symptoms

to dysfunction of the prefrontal cortex (PFC), the limbic system, and the basal ganglia

(Goff & Evins 1998; Winterer & Weinberger, 2004). Beyond general attention deficits,

one of the core features of schizophrenia is working memory (WM) dysfunction as part

of a disturbed central executive system (Cannon et al., 2005; Silver et al., 2003), which

is the main objective of the third manuscript of the thesis (see 2.3).

1.1.2 Working Memory Deficits and Cerebral Correlates

Working memory implies the short-term retention of information that is no longer

accessible in the environment and the manipulation and processing of this information

for guiding behaviour (D’Esposito et al., 2000). Baddeley (1986, 2000) advanced the

- 6 -

approach that WM is composed of a central executive supervising three so-called slave

components: the visuo-spatial sketchpad, the phonological loop and the episodic buffer.

The phonological loop is supposed to be essential for speech or language perception/

comprehension and is involved in the temporary maintenance of verbal information via

subvocal rehearsal. The counterpart is built by the visuo-spatial sketchpad, which

temporarily sustains incoming information as visual images. The third system, the

episodic buffer, describes an unspecific multimodal storage with limited capacity that

integrates information from different sources as “chunks”. The central executive plays a

crucial role in the selection of appropriate control processes and their supervision as

well as flexible modulation in a changing environment. Therefore, a dynamic up- and

down regulation of neurotransmitter subsystems is necessary for higher order cognitive

processes. In this context, it is suggested that prospective and retrospective information

are needed for fast updating and modulation during WM performance. Regarding this

proposed model, working memory is an important concept for understanding

mechanisms of complex cognitive functioning such as planning, reasoning, speech

comprehension or decision-making (Funahashi, 2007).

Besides these abstract constructs, recent studies emphasized process-based models

using functional imaging techniques to investigate the corresponding cerebral

correlates. Over the past few decades, studies have provided a substantial body of

evidence that supports a crucial role for bilateral prefrontal, anterior cingulate and

parietal regions in mediating WM performance (e.g. Rypma et al., 2002; for review

Owen et al., 2005 or Smith and Jonides, 1999). The middle frontal gyrus (Brodmann

area (BA) 9/46) is described to be mainly activated during the manipulation and

executive monitoring of incoming stimuli (e.g. Smith et al., 1996; Menon et al., 2001),

whereas the inferior frontal gyrus (BA 44) and parts of the superior frontal gyrus

(premotor and supplementary motor area, BA 6) as well as parietal association cortices

are likely to be most sensitive for maintenance processes (e.g. Paulesu et al, 1993).

These results are in line with functional and cytoarchitectural studies pointing to a

tightly knit and specific network of frontal-mediated working memory functions (for

review Owen et al., 2005; Petrides, 2005; Wager et al., 2003). Overall, the prefrontal

cortex, especially the dorsolateral prefrontal part (DLPFC, BA 9/46), plays an important

role in WM operations. Results from functional imaging studies on schizophrenia

patients are heterogeneous as some report decreased prefrontal activation (so called

- 7 -

hypofrontality) and others increased activation (hyperfrontality) during cognitive tasks

that affect prefrontal regions (e.g. Callicott et al., 2000; Manoach et al., 1999; Volz et

al., 1999). Callicott et al. (2003) provided a model of an inverted-U-shaped curve of the

blood-oxygen-level-dependent (BOLD-) response in the DLPFC during a WM task with

parametric increasing demand (Figure 2A, Callicott et al., 2003).

A

B

Figure 2: Assumed inverted U-curves of (A) the relationship of BOLD-response in the DLPFC and increasing WM load in SZ patients (left) and HC (right) (in Callicott et al., 2003) and of (B) the relationship of dopamine transmission and working memory performance (in Williams & Castner, 2006). HC = healthy controls, SZ = patients with schizophrenia.

They supposed that patients operate on a distinct inverted U-curve that is assumed

to be left-shifted compared to healthy controls. A principle consideration in this study

was that patients’ WM capacity may be exceeded earlier compared to controls, leading

to a relative decrease of DLPFC activations at higher loads. The opposite was assumed

for lower demands, at which patients were supposed to exhibit relatively increased

DLPFC activations, possibly reflecting greater exertion at lower level. In place of the

- 8 -

controversial discussion of DLPFC dysfunction and the assumption of general

hypofrontality, an inefficient dynamic modulation of DLPFC activity during WM

operations has been supposed in schizophrenia, leading in general to poorer task

performance compared to healthy controls (Callicott et al., 2000 & 2003; Johnson et al.,

2005; Perlstein et al., 2001). Overall, results indicate different parts of the brain to be

hypo- and hyperfrontal depending on task demand and individual operating abilities.

In this context it is of importance that an imbalance in dopamine (DA) signalling

within the fronto-striatal circuit plays a crucial role in schizophrenia symptoms and

working memory deficits (Abi-Dargham, 2004; Menon et al., 2001; Williams &

Castner, 2006). Dopamine transmission in the DLPFC and the integrity of working

memory have been described to follow a similar inverted U-curve as it has been

provided for the BOLD-response mentioned above and depicted in Figure 2A (Herold

et al., 2008; Williams & Castner, 2006; Figure 2B, Williams & Castner, 2006). These

effects can be provoked by administration of dopamine DA1 receptor agonists or

antagonists leading to different working memory performances, respectively. An

optimal DA level is essential for WM processing, whereas hypo- or hyperdopaminergic

states result in WM impairment. This is the case for example in aging, acute stress or

different neuropsychiatric diseases such as schizophrenia (Arnsten et al., 1998; Herold

et al., 2008; Williams & Castner, 2006). In a study using Positron-Emission-

Tomography (PET) Okubo et al. (1997) found decreased prefrontal dopamine D1

receptors in schizophrenic patients that were related to the severity of negative

symptoms and to poor performance in the Wisconsin Card Sorting Test (WCST, a test

for executive functions, Grant & Berg et al., 1993). This is important against the

background that antipsychotic medication has not been shown to influence negative

symptoms or cognition to a sufficient extent. It seems obvious that these features may

underlie more stable mechanisms which can be poorly targeted with common agents.

Reduced receptor density is a structural deficit possibly requiring more than a transient

focal up-or down-regulation of neurotransmission. Transcranial magnetic stimulation

(TMS) for example has been demonstrated to act otherwise on neural systems than

antipsychotic medication (see 1.2). However, its applicability and impact for therapeutic

standard use is not known thoroughly. The next chapter provides an overview of the

principles of this technique with regard to clinical applications.

- 9 -

1.2 Transcranial Magnetic Stimulation

Transcranial magnetic stimulation was originally introduced by Barker et al. (1985)

as a non-invasive tool for the investigation of the motor cortex. TMS is based on an

electromagnetic coil applied to the scalp producing an intense, localized magnetic field

which either excites or inhibits a focal cortical area. Repetitive TMS uses alternating

magnetic fields to induce electric currents in the cortical tissue affecting electric

conducting structures (Burt et al., 2002). Today TMS has emerged as an important

technique in several areas of neuroscience. Originally contemplated as a method to

measure the responsiveness and conduction speed of neurons and synapses in the brain

and spinal cord, TMS now plays a crucial role in changing the activity of cerebral

neurons and thus of specific functions (e.g. Speer et al., 2000). TMS has further become

an essential adjunct to brain imaging or mapping methods described below.

1.2.1 Physical and Physiological Principles

The physical principle of TMS is electromagnetic induction due to Faraday’s law

(1830). A capacitor generates short intense discharges, which induce a changing

magnetic field of 2-2,5 Tesla in the TMS coil leading to an electric field in the adjacent

conductive cortical tissue. The magnetic field traverses intermediate structures (e.g.

scalp, skull, liquor) with quite minimal impedance, focally depolarizes neurons and

generates action potentials, provided amplitude, duration and direction are appropriate

(Rothwell et al., 1999; Siebner et al., 2003). Thereby, cortical axons are the electric

conducting structures. The field strength decreases proportional to the square of the

distance. Therefore, only cortical structures and no deeper subcortical regions can be

directly affected with TMS. The penetration depth for an effective neuronal excitation is

about 1,5-2 cm (Epstein et al., 1990) if stimulated with a figure-of-eight shaped coil

allowing a circumscribed stimulation of the brain (Cohen et al., 1990). Current direction

can be varied by coil shape (e.g. circular or 8-coil) and orientation (e.g. posterior-

anterior, lateral-medial) (Figure 3A, Maccabee & Amassian, 2008). In a standard

figure-8 coil two electric field loops are induced which superimpose maximally under

the long axis of the junction (Ueno et al., 1988). Given that the coil is oriented

- 10 -

tangentially to the skull, the induced magnetic field deflects perpendicular to the axis of

the coil leading to an orthogonal current flow parallel to the coil plane. The isopotential

lines of the induced electric field form an oval whose long axis is parallel to the

direction of current flow at the coil junction (Epstein, 2008; Sandbrink, 2008; Figure

3B, Eptein, 2008).

A B

Figure 3A, B: (A) Current direction (in Maccabee & Amassian, 2008) and (B) the relation to coil orientation and magnetic field (in Epstein, 2008).

TMS thus preferentially affects structures that are organized horizontally in the

cortical surface, e.g. axons of intra-cortical neurons. Within the homogeneous electric

field (along the cortical surface) only axons with a curved path are affected providing an

outwards directed depolarizing membrane current, that generates action potentials if

strength and duration are sufficient (see 1.2.2). Vertical neuron bundles are then excited

secondarily via trans-synaptic transmission (Sandbrink, 2008). Overall, focal TMS is

able to affect cortico-cortical or cortico-subcortical axons, but the specific outcome

depends on the stimulation protocol selected, on the area stimulated and on inter-

individual tissue properties.

1.2.2 Stimulation Parameters of Repetitive Transcranial Magnetic Stimulation

TMS can be applied in different modes dependent on the individual scientific

hypothesis. For therapeutic purposes TMS is commonly administered in an alternating

mode consisting of continuous series of stimuli with more than two single pulses of

constant repetition rate (for details of therapeutic applications see 1.2.3). A slow

repetition rate is determined ~1 Hz (low-frequency) and a fast repetition rate is >5 Hz

- 11 -

up to 50 Hz (high-frequency). The repetition rate is essential according to the intention

of inhibition or excitation of a particular cerebral region. Generally, low frequency

stimulation (≤1 Hz) is likely to cause temporal inhibition of neuronal firing, whereas

high frequency (>5 Hz) repetitive TMS (rTMS) for the most part evokes neuronal

depolarization leading to transient neuronal facilitation or enhancement (Fitzgerald et

al., 2006; Haraldsson et al., 2004; Klimesch et al., 2003). Some research has provided

evidence for an inverse relationship between regional cerebral blood flow (rCBF) and

low-frequency rTMS (in the sense of an excitatory effect of slow rTMS) when high

stimulation intensities or intensities at motor threshold are applied (Li et al., 2004; Speer

et al., 2003).

The resting motor threshold (RMT) is commonly used as reference to set the

stimulation intensity. The RMT is defined as the lowest intensity that produces a motor

evoked potential of <50µV in the relaxed first-dorsal interosseus muscle (FDI) in at

least five of ten trials. Therefore, a standard figure-of-eight coil is applied to the hand

area of the motor cortex and motor-evoked potentials are recorded via

electromyography (EMG) surface electrodes from the (FDI) (Rossini et al., 1994;

Rothwell et al., 1999). The stimulation can thus be conducted to e.g. 90, 100 or 110% of

this threshold. The standard rTMS protocol settings further include the definition of

number and duration of TMS trains (repetitive volleys) as well as the resting time

between trains, called inter-train-interval.

For exact coil placement, today, many researcher groups revert to neuro-navigated

targeting, especially when the outcome depends on the accuracy of the target area, e.g.

in case of specific functional interruption. In clinical trials the seed region is often

targeted using the electrode positions of the 10-20 EEG system (Figures 4A, B). The

nasion-to-inion axis (front-back distance) and the pre-auricular axis (right-left distance),

both crossing the vertex, are used as reference system to identify the target region. The

position of the coil centre can then be located at the electrode position (Fitzgerald et al.,

2009; Rusjan et al., 2010).

- 12 -

Figure 4A, B: 10-20 EEG-System coordinates for the identification of a target region1.

1.2.3 Therapeutic Applications of rTMS

Focal non-invasive stimulation of the brain represents a previously unprecedented

therapeutic potential in psychiatry and neurology due to the fact that systematically

administered pharmacological agents may be ineffective or cause treatment-interfering

side effects in many patients. TMS avoids systemic side effects and affects the brain

with a temporal and spatial specificity which currently cannot be achieved

pharmacologically or via methods such as electroconvulsive therapy (Lisanby, 2008).

The exact mechanisms by which focal intermittent brain stimulation could evoke lasting

effects in illnesses via distributed neuronal networks remain unclear. One possibility is

based on the demonstration that some established TMS protocols, which administer

repetitive pulses, have the capacity to induce plasticity shifts of the stimulated and

interconnected brain areas (Esser et al., 2006; for review see Reis et al., 2008). Plasticity

may be broadly defined as an activity-dependent enduring change in neural structure

and function, e.g. in synaptic efficacy (Vorel & Lisanby, 2008). Long-term potentiation

(LTP) is the most widely studied synaptic plasticity process and refers to enduring

strengthening of synapses due to ‘Hebbian’ characteristics (Hebb, 1949; Vorel &

Lisanby, 2008). Typically, synaptic strength is measured as a sum of excitatory

postsynaptic potentials (EPSPs) in response to electrical stimulation. This requires

repeated electrical stimulation of a pre-synaptic neuron as evidenced by an increase in

1 image source: http://www.bci2000.org/wiki/index.php/User_Tutorial:EEG_Measurement_Setup

- 13 -

EPSP. Beyond the hippocampus, LTP has been demonstrated in other brain areas such

as the prefrontal cortex (Floresco & Grace, 2003; Maroun & Richter-Levin, 2003; Vorel

& Lisanby, 2008). However, there is no clear knowledge about whether repetitive

transcranial magnetic stimulation would have the potential to trigger these processes in

such a way that would be essential for a beneficial clinical outcome. Principally, these

considerations provide the possibility of both cognitive and clinical improvement.

1.2.3.1 rTMS Effects on Psychopathology

Regarding the impact of rTMS on psychopathology, pilot studies have suggested a

putative application of repetitive TMS as a therapeutic tool, based on the idea of

targeted stimulation of dysfunctional cortico-subcortical circuits involved in the

pathophysiology (George et al. 2000; Lisanby et al. 2000; Wassermann and Lisanby

2001; Hoffman and Cavus 2002). During the last few decades, a prevalent issue has

been the application in major depression (for review Burt et al, 2002, Padberg et al.,

2009; Fitzgerald et al., 2006), characterized by potential reversible functional deviations

in limbic or para-limbic circuits, especially monoaminergic transmitter systems and

specific molecular mediating systems (Bajbouj, 2007; Padberg et al., 2007). According

to long-time research on this topic the target region in antidepressive rTMS

interventions is commonly the DLPFC, at which the left DLPFC is mainly stimulated at

high frequencies (5-20 Hz) or the right DLPFC at low frequencies (~1 Hz). However,

the clinical outcome does not reach the effect size of electroconvulsive therapy (ECT) in

medication resistant patients (review Padberg & George, 2009).

Similar rTMS protocols were used in studies which investigated the impact of

rTMS on negative symptoms in schizophrenic patients (Table 1). Based on encouraging

results of first case series (Cohen et al., 1999; Jandl et al., 2004; Sachdev et al., 2005;

Rollnik et al., 2001), some randomised double-blind sham- controlled studies have been

conducted in the field (Table 1). The first one applied low-frequency rTMS over the

right prefrontal cortex at 110 % motor threshold (total stimuli 1200) in 35 patients with

schizophrenic or schizoaffective psychoses. There were no significant group differences

except for the use of mood stabilizers in four participants of the active group (Klein et

al. 1999). Studies using high-frequency rTMS (10 Hz and 20 Hz) over the left DLPFC

revealed more success. In a cross-over study, a significant improvement compared to

- 14 -

sham in the average Brief Psychiatric Rating Scale (BPRS, Overall & Gorham, 1962)

score in the active stimulation group after application of a total of ten 20 Hz rTMS

adjuvant treatments with prefrontal stimulation of the dominant hemisphere at 80 % of

the motor threshold (total stimuli 8000) in 12 schizophrenia patients was reported

(Rollnik et al. 2000, Huber et al. 2003). The authors did not differentiate between

positive or negative schizophrenic symptoms. Concerning other symptoms such as

depression or anxiety, which were also recorded separately, no differences could be

detected due to the stimulation. Two other studies using 20 Hz rTMS revealed no

significant improvement of negative symptoms in the active group compared to sham

group (Nahas et al. 1999, Novak et al. 2006). In contrast, studies delivering 10 Hz

rTMS, applied over the left DLPFC (10 sessions in 2 weeks, 110 % motor threshold,

total stimuli 10000) demonstrated significant superiority of the active stimulation

compared to sham in the improvement of the negative score of the Positive and

Negative Syndrome Scale (PANSS, Kay et al., 1986) (Hajak et al. 2004, Cordes et al.

2005). In a double-blind cross-over dose finding study on 27 schizophrenia patients

with predominantly negative symptoms, a significantly higher therapeutic effect was

shown at an alpha EEG peak frequency determined for each individual subject at 8 -13

Hz rTMS over the dorsolateral prefrontal cortex at 80 % motor threshold compared to

treatment at 3 or 20 Hz and sham as controls (Jin et al. 2006). The above mentioned

studies represent the data status until implementation of our trial (Table 1). However,

more recent studies support these results (e.g. Prikryl et al., 2007, Goyal et al., 2007,

Fitzgerald et al., 2008; Schneider et al., 2008; for a meta-analysis see Slotema et al.,

2010).

- 15 -

Table 1: Randomised double-blind sham-controlled studies (including cross-over trials) in the treatment of negative symptoms until 2006.

Study N Location Frequency (Hz) MT (%) Stimuli (N) Significance (p)

Klein 1999 31 RPFC 1 110 1200 n.s.

Nahas 1999 8 LDLPFC 20 100 1600 n.s.

Rollnik 2000 12 DLPFC 20 80 8000 BPRS p = 0.015

Hajak 2004 20 LDLPFC 10 110 10000 PANSS negative subscale p = 0.046

Holi 2004 22 LDLPFC 10 100 10000 n.s.

Jin 2006 27 bilateral DLPFC

3, 10*, 20 80 1200, 4000, 8000

PANSS negative subscale p = 0.007 at 10* Hz

Cordes 2005 25 LDLPFC 10 110 10000 PANSS negative subscale p= 0.046

Novak 2006 16 LDLPFC 20 90 20000 n.s.

Legend: DLPFC: Dorsolateral Prefrontal Cortex, Hz: Hertz, LDLPFC: Left Dorsolateral Prefrontal Cortex, PANSS: Positive and Negative Syndrome Scale, RPFC: Right prefrontal cortex, MT: motor threshold, N.S.: Not significant, *: Individualized Alpha Frequency (8 – 13 Hz).

In conclusion, one can state that the data are convincing that the paradigm of 10 Hz

rTMS applied over the left DLFPC is the most promising design so far for the clinical

use in schizophrenia negative symptoms. However, results remain limited due to small

sample sizes, the lack of control groups or other methodological limitations. Further, the

underlying neurophysiological mechanisms are outstanding and have to be

systematically investigated using imaging or neurophysiological methods such as

functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). Our

first manuscript, outlined in 2.1, addresses the influence of long-term high frequency

rTMS on negative symptoms and general psychopathology using a randomized double-

blind, placebo controlled parallel design.

1.2.3.2 rTMS Effects on Cognition

Let’s consider the impact of rTMS on cognition. Until our trial conception in

2007/2008, most of the results emerged from single session studies measuring the direct

after-effect of rTMS on cognitive processing. Evers et al. (2001) performed a study on

the impact of a single 20 Hz rTMS session on cognitive processing in 14 healthy

subjects as measured by visually evoked event-related potentials (ERP) and mean

choice reaction time. rTMS was applied over the left and right DLPFC consecutively

- 16 -

(about F3/ F4 according to the international 10-20-EEG system). Data were compared

to sham and to 1 Hz single TMS (a continuous series of stimuli). P3 latencies and

reaction time were significantly decreased after 20 Hz real rTMS over the left side, but

not for the right side. 1 Hz single TMS did not have any impact on ERP components.

The authors concluded that rTMS has a fascilitating effect on cognitive processing,

proven by objective neurophysiological measures (Evers et al., 2001). Boroojerdi et al.

(2001) aimed to investigate the role of the left DLPFC in analogic reasoning. They

demonstrated that rTMS over the left DLPFC (compared with right DLPFC, left motor

cortex and sham stimulation) in healthy subjects led to a significant decrease in

response times in the analogy condition without affecting accuracy. The results

underline the relevance of the left DLPFC in analogic reasoning but also indicate that

rTMS applied to this region can speed up solution time (Boroojerdi et al. (2001).

Töpper et al. (1998) and Mottaghy et al. (1999) could show an enhancing cognitive

effect of TMS over Wernicke’s area. Picture naming latencies were shortened in healthy

subjects when TMS was delivered to Wernicke’s area. Töpper et al. (1998) performed

suprathreshold TMS with varying inter-stimulus-intervals, Mottaghy et al. (1999)

applied 20 Hz high-frequency rTMS. Klimesch et al. (2003), could show that rTMS at

individual upper alpha frequency (IAF+1Hz) delivered mesial frontal (Fz) and the right

parietal (P6) cortex in healthy volunteers can enhance the performance in a mental

rotation task. These and many other results on this topic confirm the modulating effect

of one single session of high-frequency rTMS on cognitive processing. However,

neuronal enhancement with consequent cognitive improvement remained transient as

effects disappeared directly after the session. For therapeutic purposes extended effects

would be promising. Our review article (outlined in chapter 2.2) explicitly addresses

cognitive effects following long-term (repeated session) high-frequency rTMS

treatment.

To date, our knowledge about the exact mode of functioning of rTMS is restricted.

Future studies to investigate its effectiveness in the field of neuropsychiatry may prove

promising. For an adequate integration of results it is worth considering the combination

of rTMS with neurophysiological or imaging methods such as EEG or fMRI. This is

one objective of our manuscript outlined in 2.3. The following chapter provides an

insight into (f)MRI technique and gives an overview in combination with rTMS.

- 17 -

1.3 Functional Magnetic Resonance Imaging

The method of magnetic resonance imaging (MRI) has been enormously advanced

since its introduction in 1973 and is now used in clinical routine. Besides the non-

invasiveness of this diagnostic technique the impact of MRI relies on the ability of

imaging different tissue contrasts. Since 1992 then brain functions have been

investigated via functional MRI (Kellermann, 2007). To understand the principles of

MR technique and its modes of application some physical and physiological basics are

essential as described in the following section.

1.3.1 Physical and Physiological Principles

Subatomic particles have the impulse to spin around themselves, thus to produce a

magnetic field if these particles feature electric charge. The nucleus of a hydrogen atom

is composed of a positively charged proton with this property. Due to its high incidence

in the human organism the hydrogen atom is of great interest in medical MRI. If a

proton is arranged in an external magnetic field, the magnetic moment rotates (or

precesses) around the axis of this external magnetic field. The strength of the magnetic

field is measured in Tesla (T). The frequency of the proton precession around the

external magnetic field is called Lamor frequency and it is particle specific. Therefore,

the Lamor frequency increases proportionately to the strength of the external magnetic

field. Most of the spins align parallel to this external magnetic field leading to a

measurable magnetism in a probe (e.g. a patient) along the field direction (Kellermann,

2007; Kellermann et al., 2008). In the equilibrium state, after positioning a probe in a

magnetic field (or patient in a tomograph) and the alignment of all spins, there are no

further interactions. For the MR signal measure, this system has to be disequilibrated.

Therefore, an MR signal is generated by an electromagnetic high-frequency pulse (HF-

pulse) that has to be administered with the same Lamor frequency of the proton spins.

This HF pulse rotates the proton spins in the x-y-axis. When the pulse is turned off they

return back to thermodynamic equilibrium and the main magnetization becomes

realigned with the static magnetic field. During this process electromagnetic radiation is

emitted which is recorded by receiver coils due to Faraday’s law of induction

(Kellermann et al., 2008; Huettel et al., 2004).

- 18 -

The clinical relevance of the MRI method results from the fact that different

imaging contrasts can be extracted due to different tissue characteristics. For fMRI

experiments static contrasts are used to determine brain anatomy. These contrasts are

sensitive to type, number and relaxation properties of atomic nuclei. Typical static

contrasts include density (e.g. proton density), relaxation time (T1, T2, T2*), content of a

particular molecular type (e.g. magnetization transfer to detect large or small

molecules), and general chemical content (e.g. spectroscopy) (Huettel et al., 2004).

For the reconstruction of images it is essential to decode the origin of the signal. For

this purpose, proportions of the MR signal have to be attributed to predefined 3D-

volumes (voxels) within the probe. Gradient coils enable this correlation by generating

gradient fields which slightly overlay the static magnetic field. Lamor frequencies of the

protons thus differ according to their spatial position. The MR image can then be

reconstructed due to a frequency analysis (Fourier-Analysis) of the measured MR signal

by extracting the spatial position of the different frequency proportions (Huettel et al.,

2004; Kellermann et al., 2008).

There are two factors that govern the time in which MR images are collected. The

first is the time interval between successive excitation pulses, which is known as

repetition time or TR. The other factor is the echo time (TE) used for BOLD-contrast

fMRI images. The TE describes the time interval between an excitation pulse and data

acquisition, expressed in milliseconds (Huettel et al., 2004).

For the creation of images that are sensitive to brain function, thus, for

functional imaging (fMRI), it is necessary to identify a biophysical property that is

altered by information processing within the brain. The basis of functional imaging is

due to the fact that information-processing activity of neurons increases their metabolic

requirements. For this purpose, energy has to be provided. The vascular system supplies

cells with two fuel sources, glucose and oxygen, whereby the latter bounds to

haemoglobin molecules. Haemoglobin has magnetic properties depending on whether

or not it is bound to oxygen. Oxygenated haemoglobin (Hb) is diamagnetic, that is the

property of a weak repulsion from a magnetic field. Deoxygenated haemoglobin (dHb)

has a paramagnetic property. The magnetic susceptibility of dHb blood is about 20%

greater than fully oxygenated blood. This leads to a differentiability of arterial blood

(which contains only oxygenated haemoglobin) and venous blood (which contains both

- 19 -

oxy- and deoxygenated haemoglobin). MR pulse sequences sensitive to T2* show more

MR signal where blood is highly oxygenated, that is in case of neuronal activity during

cognitive processes, and less MR Signal where blood is highly deoxygenated. This

provides a basis for measurement of blood oxygenation changes using the so-called

blood-oxygen-level-dependent (BOLD) fMRI. The BOLD contrast is defined to be the

difference in signal on T2* -weighted images as the function of amount of deoxygenated

haemoglobin. BOLD fMRI today plays an important role in the field of cognitive

neuroscience as this technique enables the relation of changes in brain physiology over

time to an experimental manipulation due to specific cognitive tasks (Huettel et al.,

2004).

1.3.2 Imaging rTMS Effects

One possibility to modulate activity states and to interfere with the function of

certain brain areas is the application of rTMS. Physiological studies of the primary

motor cortex conducted in healthy subjects indicate that repetitive TMS can induce a

long-lasting enhancement or reduction of cortical excitability (for review see Ziemann

et al., 2008; Hallet, 2007). These and other effects can be mapped on-or offline using

different imaging methods. So far, various functional imaging techniques have been

used to visualize effects of rTMS on the brain. These include functional magnetic

resonance imaging (fMRI), positron emission computed tomography (PET), and single

photon emission computed tomography (SPECT). rTMS can serve as a probe of

functional connectivity when combined with these techniques. Pioneering studies

demonstrated that rTMS delivered to the frontal eye field or to the primary motor cortex

produced a pattern of dose-dependent distal effects in connected brain regions (Paus et

al. 1997; Fox et al. 1997). Similarly, studies showed that rTMS of the prefrontal cortex

modulated brain activity at both the stimulation site and in several distant regions

presumably connected with the stimulated cortex (Teneback et al. 1999; Paus et al.

2001; Shajahan et al. 2002; Kimbrell et al. 2002). Additionally, amongst healthy

volunteers rTMS of the left prefrontal cortex was shown to cause a reduction in [11C]

raclopride binding resulting from the release of endogenous dopamine in the left dorsal

caudate nucleus (Strafella et al. 2001). It was possible to induce dopamine release by

direct stimulation of corticofugal axons or by reducing GABA-mediated intra-cortical

- 20 -

inhibition and to image this effect using PET. Apart from imaging direct after-effects or

using online- rTMS during the fMRI session, one should consider imaging outlasting

effects off-line. Combining rTMS with functional imaging provides great impact for

research in cognitive neuroscience and raises new insights into the pathophysiology of

neuropsychiatric disorders. Triggering neural network firing with specific cognitive

tasks as well as imaging their manipulation following rTMS is of special interest in the

field. In our third presented work (see 2.3) we aimed to cope with these issues and

combined rTMS with offline fMRI. The primary objective of the study is the

investigation of long-term rTMS effects on working memory processes.

1.4 Summary and Unresolved Issues

Negative symptoms (such as apathy, blunted affect and social/ emotional

withdrawal) often occur in patients with schizophrenia and have been described to be

closely connected to DLPFC dysfunction due to deficient neuronal integrity and brain

metabolism. Inefficient dynamic modulation of DLPFC activity has been revealed to

impair working memory and other executive processes in schizophrenia (Cannon et al.,

2005; Goff & Evins 1998; Silver et al., 2003; Winterer & Weinberger, 2004). Some

consistency has been documented in the association between negative symptoms and

the severity of cognitive impairment, particularly in executive functions (Green et al.,

2000; Henry & Crawford, 2005; Johnson-Selfridge & Zalewski, 2001; for a review see

Reichenberg et al. 2010). Since negative symptoms and cognitive disturbance are often

persistent after antipsychotic medication, other therapeutic interventions should be

evaluated to increase life quality. Repetitive TMS is a method that is proven to evoke

outlasting or consolidation effects in the human motor system indicating behavioural

effects (e.g. Reis et al., 2008, 2009; Ziemann et al. 2008). Some TMS protocols which

administer repetitive pulses have the capacity to induce plasticity shifts of the

stimulated and interconnected brain areas (Esser et al., 2006; Reis et al., 2008).

Plasticity has been broadly defined as an activity-dependent enduring change in neural

structure and function, e.g. in synaptic efficacy (Vorel & Lisanby, 2008). According to

the ‘Hebbian’ characteristics of long-term potentiation (LTP), repeated electrical

stimulation of a pre-synaptic neuron increases the sum of excitatory postsynaptic

potentials (EPSP) with consequent synaptic strengthening and functional changes

- 21 -

(Hebb, 1949; Vorel & Lisanby, 2008). These mechanisms have been demonstrated also

in brain areas such as the prefrontal cortex (Floresco & Grace, 2003; Maroun & Richter-

Levin, 2003; Vorel & Lisanby, 2008). However, the mechanisms by which intermittent

brain stimulation such as excitatory rTMS could evoke lasting neuroplastic changes in

illnesses remain unclear until today. The effectiveness of rTMS in symptom

improvement or cognitive modulation is still outstanding. As we know from clinical

pilot trials on depression or schizophrenia, long-term high-frequency rTMS over the

right or left DLPFC seems to be a promising technique to improve certain depressive or

negative symptoms, respectively (see 1.2.3.1). However, the impact of rTMS on

cognitive processing remains questionable at this time. Single session TMS studies have

provided evidence for a transient enhancing effect of focal higher frequency stimulation

(e.g. Boroojerdi et al., 2001; Evers et al., 2001; Klimesch et al., 2003; Mottaghy et al.,

1999; Töpper et al., 1998). But there is no clear knowledge about the effect of repeated

rTMS sessions on cognition and the neurophysiological mechanisms. It seems likely

that repeated rTMS sessions cumulate the occurring effects and that intermittent

stimulation supports neuronal integration and consolidation. Systematic studies

addressing this issue are promising for potential clinical implementation. Furthermore,

brain imaging techniques such as fMRI would provide more profound insight into the

working mechanism of rTMS in the brain.

- 22 -

This thesis aims to reply to the following major questions:

Does long-term high frequency rTMS improve psychopathology, primarily

negative symptoms, in patients with schizophrenia?

This question will be addressed in the first multi-centre study outlined in chapter

2.1.

Does long-term high frequency rTMS influence cognition?

This question is main part of the second manuscript, the review article, illustrated in

chapter 2.2.

Does long-term high frequency rTMS improve WM dysfunction in patients

with schizophrenia?

Does long-term high frequency rTMS alter brain activation within the WM

network?

This twofold question will be addressed in the third presented study outlined in

chapter 2.3.

The third study is a sub-project of the first multi-centre study following the same

methodology in a smaller sample. The most relevant difference of the third study is

the clear focus on working memory and the additional implementation of fMRI

measures. Only in the sub-project has a healthy control group been included.

- 23 -

2 Publications

This chapter is comprised of the following articles that were either published or

accepted for publication up to submission of the thesis.

1. Cordes J, Falkai P, Guse B, Hasan A, Schneider-Axmann T, Arends M et al.

(2009). Repetitive transcranial magnetic stimulation for the treatment of negative

symptoms in residual schizophrenia: rationale and design of a sham-controlled,

randomized multicentre study. European Archives of Psychiatry and Clinical

Neuroscience 259 (Suppl 2):189-97.

2. Guse B, Falkai P, Wobrock T (2010). Cognitive effects of high-frequency

repetitive transcranial magnetic stimulation: a systematic review. Journal of

Neural Transmission 117(1): 105-22.

3. Guse B, Falkai P, Gruber O, Whalley H, Gibson L, Hasan A et al. (2013). The

effect of long-term high frequency repetitive transcranial magnetic stimulation on

working memory in schizophrenia and healthy controls – a randomized placebo-

controlled, double-blind fMRI study. Behavioural Brain Research, Jan 15,

237:300-7.

Further publications can be found at the end of this thesis.

- 24 -

2.1 Repetitive transcranial magnetic stimulation for the treatment of negative

symptoms in residual schizophrenia: rationale and design of a sham-controlled,

randomized multicentre study

This study addresses the effect of long-term excitatory rTMS over the left DLPFC

on negative symptoms in schizophrenia patients. The current manuscript describes the

trial design and rationale to provide an overview of this complex issue. The trial is

constructed as a randomized, placebo-controlled, observer-and patient-blind, parallel-

group treatment over three participating centres. Primary objective is to prove whether

active rTMS is more effective than sham rTMS regarding the improvement of negative

symptoms. Patients in the active condition receive 15 successive sessions of high

frequency 10 Hz rTMS over the left DLPFC (F3, EEG-System), with an intensity of

110% of the individual resting motor threshold, 1000 Stimuli per session (15000 in

total) with an inter-train interval of 30 seconds. In the placebo condition the same coil is

positioned 5 cm latero-caudal to F3 and distorted 45° away from the skull. The

intervention is in addition to antipsychotic medication. The primary efficacy endpoint is

a reduction of negative symptoms as assessed by the negative sum score of the Positive

and Negative Syndrome Scale (PANSS). A sample size of 63 in each group has 80%

power to detect an effect size of 0.50. Besides psychopathological ratings, further

outcome measures are social functioning, quality of life and some neurobiological and

neurocognitive parameters. The outcome is evaluated pre- versus post-treatment and

during a 12 weeks follow-up. Data analysis is based on the intention- to- treat

population.

- 25 -

Repetitive transcranial magnetic stimulation for the treatmentof negative symptoms in residual schizophrenia: rationaleand design of a sham-controlled, randomized multicenter study

Joachim Cordes Æ P. Falkai Æ B. Guse Æ A. Hasan Æ T. Schneider-Axmann Æ M. Arends Æ G. Winterer ÆW. Wolwer Æ E. Ben Sliman Æ M. Ramacher Æ C. Schmidt-Kraepelin Æ C. Ohmann Æ B. Langguth ÆM. Landgrebe Æ P. Eichhammer Æ E. Frank Æ J. Burger Æ G. Hajak Æ M. Rietschel Æ T. Wobrock

� Springer-Verlag 2009

Abstract Current meta-analysis revealed small, but sig-

nificant effects of repetitive transcranial magnetic stimu-

lation (rTMS) on negative symptoms in patients with

schizophrenia. There is a need for further controlled,

multicenter trials to assess the clinical efficacy of rTMS on

negative symptoms in schizophrenia in a larger sample of

patients. The objective of this multicenter, randomized,

sham-controlled, rater- and patient-blind clinical trial is to

investigate the efficacy of 3-week 10-Hz high frequency

rTMS add on to antipsychotic therapy, 15 sessions per

3 weeks, 1,000 stimuli per session, stimulation intensity

110% of the individual motor threshold) of the left

dorsolateral prefrontal cortex for treating negative symp-

toms in schizophrenia, and to evaluate the effect during a

12 weeks of follow-up. The primary efficacy endpoint is a

reduction of negative symptoms as assessed by the nega-

tive sum score of the positive and negative symptom score

(PANSS). A sample size of 63 in each group will have 80%

power to detect an effect size of 0.50. Data analysis will be

based on the intention to treat population. The study will be

conducted at three university hospitals in Germany. This

study will provide information about the efficacy of rTMS

in the treatment of negative symptoms. In addition to

psychopathology, other outcome measures such as neuro-

cognition, social functioning, quality of life and neuro-

biological parameters will be assessed to investigate basic

mechanisms of rTMS in schizophrenia. Main limitations of

the trial are the potential influence of antipsychotic dosage

changes and the difficulty to ensure adequate blinding.

Keywords Residual schizophrenia � Repetitive

transcranial magnetic stimulation � Neurobiology

Background

Depending on the definition of treatment-resistant schizo-

phrenia, about 10–30% of patients have little or no

response, and up to 30% have only partial responses to

antipsychotic medication [7, 8]. Residual symptoms, e.g.

negative symptoms and cognitive impairment, often persist

and determine an unfavorable course of the disease

including disabilities in many domains such as a reduction

in the quality of life. Second generation antipsychotics

provide some benefits by improving negative symptoms

compared with conventional antipsychotic treatment, but

still a considerable number of patients suffer from negative

Trial registration: clinicaltrials.gov NCT00783120.

J. Cordes (&) � M. Arends � G. Winterer � W. Wolwer �E. B. Sliman � M. Ramacher � C. Schmidt-Kraepelin

Department of Psychiatry and Psychotherapy,

Heinrich-Heine University of Dusseldorf,

Bergische Landstr. 2, 40629 Dusseldorf, Germany

e-mail: joachim.cordes@lvr.de

P. Falkai � B. Guse � A. Hasan � T. Schneider-Axmann �T. Wobrock

Department of Psychiatry and Psychotherapy,

University of Gottingen, Gottingen, Germany

B. Langguth � M. Landgrebe � P. Eichhammer � E. Frank �J. Burger � G. Hajak

Department of Psychiatry and Psychotherapy,

University of Regensburg, Regensburg, Germany

C. Ohmann

Coordination Centre for Clinical Trials,

Heinrich-Heine University, Dusseldorf, Germany

M. Rietschel

Department of Genetic Epidemiology in Psychiatry,

Institute of Central Mental Health, Mannheim, Germany

123

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197

DOI 10.1007/s00406-009-0060-y

- 26 -

symptoms associated with cognitive deficits, apathy,

anhedonia, depressive mood and affective flattening [7, 8].

Despite the clinical relevance of these negative symptoms,

there are only few treatment strategies available. Therefore,

looking for alternative treatment approaches to negative

symptoms is currently a central issue in schizophrenia

research [8].

Repetitive transcranial magnetic stimulation (rTMS)

modulates cortical excitability and function in a non-

invasive way. It uses alternating magnetic fields to induce

electric currents in cortical tissue in specific brain regions

[3]. Several studies have found that high frequency rTMS

increased excitability in various brain areas [16]. Evidence

from lesioning and neuroimaging studies has linked nega-

tive symptoms to dysfunctions of the dorsolateral pre-

frontal cortex (DLPFC), the limbic system, and the basal

ganglia, which has been associated with diminished

dopamine signaling in DLPFC [13, 40]. Activation of

mesostriatal dopaminergic pathways by excitatory high

frequency rTMS applied over the DLPFC has been dem-

onstrated in clinical studies [37].

Pilot studies have suggested an application of rTMS as a

novel therapeutic tool in schizophrenia, based on the idea

of targeted stimulation of dysfunctional cortico-subcortical

circuits involved in the pathophysiology of schizophrenia

[10, 18, 25, 26, 39]. Present evidence suggests that rTMS

may be considered safe [27]. Stimulation of the DLPFC

may trans-synaptically lead to an activation of dopami-

nergic neurons in the mesencephalon, and noradrenergic

and serotonergic neurons in the brainstem. RTMS appears

to have an effect on neurotransmitter systems which are

involved in the pathophysiology of negative symptoms in

schizophrenia [37]. Negative symptoms and acoustic hal-

lucinations were the target of interventions by rTMS in

previous studies [4, 9, 16]. At the time our trial was

designed, three out of four controlled high frequency 10 Hz

studies indicated a significant improvement of negative

symptoms. Other studies (one with 1 Hz and three with

20 Hz stimulation frequency) did not show this effect in

schizophrenia patients. In a double-blind crossover dose-

finding study on 27 schizophrenic patients with predomi-

nantly negative symptoms, a significantly higher thera-

peutic effect was shown at an alpha EEG peak frequency

determined for each individual subject 8–13 Hz rTMS over

the DLPFC at 80% motor threshold compared with treat-

ment at 3 or 20 Hz and sham as controls [21]. Freitas et al.

pooled the results of eight studies assessing negative

symptoms, and compared the results of post-rTMS treat-

ment versus baseline. High frequency rTMS induced a

significant reduction in negative symptoms [9]. These

authors did not assess whether the therapeutic effects were

longlasting as only a few studies report follow-up assess-

ments. In summary, high frequency rTMS is a promising

technique to treat negative symptoms in schizophrenia.

However, available trials are characterized by small sample

sizes and heterogeneous results [4, 9, 16, 33].

Thus, randomized controlled trials with higher statistical

power and improved methodology are needed. For this

reason, a randomized, multicenter study to investigate the

efficacy of high frequency rTMS in the treatment of neg-

ative symptoms in schizophrenia in Germany was designed

by the authors [repetitive rTMS for the treatment of neg-

ative symptoms in schizophrenia—a multicenter study

(RESIS Trial)]. After the successful application for funding

by the German Research Foundation in December 2006,

active recruitment was started in January 2008.

Methods

Design of the trial

The trial is a randomized, sham-controlled, observer- and

patient-blind, two-arm, parallel group study of 3-week high

frequency (10 Hz) rTMS treatment plus 3 months follow-up

in schizophrenia patients with predominantly negative

symptoms (see Fig. 1).

Study population, inclusion and exclusion criteria

The inclusion criteria warrant that patients with predomi-

nantly and clinically relevant negative syndromes will be

recruited for the trial. Female and male in- and outpatients

aged 18–60 years are eligible for study participation if they

meet the following key inclusion criteria:

• signed informed consent, patient able and willing to

participate in the study;

• diagnosis of schizophrenia according to the interna-

tional classification of disorders (ICD-10) F 20 criteria.

The mini international neuropsychiatric interview

(MINI-Plus) is a structured interview for classification

of axis-I disorders according to DSM-IV and ICD-10)

[35]. Illness duration [1 year;

• positive and negative symptom score (PANSS)-nega-

tive sum score [20 points, at least one of the PANSS-

negative items N1–N7 (range 1–7) C4 (at least

moderate, clinically relevant negative symptoms),

improvement in PANSS-negative sum score (N1–N7

items with a range 1–7) \10% in the last 2 weeks,

stable medication intake for C2 weeks.

Key exclusion criteria are

• involuntary stay in hospital at the time of recruitment;

• clinically relevant unstable medical conditions;

• previous treatment by rTMS;

S190 Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197

123

- 27 -

• clinically relevant psychiatric comorbidity as opera-

tionalized by the mini international neuropsychiatric

interview, including present misuse or dependence of

drugs or alcohol;

• insufficient cognitive abilities measured by verbal IQ

\85 [Mehrfach-Wahl-Wortschatztest (MWT-B)] [23];

• concomitant treatment with anticonvulsant acting

drugs, e.g. anticonvulsants, benzodiazepines (lorazepam

[2 mg/day, diazepam [10 mg/day);

• history of epileptic seizures or epileptic activity

(spikes) documented in baseline EEG;

• factors not compatible with the use of TMS, e.g.

cardiac pace makers or other metallic implants;

• German language ability insufficient for performing

tests in a valid way;

• pregnancy.

.

Participating centers

The trial is conducted in three German centers, located at

the Departments of Psychiatry and Psychotherapy of the

Georg-August University, Gottingen, Heinrich-Heine

University Dusseldorf and University of Regensburg. All

participating centers have experience in conducting rTMS

treatment studies [4, 5, 15].

Treatment conditions

Patients eligible for participation are randomized to two

parallel treatment groups which receive verum or sham

stimulation. Both groups will receive 3 weeks treatment

with five sessions per week of the left DLPFC (LDLPFC).

The verum treatment group will receive stimulation with

3 9 5 sessions, 10 Hz rTMS, stimulation intensity 110%

related to the individual resting motor threshold, 1,000

stimuli per session, in total 15,000 stimuli per patient, coil

position guided by the 10–20 EEG system over LDLPFC.

The control group will receive sham stimulation by dis-

tortion of the magnetic coil 45� away from the skull with

coil positioning and stimulation parameters otherwise

identical to the treatment group. Figure 8 coils and Med-

tronic MagPro (Medtronic GmbH & Co. KG, Dusseldorf,

Germany) stimulators will be used for stimulation. Despite

the influence of rTMS on motor threshold and its natural

variability only once during the study at the beginning of

the first treatment session, the individual resting motor

threshold for the right first dorsal interosseus muscle (FDI)

of each participant will be determined [32]. Neuronavi-

gated rTMS based on individual positron emission

tomography and magnetic resonance imaging (MRI) data,

as used in some rTMS studies, is sophisticated, costly,

time-consuming and not widely applicable in routine

activity. For these reasons in the present trial, we will use

an easy and reliable method for stimulating the DLPFC

based on the 10–20 electroencephalogram (EEG) system.

The position of the center of the treatment coil will be

marked on the scalp and is located at the left frontal

electrode position F3.

The trial periods can be divided into a screening phase, a

baseline phase lasting 2 weeks to ensure that negative

symptoms and antipsychotic treatment remain stable, a

treatment phase lasting 3 weeks with verum or sham

rTMS, and a 12 weeks follow-up phase (Fig. 1). Medica-

tion type and dosage will be monitored closely. In general,

treatment conditions of study patients should be held

constant, although increases of antipsychotic dose and

initiation or change of psychosocial interventions are not

forbidden throughout the study. Concomitant treatment

with anticonvulsant acting drugs, e.g. anticonvulsants and

benzodiazepines (dose of lorazepam [2 mg/day or diaze-

pam[10 mg/day), is not allowed, because this may reduce

the efficacy of rTMS treatment. Electroconvulsive therapy

is not allowed during the whole trial period.

Blinding

The trial is a patient and rater-blinded study. The rater will

not be involved in the application of rTMS and the treating

physician will be instructed and trained to minimally

interfere with the treatment setting to prevent any impact

on blinding.

Detailed trial objectives and purpose

• The principal research questions addressed by the trial

include a primary objective and several secondary

objectives. The degree of changes will be deemed a

success, if at day 21 a significant difference between

verum and sham will be assumed at a level of P \ 0.05.

Follow-up

Day 1 21 .................................

Screening Baseline Treatment

Visit

skeeW21skeeW3skeeW2Time

-2 2 3 45 10528 -14

Fig. 1 Sequence of trial periods

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197 S191

123

- 28 -

Primary objective

• The primary objective of the study is to prove if verum

rTMS is clinically more effective than sham rTMS as

an add-on treatment in schizophrenic patients with

predominantly negative symptoms as measured by

showing a superior improvement in the PANSS-nega-

tive score [22] (day 21).

Secondary objectives

To evaluate the efficacy of verum rTMS versus sham rTMS

on later time points than the primary objective.

• In reducing negative symptoms measured at follow-up by

change of PANSS-negative score on any of these days (days

28, 45, 105) and additional clinical response defined as

improvement of C20% PANSS-negative baseline score.

• Influence on positive symptoms immediately after

finishing intervention (day 21) and at follow-up mea-

sured by change of PANSS-positive score (days 28, 45,

105).

• In reducing depressive symptoms immediately after

finishing intervention (day 21) and at follow-up mea-

sured by change of Calgary Depression Rating Scale

for Schizophrenia [1] and Montgomery and Asberg

Depression Rating Scale [28] (days 28, 45, 105).

• In changes of global functioning and disease severity

measured by changes in CGI and GAF score [6], and

social adjustment/life quality by changes in scale for

quality of life (SAS II score) [36] immediately after

finishing intervention (day 21) and at follow-up (days

28, 45, 105). On cognition measured by changes in

scores of Wisconsin card sorting test [14], Regens-

burger Wortflussigkeits test [2], Verbaler Lern- und

Merkfahigkeitstest [17] the trail making test to organic

brain damage (TMT A/B) [30] and digit span [38]

immediately after finishing intervention (day 21) and at

follow-up (days 28, 45, 105).

• On extrapyramidal motoric symptoms (EPS) measured

by changes in St. Hans scale score [11, 31] immediately

after finishing intervention (day 21) and at follow-up

(days 28, 45, 105).

Neurobiological markers as adjunctive secondary out-

come measures are to evaluate the efficacy of real rTMS

versus sham rTMS:

• Changes in short interval cortical inhibition (SICI,

interstimulus interval 3 ms), intracortical facilitation

(ICF, interstimulus interval 15 ms) and duration of

contralateral cortical silent period (CSP) in the FDI are

measured by paired- and single-pulse dTMS of the right

and left motor cortex.

• Changes in spontaneous EEG frequency spectrum

activity changes will be registered by 28 electrodes

according to the extended 10/20 system.

• Changes in the identification rate of facial expressions

after presenting ‘‘pictures of facial affect’’ will be

assessed and evoked potentials during facial expression

recognition tests at about 170 ms (N170) and 240 ms

(P240) amplitudes will be recorded.

• Changes in regional brain metabolism will be measured

by changes in metabolite ratios (N-acetylaspartate

(NAA)/creatine ratio or NAA/choline ratio) with single

voxel proton magnetic resonance spectroscopy,

whereby voxels are placed in right dorsal prefrontal

areas, in basal ganglia (covering caudate nucleus/

putamen), the internal capsule, and in the hippocampus.

• Changes in prefrontal attentional network activation

during a selective attention requiring visual oddball task

measured with simultaneously acquired EEG/functional

MRI (fMRI), i.e., BOLD-response, slow wave (‘‘Theta’’)

oscillations for a subgroup of individuals.

• Changes in mRNA/protein expression of selected

candidate genes measured by blood tests.

• And to evaluate the influence of genetic background on

the response to rTMS. The groups will be stratified, e.g.

comparing BDNF Val66Met polymophisms (Val/Val

vs. ValMet).

Key safety parameters in this trial are vital signs (blood

pressure, heart rate), EEG recording immediately before

and after the rTMS treatment period (day 21), and stan-

dardized questions about physical and mental state during

and after daily tTMS treatment.

Visit schedule and data collection/management

An overview on the time schedule for assessing and

recording of efficacy and safety parameters is given in

Table 1. An independent data safety and monitor board

(DSMB) consisting of clinical and statistical experts will

critically assess adherence to the study protocol as well as

to International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for

Human Use (ICH)—Good Clinical Practice (GCP)—

guidelines. Together with the sponsor, the DSMB will

decide whether the trial has to be terminated prematurely.

Any patient eligible for participation in the investigation

according to the inclusion criteria will be advised of

potential risks and benefits before signing the patient

consent form. Patient information and consent forms were

approved by the responsible ethics committees.

The data management follows a remote data entry

approach. The electronical case report form (eCRF) is

implemented in a modern clinical data management system

S192 Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197

123

- 29 -

(CDMS) with electronical data capture functionality. The

system complies with the relevant international standards

and provides the capability to perform the major data

management activities within a consistent, auditable, and

integrated electronical environment (query management,

data entry, data validation).

All measures concerning monitoring/quality assurance

are conducted in accordance to ICH-GCP. Monitoring is

conducted according to the harmonized standard operating

procedures of the coordination center for clinical trials

study-specific processes are described in detail by working

instructions.

Power and sample size justification

Sample size calculation is motivated by the primary end-

point, based on the PANSS-negative symptoms score on

day 21. This score has been documented with a mean value

Table 1 Study visits and assessments

Study visit V0 (t0) V1 (t1) V2 (t2) V3 (t3) V4 (t4) V5 (t5) V6 (t6)

Phase Screening Baseline Treatment Follow-up

Day -28 bis -14 -14 0 21 28 45 105

Inclusion/exclusion x

MINI-Plus x

Informed consent x

Demographic data x

Psychiatric history x

Medical history x

EHI x

Randomization x

Concomitant medication x x x x x x x

Adverse events x x x x x x x

UKU x x x x x

St. Hans scale x x x x x

PANSS x x x x x x x

CDSS x x x x x

MADRS x x x x x

CGI x x x x

GAF x x x x

SAS II x x x x

Neuropsychology x x x x

EEG x x

ERP x x

ECG x

Physical examination x

Vital signs (BP, HR) x x x x x x

MRI/MRS x x

EEG/fMRI x x

dTMS x x x

Laboratory x x

Genetics x x x

Visit V1–V4 are scheduled on the respective day ±2 days, visit V5–V6 ±1 week

At day 0 the stimulation period starts

MINI-Plus MINI-Plus Interview for ICD-10 and DSM-IV diagnosis, EHI Edinburgh Handedness Inventory, UKU Udvalg for Kliniske Und-

ersogelser—detailed Side-Effect Rating Scale, St. Hans Scale Scale for the rating of extrapyramidal motoric symptoms, PANSS positive- and

negative syndrome scale in schizophrenia, CDSS Calgary depression rating scale for schizophrenia, MADRS Montgomery and Asberg depression

rating scale, CGI clinical global impression, GAF global assessment scale of functioning, SAS II scale for quality of life, EEG electroen-

cephalogram, ECG electrocardiogram, BP blood pressure, HR heart rate, MRI magnetic resonance imaging, MRS magnetic resonance spec-

troscopy, fMRI functional magnetic resonance imaging, dTMS diagnostic transcranial magnetic stimulation

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197 S193

123

- 30 -

ranging from 20 to 24 points at baseline in previous studies

of our target population. In the control group an

improvement of about three points is expected for day 21.

Standard deviation has been reported with values between

four and six points [5, 15, 24]. A difference of three points

is considered as a clinically relevant difference. Power

calculations show that a sample size of 63 in each group

will have a 80% power to detect an effect size of 0.50,

which corresponds to a change of three points between

control and treatment group.

Randomization

The patients selected for participation will be randomly

assigned to either the control or experimental intervention

by a computer-generated multiblock randomization sche-

dule generated at the coordination center for clinical trials.

The schedule will be a 1:1 ratio, permutated in setting

blocks of 4, 6, and 8 patients. Randomization will be

stratified by participating hospitals and randomized allo-

cation to one of two treatment arms will take place after

assessment of eligibility and after obtaining informed

consent from the patients for participation.

Statistics

The efficacy analysis with primary and secondary outcome

criteria will be done in the intention to treat population.

Conclusions of the trial will be based only on the intention to

treat population. For confirmatory analysis, a modeling

approach will be applied. A linear model will be used:

yi,j,c = l ? aj ? gc ? ei,j,c (ei,j,c : random effects), where

yi,j,c is the response of individual i (i = 1,…, mC) random-

ized to treatment j (j = 1, 2) for the center c (c = 1,…, C).

The parameters in the model are l (the grand mean), aj (the

group effects) and gc (the center effects). The parameters of

interest in this analysis are the mean of the control group

l ? a1 and the contrast of means a1 ? a2 (which indicates

treatment effect). Estimation of model parameters will be

calculated with maximum likelihood. Treatment effects will

be tested with a likelihood ratio test. In addition, centers

effects will be analyzed. Distributional assumptions will be

assessed (e.g. residual analysis) and transformation on the

response variable will be done if it is necessary. In addition, if

adjustment for covariates is necessary, these will be included

in the model. Descriptive statistics will be calculated for each

treatment group. Demographic and baseline data will be

compared using appropriate statistical techniques.

Recruitment

By the end of June 2009, we have included 93 schizo-

phrenia patients suffering from predominant negative

symptomatic in the trial. The baseline data from 70 patients

were already captured in the electronic database. Half of

the sample received active verum stimulation and the other

half sham stimulation. In Table 2 some preliminary base-

line data are presented. The majority of patients are male.

The psychopathological data (PANSS scores) seem to be

comparable to that of pharmacological studies involving

chronically ill schizophrenia patients. In summary, the

included patients may represent the typical schizophrenia

patient population treated in a hospital setting in the three

participating centers.

Owing to the safety assessment, 23 adverse events were

observed in 17 patients. In seven patients, the adverse

events were classified as severe: two patients showed

worsening of positive symptoms, but only in one patient a

relationship between study intervention and worsening of

psychopathology was estimated as possible; four patients

displayed depressive mood, two of them with suicidal

thoughts; and one patient suffered from severe sleeplessness

and was admitted to hospital. The other adverse events

included headache (1 patients), flu-like symptoms (3

patients), nausea (2 patients), transient tinnitus (1 patient),

increased anxiety (1 patient), depressive mood (2 patients),

sleeplessness and muscle pain during the stimulation period

(1 patient), parkinsonoid (1 patient), thyroidal dysfunction

(1 patient), increased libido (1 patient), dizziness and

intermittent vertigo (1 patient) and an elevation of the

muscle enzyme creatine kinase (1 patient). The majority of

these adverse events (14 of 23) could not be attributed to the

study intervention. Overall, the rTMS treatment seems to be

safe and well tolerated. Until the end of the stimulation

period (day 21), nine patients dropped out. Four patients

dropped out because of the above-described adverse events.

Discussion

High frequency rTMS over LDLPFC applied as an adju-

vant to antipsychotic medication offers a new treatment

Table 2 Preliminary baseline parameters of included patients (June

2009)

Verum

(n = 35)

Sham

(n = 35)

Male/female (%) 83/17 73/27

Education years (m/SD) 10.8 (1.8) 10.6 (1.7)

PANSS-positive score (m/SD) 12.3 (3.2) 13.1 (3.2)

PANSS-negative score (m/SD) 26.1 (4.2) 27.3 (5.2)

PANSS general psychopathology score

(m/SD)

38.9 (10.6) 38.2 (8.4)

PANSS total score (m/SD) 76.8 (15.2) 79.0 (11.1)

m mean, SD standard deviation

S194 Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197

123

- 31 -

option for negative symptoms in patients with schizo-

phrenia. Regarding clinical and neurobiological results,

there is increasing evidence for the efficacy of 10 Hz rTMS

treatment in negative symptoms.

Possible explanations for the moderate effect size and

for the divergence across studies can be offered. One

explanation might be the variation of the baseline psy-

chopathology that probably influences the treatment

response [9]. It seems that trials with stimuli lower than

10,000 delivered negative [19] or worse results [20] and

better results were detected when total number of stimuli

were 10,000 or higher [29, 34]. In most studies, cognitive

and functional outcome measures were scarcely used, but

led to interesting results. All studies available consisted of

small sample sizes. Data are convincing that the paradigm

of 10 Hz rTMS applied over left DLFPC is the most

promising design to be proven in a trial with larger sample

size. If the efficacy and effectiveness of this treatment is

proven in a larger sized sample, this technique will be easy

to establish and highly feasible in clinical practice. A dose-

finding trial to detect significant advantages between dif-

ferent stimulation frequencies, different rates of total

stimuli numbers and different treatment durations will

require a very high sample size. In our study, an active

rTMS treatment period over 3 weeks (total number of

stimuli = 15,000) is planned. Because a review clearly

identified number of days with stimulus application as a

main outcome factor of rTMS in depression [12], we

considered a longer period (3 weeks) of active treatment

than previous studies (2 weeks) in schizophrenia to

improve the outcome. Efficacy of 10 Hz rTMS in patients

with predominantly negative symptoms was only demon-

strated in two trials [5, 21]. Clinical efficacy and psycho-

social outcome was not investigated in previous studies.

Negative symptoms may account for psychosocial

impairment, but relevant ratings of social functioning,

quality of life and the fulfillment of the ability to handle the

daily occurrences, relevant to clinical practice were not

performed. A follow-up evaluation is missing in the pub-

lished studies. The quality of blinding has not been asses-

sed in available studies. In our study patients will be asked

about their guess, which stimulation condition they may

have been received to control for blinding and to avoid a

systematic bias.

Clinical data on the efficacy of rTMS are limited, mainly

due to the small sample sizes of available studies. Sham-

controlled studies of larger patient samples with defined

disease stages and a clear diagnostic typing are required.

Several methodological advantages had to be considered in

the design of our trial. We evaluate a large sample size with

a high total stimuli number and investigate whether a

lasting effect during the follow-up period can be achieved.

Also, we provide a longer period of active treatment than

previous studies (2 weeks) in schizophrenia, and this may

improve outcome.

In addition to psychopathology, a wide range of neu-

ropsychological test performances and social adaptation

will be evaluated in our trial. We will measure several

neurobiological parameters to investigate the basic mech-

anisms of rTMS efficacy in schizophrenia. Limitations of

our trial are the short period of medication stability and

changes of the antipsychotic dosage during intervention,

and the exclusive inclusion of in patients. However, rTMS

was employed almost exclusively as an adjuvant therapy to

antipsychotic pharmacotherapy, whereby most studies

provided no or only little information about the nature and

dose of the employed antipsychotics or the duration of

antipsychotic treatment. The accompanying medication

will be completely assessed and will be mentioned as a

confounding factor in our study. The type of medication

and the antipsychotic dose will be handled as a covariate in

the statistical analysis. Because anticonvulsive medication

may reduce the therapeutic effect of rTMS, treatment with

anticonvulsants is an exclusion criterion in our study.

An ongoing issue in controlled clinical studies is the

question of an adequate control condition [25]. For the

proposed study, we will use angulations of the active

magnetic coil 45� away from the skull as the control con-

dition. This procedure minimizes the magnetic field effect

on the brain, but simultaneously generates some skull

sensation [25]. An alternative option is the use of a

so-called ‘‘sham-coil system’’, mimicking the sound of a

real coil without generating any magnetic field. However,

this sham-coil system does not elicit a skull sensation. The

above-described procedure as a control condition has the

major advantage to induce sensations similar to the verum

condition. In terms of blinding conditions, skull sensation

makes it more difficult for patients to guess whether they

receive verum or sham TMS application.

The implementation of a randomized patient allocation

to either the verum or the sham group, and particularly the

sham control itself deserve special methodological con-

sideration. A modified double-blind design will be applied,

in which patients and clinical observers will be blind to

treatment conditions. Patients have to be naıve regarding

verum or sham rTMS treatment and will not be informed

about technical details of rTMS application. As the treating

physician knows whether verum or sham rTMS is applied,

and because automatic rTMS is methodologically not fea-

sible in clinical settings to date, the personnel applying

rTMS will be instructed and trained to minimally interfere

with the treatment setting to prevent any impact on

blinding. The rating and all study-specific procedures are

carried out by a person who is not involved in the rTMS

treatment. To avoid any impact of side-effect complaints

on the clinical rating, side effects will be assessed by the

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197 S195

123

- 32 -

rTMS performing physician immediately after each

rTMS session and at follow-up using a standardized

questionnaire.

The design of our rTMS trial has to consider ethical

aspects. Applied under previously published safety guide-

lines [39], rTMS has been proven to be a safe and well

tolerated therapy in a broad range of studies encompassing

distinct neuropsychiatric diseases [27]. The study protocol

as well as the documents to obtain patient’s informed

consent has been approved by the ethics committees. The

study will be performed in accordance with the ethics

principles that have their origin in the Declaration of

Helsinki and are consistent with the ICH Guidelines for

Good Clinical Practice and expert consensus.

The study protocol takes into account all of the descri-

bed methodological difficulties and will hopefully dem-

onstrate the feasibility and efficacy of a controlled

multicenter rTMS trial thereby enhancing the quality of the

collected data on the role of rTMS for treating mental

disorders.

Trial centres

Department of Psychiatry and Psychotherapy, Georg-

August-University Gottingen, Germany.

Department of Psychiatry, University of Dusseldorf,

Germany.

Department of Psychiatry and Psychotherapy, Univer-

sity of Regensburg.

Monitoring

Coordination Centre for Clinical Trials, University of

Dusseldorf.

Additional trial site

Department of Genetic Epidemiology, Institute of Central

Mental Health, Mannheim, performing the genetic

analyses.

Acknowledgment This study is funded by the German Research

Foundation (DFG: grant FA 241/10-1).

Conflict of interest statement T. Wobrock has participated in

speaker bureaus for AstraZeneca, Bristol-Myers Squibb, Janssen-

Cilag, Eli Lilly, Organon, Pfizer, Sanofi-Synthelabo/Aventis, and

Alpine-Biomed and received grant/research support from Astra

Zeneca. J. Cordes has participated in speakers bureaus for Janssen-

Cilag, Eli Lilly, Alpine-Biomed and has received grant/research

support from Eli Lilly, Janssen-Cilag, and Pfizer. G. Winterer has

participated in speakers bureaus for Janssen-Cilag, Pfizer, AstraZeneca.

He has recived research support from Eli Lilly, AstraZeneca, Janssen-

Cilag and Johnson & Johnson. P. Falkai is a member of a speakers’

bureau for AstraZeneca, Eli Lilly, Janssen-Cilag and Lundbeck, and

has accepted paid speaking engagements in industry-sponsored

symposia from AstraZeneca, Bristol-Myers-Squibb, Eli-Lilly,

Janssen-Cilag, Lundbeck and Pfizer, and travel or hospitality not

related to a speaking engagement from Astra Zeneca, Bristol-Myers-

Squibb, Eli Lilly, Janssen Cilag, Lundbeck and Sanofi-Synthelabo,

and received a research grant from Astra Zeneca. B. Langguth has

participated in speakers bureaus for Eli Lilly, Boehringer-Ingelheim,

Pfizer, Alpine-Biomed and has received grant/research support

from Astra Zeneca and the Tinnitus Research Initative. W. Wolwer,

A. Hasan, B. Guse, E. Ben Sliman, T. Schneider-Axmann, M. Arends,

M. Ramacher, C. Schmidt-Kraepelin, C. Ohmann, M. Landgrebe,

P. Eichhammer, E. Frank, J. Burger, G. Hajak and M. Rietschel report

no additional financial or other relationships relevant to the subject of

this article.

References

1. Addington D, Addington J, Maticka-Tyndale E (1993) Assessing

depression in schizophrenia: the Calgary depression scale. Br J

Psychiatry 22(Suppl):39–44

2. Aschenbrenner S, Tucha O, Lange KW (2000) Regensburger

Wortflussigkeits-Test (RWT): Handanweisung. Hogrefe, Verlag

fur Psychologie, Gottingen

3. Burt T, Lisanby SH, Sackeim HA (2002) Neuropsychiatric

applications of transcranial magnetic stimulation: a meta-analy-

sis. Int J Neuropsychopharmacol 5:73–103

4. Cordes J, Arends M, Mobascher A, Brinkmeyer J, Kornischka J,

Eichhammer P, Klimke A, Winterer G, Agelink MW (2006)

Potential clinical targets of repetitive transcranial magnetic stim-

ulation treatment in schizophrenia. Neuropsychobiology 54:87–99

5. Cordes J, Thunker J, Agelink MW, Arends M, Mobascher A,

Wobrock T, Schneider-Axmann T, Brinkmeyer J, Mittrach M,

Regenbrecht G, Wolwer W, Winterer G, Gaebel W (2009)

Effects of 10 Hz repetitive transcranial magnetic stimulation

(rTMS) on Clinical Global Impression in chronic schizophrenia.

Psychiatry Res (accepted)

6. Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976) The global

assessment scale: a procedure for measuring overall severity of

psychiatric disturbance. Arch Gen Psychiatry 33:766–771

7. Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF,

Moller HJ (2005) WFSBP Task Force on Treatment Guidelines

for Schizophrenia Guidelines for biological treatment of schizo-

phrenia, part 1: acute treatment of schizophrenia. World J Biol

Psychiatry 6:132–191

8. Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF,

Moller HJ (2006) WFSBP Task Force on Treatment Guidelines

for Schizophrenia Guidelines for biological treatment of schizo-

phrenia, part 2: long-term treatment of schizophrenia. World J

Biol Psychiatry 7:5–40

9. Freitas C, Fregni F, Pascual-Leone A (2009) Meta-analysis of the

effects of repetitive transcranial magnetic stimulation (rTMS) on

negative and positive symptoms in schizophrenia. Schizophr Res

108:11–24

10. George MS, Nahas Z, Molloy M, Speer AM, Oliver NC, Li XB,

Arana GW, Risch SC, Ballenger JC (2000) A controlled trial of

daily left prefrontal cortex TMS for treating depression. Biol

Psychiatry 48:962–970

11. Gerlach J, Korsgaard S, Clemmesen P, Lauersen AM, Magelund

G, Noring U, Povlsen UJ, Bech P, Casey DE (1993) The St Hans

Rating Scale for extrapyramidal syndromes: reliability and

validity. Acta Psychiatr Scand 87:244–252

12. Gershon AA, Dannon PN, Grunhaus L (2003) Transcranial

magnetic stimulation in the treatment of depression. Am J Psy-

chiatry 160:835–845

S196 Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197

123

- 33 -

13. Goff DC, Evins AE (1998) Negative symptoms in schizophrenia:

neurobiological models and treatment response. Harv Rev Psy-

chiatry 6:59–77

14. Grant DA, Berg EA (1993) Wisconsin card sorting test. Hofgrefe,

Gottingen

15. Hajak G, Marienhagen J, Langguth B, Werner S, Binder H,

Eichhammer P (2004) High-frequency repetitive transcranial

magnetic stimulation in schizophrenia: a combined treatment and

neuroimaging study. Psychol Med 34:1157–1163

16. Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G (2004)

Transcranial magnetic stimulation in the investigation and treat-

ment of schizophrenia: a review. Schizophr Res 71:1–16

17. Helmstaedter C, Lendt M, Lux S (2000) Testhandbuch Verbaler

Lern- und Merkfahigkeitstest. Hogrefe, Gottingen

18. Hoffman RE, Cavus I (2002) Slow transcranial magnetic stimu-

lation, long-term depotentiation, and brain hyperexcitability dis-

orders. Am J Psychiatry 159:1093–1102

19. Holi MM, Eronen M, Toivonen K, Toivonen P, Marttunen M,

Naukkarinen H (2004) Left prefrontal repetitive transcranial

magnetic stimulation in schizophrenia. Schizophr Bull 30:429–

434

20. Jandl M, Bittner R, Sack A, Weber B, Gunther T, Maurer K,

Kaschka WP (2005) Therapeutic effects of individualized alpha

frequency transcranial magnetic stimulation (aTMS) on the neg-

ative symptoms of schizophrenia. Schizophr Bull 112:955–967

21. Jin Y, Potkin SG, Kemp AS, Huerta ST, Alva G, Thai TM,

Carreon D, Bunney WE Jr (2005) Therapeutic effects of indi-

vidualized alpha frequency transcranial magnetic stimulation

(aTMS) on the negative symptoms of schizophrenia. Schizophr

Bull 32:556–p561

22. Kay SR, Fiszbein A, Opler LA (1987) The positive and negative

syndrome scale (PANSS) for schizophrenia. Schizophr Bull

13:261–276

23. Lehrl S (1991) Manual zum MWT-B. (3 uberarbeitete Auflage).

Perimed-Fachbuch Verlagsgesellschaft Erlangen

24. Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst

KP, Markwick A, Lloyd H, Jones PB (2006) Randomized con-

trolled trial of effect of prescription of clozapine versus other

second-generation antipsychotic drugs in resistant schizophrenia.

Schizophr Bull 32:715–723

25. Lisanby SH, Luber B, Perera T, Sackeim HA (2000) Transcranial

magnetic stimulation: applications in basic neuroscience and

neuropsychopharmacology. Int J Neuropsychopharm 3:259–273

26. Lisanby SH, Belmaker RH (2000) Animal models of the mech-

anisms of action of repetitive transcranial magnetic stimulation

(RTMS): comparisons with electroconvulsive shock (ECS).

Depress Anxiety 12:78–87

27. Loo CK, McFarquhar TF, Mitchell PB (2008) A review of the

safety of repetitive transcranial magnetic stimulation as a clinical

treatment for depression. Int J Neuropsychopharmacol 11:131–147

28. Montgomery SA, Asberg M (1979) A new depression scale

designed to be sensitive to change. Br J Psychiatry 134:382–389

29. Prikryl R, Kasparek T, Skotakova S, Ustohal L, Kucerova H,

Ceskova E (2007) Treatment of negative symptoms of schizo-

phrenia using repetitive transcranial magnetic stimulation in a

double-blind, randomized controlled study. Schizophr Res

95(1–3):151–157

30. Reitan RM (1958) The relation of the trail making test to organic

brain damage. J Consult Psychology 19:393–394

31. Ringo DL, Half LM, Faustman WO (1996) Validating the St.

Hans rating scale with the abnormal involuntary movement scale

(AIMS) in the assessment of tardive dyskinesia. J Clin Psycho-

pharmacol 16(1):94–95

32. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G,

Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lucking

CH et al (1994) Non-invasive electrical and magnetic stimulation

of the brain, spinal cord and roots: basic principles and proce-

dures for routine clinical application: report of an IFCN com-

mittee. Electroencephalogr Clin Neurophysiol 91:79–92

33. Saba G, Schurhoff F, Leboyer M (2006) Therapeutic and neu-

rophysiologic aspects of transcranial magnetic stimulation in

schizophrenia. Neurophysiol Clin 36(3):185–194

34. Sachdev P, Loo C, Mitchell P, Malhi G (2005) Transcranial

magnetic stimulation for the deficit syndrome of schizophrenia: a

pilot investigation. Psychiatry Clin Neurosci 59(3):354–357

35. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J,

Weiller E, Hergueta T, Baker R, Dubar GC (1998) The mini-

international neuropsychiatric interview: the development and

validation of a structured diagnostic psychiatric interview for

DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33

36. Schooler NR, Hogarty GE, Weissman MM (1979) Social

Adjustment Scale II. In: Hargreaves WP, Attkisson CC, Sorenson

JE (eds) Resource materials for community health program

evaluations, 2nd edn. US Department of Health, Education, and

Welfare, Rockville, pp 290–302

37. Strafella AP, Paus T, Barrett J, Dagher A (2001) Repetitive

transcranial magnetic stimulation of the human prefrontal cortex

induces dopamine release in the caudate nucleus. J Neurosci 21

(15): RC157, 1–4

38. Tewes U (1991) Hamburg-Wechsler-Intelligenztest fur Erwach-

sene. Handbuch und Testanweisung. Revision. Verlag Hans

Huber, Bern

39. Wassermann EM (1998) Risk and safety of repetitive transcranial

magnetic stimulation: report and suggested guidelines from the

international workshop on the safety of repetitive transcranial

magnetic stimulation, June 5–7, 1996. Electroencephalogr Clin

Neurophysiol 1998:1–16

40. Winterer G, Coppola R, Egan MF, Goldberg TE, Weinberger DR

(2003) Functional and effective frontotemporal connectivity and

genetic risk for schizophrenia. Biol Psychiatry 54(11):1181–1192

Eur Arch Psychiatry Clin Neurosci (2009) 259 (Suppl 2):S189–S197 S197

123

- 34 -

2.2 Cognitive effects of high-frequency repetitive transcranial magnetic

stimulation: a systematic review

This systematic review addresses cognitive effects of long-term prefrontal high

frequency rTMS treatment. It comprises clinical rTMS trials (1999-2009) which

assessed cognitive functioning in the field of neuropsychiatry. Primary objective is the

analysis of cognitive effects with regard to the impact of clinical status (patients/

healthy volunteers) and stimulation type (active/ placebo). Results indicate that rTMS at

10-20 Hz, applied over the left DLPFC, within a range of 10-15 successive sessions and

an intensity of 80-110% of the individual motor threshold, is most effective in causing

cognitive improvement. Patients seem to benefit more than healthy participants, and

active stimulation is in some cases superior to sham stimulation. However, some studies

do not include placebo stimulation or additional healthy control groups. Systematic

investigations considering the pathophysiological and neurobiological basis of cognitive

improvement are lacking in the field. Studies comprising genetics, experimental

neurophysiology and functional brain imaging are necessary to explore stimulation

related functional changes in the brain.

- 35 -

DEMENTIAS - REVIEW ARTICLE

Cognitive effects of high-frequency repetitive transcranialmagnetic stimulation: a systematic review

Birgit Guse • Peter Falkai • Thomas Wobrock

Received: 29 April 2009 / Accepted: 7 October 2009

� Springer-Verlag 2009

Abstract Transcranial magnetic stimulation (TMS) was

introduced as a non-invasive tool for the investigation of

the motor cortex. The repetitive application (rTMS),

causing longer lasting effects, was used to study the

influence on a variety of cerebral functions. High-fre-

quency ([1 Hz) rTMS is known to depolarize neurons

under the stimulating coil and to indirectly affect areas

being connected and related to emotion and behavior.

Researchers found selective cognitive improvement after

high-frequency (HF) stimulation specifically over the left

dorsolateral prefrontal cortex (DLPFC). This article pro-

vides a systematic review of HF-rTMS studies (1999–

2009) stimulating over the prefrontal cortex of patients

suffering from psychiatric/neurological diseases or healthy

volunteers, where the effects on cognitive functions were

measured. The cognitive effect was analyzed with regard to

the impact of clinical status (patients/healthy volunteers)

and stimulation type (verum/sham). RTMS at 10, 15 or

20 Hz, applied over the left DLPFC, within a range of 10–

15 successive sessions and an individual motor threshold of

80–110%, is most likely to cause significant cognitive

improvement. In comparison, patients tend to reach a

greater improvement than healthy participants. Limitations

concern the absence of healthy groups in clinical studies

and partly the absence of sham groups. Thus, future

investigations are needed to assess cognitive rTMS effects

in different psychiatric disorders versus healthy subjects

using an extended standardized neuropsychological test

battery. Since the pathophysiological and neurobiological

basis of cognitive improvement with rTMS remains

unclear, additional studies including genetics, experimental

neurophysiology and functional brain imaging are neces-

sary to explore stimulation-related functional changes in

the brain.

Keywords Transcranial magnetic stimulation �High-frequency rTMS � Prefrontal cortex � Cognition

Abbreviations

DLFPC Dorsolateral prefrontal cortex

TMS Transcranial magnetic stimulation

rTMS Repetitive transcranial magnetic

stimulation

D Depression

BD Bipolar disorder

ExDys Executive dysfunction

H Healthy

MC Memory complaints

PD ? D Parkinson’s Disease ? Depression

Pstr D Poststroke depression

SZ Schizophrenia

PC Parietal cortex

AMI Autobiographical Memory Interview

(R)/(H)AVLT (Rey)/(Hopkins) Auditory Verbal

Learning Test

BSRT Buschke Selective Reminding Test

BVRT Benton’s Visual Retention Test

COWAT Controlled Oral Word Association

Test

CPM Colored Progressive Matrices

CPT Continuous Performance Test

CVLT California Verbal Learning Test

DSST Digit Symbol Substitution Test

B. Guse (&) � P. Falkai � T. Wobrock

Department of Psychiatry and Psychotherapy,

Georg-August-University Gottingen,

Von-Siebold-Straße 5, 37075 Gottingen, Germany

e-mail: bguse@gwdg.de

123

J Neural Transm

DOI 10.1007/s00702-009-0333-7

- 36 -

EPAT Expanded Paired Associate Test

GOAT Galveston Orientation and Amnesia

Test

HVOT Hooper Visual Organization Test

JLO Judgement of line orientation

LPS Lernprufsystem

MMST Mini Mental Status Test

MPT Memory for Past Test

MVG Munchner Verbaler Gedachtnistest

NART New Adult Reading Test

NCT Number Connection Test

PAG ‘Traffic Lights Test’

SILS Shipley Institute of Living Scale

SSMQ Squire Subjective Memory

Questionnaire

Stroop Stroop Interference Test

TMT (A/B) Trail Making Test Version A/B

VFT (Letter) Verbal Fluency Test

VPAL Visual paired associates learning

WAIS(-R) Wechsler intelligence scale

(Revised)

WMS(-R)/WMSIII Wechsler memory scale

(Revised)/3 version

ExFunction Executive function

WM Working memory

Introduction

Since transcranial magnetic stimulation (TMS) was intro-

duced by Barker et al. (1985) as a non-invasive tool for the

investigation of the motor cortex, repetitive applications of

this technique (rTMS) were used to study the influence on a

variety of cerebral functions. TMS is based on an electro-

magnetic coil applied to the scalp producing an intense,

localized magnetic field which either excites or inhibits

a focal cortical area. Repetitive TMS uses alternating

magnetic fields to induce electric currents in the cortical

tissue (Burt et al. 2002). Low-frequency (B1 Hz) rTMS is

likely to cause inhibition of neuronal firing in a localized

area, whereas high-frequency ([1 Hz) rTMS inversely

leads to neuronal depolarization under the stimulating coil

(Haraldsson et al. 2004). The effects induced are not limited

to the targeted cortical region, changes can also occur at

distant interconnected sites in the brain. The efficacy of

rTMS treatment on affective disorders may not be restricted

to the activating effects under the stimulated prefrontal area,

but also due to the secondary affection of subcortical areas

being functionally related to emotion and behavior (Burt

et al. 2002; Post and Keck 2001; Ben-Shachar et al. 1997;

Conca et al. 1996; Cordes et al. 2005; Gershon et al. 2003).

Recently, rTMS has also been employed to explore the

treatment options for schizophrenia patients due to the

growing observation of non-responders to antipsychotic

agents (Hajak et al. 2004; Hoffmann et al. 2005; Jandl et al.

2004). According to different stimulation protocols evi-

dence is accumulating about the improving effect of rTMS

on acoustic hallucinations and negative symptoms in schizo-

phrenia (Hoffmann et al. 2005; Jandl et al. 2004, 2005; Poulet

et al. 2005). The well-established electroconvulsive therapy

(ECT) exhibits proven antidepressant effects, but it is also

known to produce temporary adverse cognitive effects (e.g.

memory deficits) (Squire 1982; Sackeim et al. 1986; Weiner

et al. 1986). Behind this background many rTMS studies were

used to assess cognitive functions additionally to control for

cognitive disturbances (Triggs et al. 1999; Padberg et al.

1999; Schulze-Rauschenbach et al. 2005). In contrast to the

original assumption of cognitive deterioration selective

improvements in patients after high-frequency rTMS (10 Hz

or 20 Hz) over the left prefrontal sites were observed.

This finding leads to further investigations measuring

rTMS-related cognitive changes in patients or healthy

volunteers. However, the influence of the various stimulation

parameters (e.g. frequency, intensity, train duration and

duration of whole stimulation period) on cognition and

the extent of changes in cognitive performance remained

unclear.

The aim of the presented work is to provide a systematic

overview of high-frequency rTMS (HF-rTMS) studies

assessing neurocognition for better understanding the

potential of rTMS to induce long-term effects on cognition.

In addition, the efficacy of HF-rTMS on distinct cognitive

domains will be outlined. The aim of the review is not to

summarize the effects of studies with rTMS to study cog-

nitive function by creating a ‘functional lesion’. Most of

these studies use rTMS as ‘‘online rTMS’’ to interfere

temporarily with neuronal functioning in order to gain

information about the functional contribution of the stim-

ulated area during performing a particular task (Sack

and Linden 2003). We primarily included studies in our

systematic review which investigate the after effects of

HF-rTMS, as ‘‘offline rTMS’’, at first glance independent

of the amount of rTMS sessions, but we were interested in

studies investigating cognitive effects using more than a

single rTMS session.

Method

We performed a systematic literature search in the fol-

lowing databases: PubMed (1999–2009) and MEDLINE

(1999–2009). A great range of search terms were used:

‘‘repetitive TMS’’ or ‘‘rTMS’’ and ‘‘cognition’’ or ‘‘cognitive

dysfunction’’, ‘‘cognitive impairment’’, ‘‘executive function’’,

B. Guse et al.

123

- 37 -

‘‘information processing’’, ‘‘processing speed’’, ‘‘reaction

time’’, ‘‘learning’’, ‘‘memory’’, ‘‘set shifting’’, ‘‘flexibility’’,

‘‘Wisconsin Card Sorting Test’’, ‘‘response inhibition’’,

‘‘response suppression’’, ‘‘attention’’ or ‘‘verbal fluency’’.

In the literature search, we identified 80 hits that

appeared to be suitable upon careful review of their titles

and abstracts. Of these 80 publications there were 5 studies

dealing with effects of other stimulation techniques (e.g.

transcranial direct current stimulation, tDCS) and exclu-

ded, 45 studies using low-frequency repetitive transcranial

magnetic stimulation (LF-rTMS) and 30 studies with

HF-rTMS. We then read through the full text of the 30

papers summarizing the results of HF-rTMS studies,

evaluated and included the data in our review. Review

papers and the references in the appraised studies were

therefore used for a renewed search for further relevant

literature. This did not lead to further inclusions in our

systematic review. Studies were considered only if they

had been published in English or German language and

described adequately the sample, the application procedure

and the trial design. We only included offline-paradigms.

Although we focused on high-frequency stimulation, we

initially took into account low-frequency studies (n = 45)

to better evaluate frequency-dependent cognitive changes.

A great amount of them were excluded (n = 41) subse-

quently because (1) they focus on disruptive effect mea-

sures (e.g. by inducing ‘virtual lesions’ in online-

paradigms), or (2) they focus on other topics not describing

cognitive testing or the stimulation procedure adequately

(e.g. methodology and safety studies, some case reports or

meta-analyses).

In conclusion, all studies fulfilling our predefined

selection criteria were taken into account and evaluated

according to their relative cognitive outcome.

Results

Description of the studies

The identified publications consist of 6 open studies and

24 controlled studies including within-subject-, sham-

controlled- or crossover designs. The studies comprise

22 clinical trials with major depression, that contain one

comparative trial with healthy subjects being matched to

the patient population in age, gender and level of educa-

tion. One of these studies includes patients with Parkinson

Disease and major or minor depression, one includes only

elders (between 40 and 90 years) with major depression

and another one contains post-stroke depressives. Further,

three clinical studies integrate schizophrenic patients, one

study contains patients with cerebrovascular disease and

mild executive dysfunction, another trial investigates elder

people with memory complaints. Overall, three studies

involve only healthy volunteers. The majority of the

included psychiatric patients were diagnosed and classified

on operational criterion-based systems for depression

(Diagnostic and Statistical Manual of Mental Disorder IV),

a smaller part met criteria by formal diagnostic interview

on the Structured Clinical Interview for DSM-IV Axis I

Disorders (SCID). The others were rated by means of

particular neurological/psychological tests and imaging

data. The characteristics of the included subjects, stimu-

lation protocols, cognitive ratings and outcomes of all

identified studies assessing the efficacy of rTMS on cog-

nition are outlined in Table 1.

The cognitive assessments used in the listed studies

differ from study to study, no standardized cognitive test

battery has been used consistently. Therefore, various

cognitive domains are involved to perform the selected

cognitive testing and the results of the studies are not

completely comparable.

Cognitive effects of high-frequency rTMS

over the prefrontal cortex

The differential cognitive effect of excitatory rTMS is

outlined in Table 2. Cognitive domains are subdivided and

the reported ameliorations, deteriorations or missing cog-

nitive rTMS effects are linked to the corresponding studies.

The studies were grouped by significant improvement or

deterioration in the columns, studies showing trends toward

improvements or deterioration were summarized among in

the column ‘‘no effects (n. s.)’’. One study (Vanderhasselt

et al. 2009) was not included in the table because cognitive

effects were too specific to be adequately categorized.

In the literature search about 19 studies were found

assessing changes of attention after stimulation, showing

inconsistent results. Among these studies there are 13

clinical trials and 3 non-clinical trials. In alertness/simple

reaction time no significant effect was found when mea-

sured separately (Padberg et al. 1999; Loo 2001; Shajahan

et al. 2002). With the Go-/No Go- or the Stroop-Paradigm

some authors could detect improvements in selective

attention (Hausmann et al. 2004; Martis et al. 2003;

Rektorova et al. 2005), some others did not find statistically

relevant effects (Avery et al. 2006; Boggio et al. 2005;

Huang et al. 2004; Jorge et al. 2004; Moser et al. 2002;

Mosimann et al. 2004; Speer et al. 2001; Vanderhasselt

et al. 2006; Wagner et al. 2006). One of these stud-

ies reports on deteriorations in visual reaction time in

the subtest divided attention of the ‘‘Testbatterie zur

Aufmerksamkeitsprufung (TAP, Zimmermann and Fimm

1997)’’ (Wagner et al. 2006). In sustained attention/con-

centration two studies give implications for improvements

(Hoppner et al. 2003; Rektorova et al. 2005), others failed

Cognitive effects of prefrontal rTMS

123

- 38 -

Ta

ble

1H

igh

-fre

qu

ency

rTM

San

dco

gn

itio

n

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Pad

ber

get

al.

(1999

)

(1)

6/6

(2)

6

DL

eft

DL

PF

C

5(1

)10

Hz

(2)

0.3

Hz

(1)

5s

(1)

30

s250

90% (n

.a.)

n.

a.V

erbal

lear

nin

gan

dm

emory

,

aler

tnes

s/at

tenti

on

(1)

Impro

vem

ent

inver

bal

mem

ory

(2)

No

effe

ct

Tri

ggs

etal

.

(1999

)

10

DL

eft

PF

C10/2

wee

ks

20

Hz

2s

n.

a.2,0

00

80% (n

.a.)

HV

LT

,W

AIS

-R,

CO

WA

T,

Bost

on

Nam

ing

Tes

t

Ver

bal

lear

nin

g/m

emory

,

ExF

unct

ion/W

M

Impro

vem

ent

inE

xF

unct

ion

(ver

bal

fluen

cy)

Lit

tle

etal

.

(2000

)

10

DL

eft

DL

PF

C

10/2

wee

ks

1H

z/

20

Hz

60

s/2

s5

sper

10

puls

es/

60

s

800

80% (n

.a.)

BS

RT

,C

NB

Ver

bal

/spat

ial

lear

nin

g/

mem

ory

,E

xF

unct

ion

(ver

bal

fluen

cy/r

etri

eval

)

Impro

vem

ent

of

word

reca

ll

afte

r1

wee

kin

1H

zan

d

20

Hz

condit

ion;

tren

dto

war

d

impro

ved

vis

uosp

atia

l

mem

ory

afte

r2

wee

ks

of

20

Hz

stim

ula

tion

Roll

nik

etal

.

(2000

)

12

SZ

Lef

t

DL

PF

C

10/2

wee

ks

real

?

10/2

wee

ks

sham

20

Hz

2s

61

s800

80% (n

.a.)

NC

TP

sych

om

oto

rsp

eed

No

sign

of

impro

vem

ent

Loo

etal

.

2001

9/9

DL

eft

DL

PF

C

10/ 2

wee

ks

min

.,

20/4

wee

ks

max

10

Hz

5s

25

sn.

a.110%

RM

T

RA

VL

T,

VP

AL

,

Tow

erof

London,

CO

WA

T,

MM

ST

,

AM

I,W

MS

Vis

ual

(ass

oci

ativ

e)/v

erbal

lear

nin

g/m

emory

,

ExF

unct

ion,

gen

eral

cognit

ive

stat

e,

auto

bio

gra

phic

alm

emory

,

sim

ple

and

com

ple

x

reac

tion

tim

e

No

sign

of

impro

vem

ents

;

det

erio

rati

on

inR

AV

LT

(n=

1)

Spee

ret

al.

2001

18

D,

BD

Lef

tP

FC

10/2

wee

ks

1H

z/

20

Hz

26

min

/

2s

0/2

8s

1,6

00

100%

AM

T

BS

RT

,C

olo

rado

Neu

ropsy

cholo

gic

Bat

tery

,V

erbal

/

Cat

egory

Flu

ency

Tas

k,

CP

T,

WA

IS/

SIL

S

Ver

bal

/spat

ial

lear

nin

g/

mem

ory

,E

xF

unct

ion

(ver

bal

fluen

cy,

cognit

ive

flex

ibil

ity),

atte

nti

on/

conce

ntr

atio

n,

moto

rsp

eed,

inte

llig

ence

Ten

den

cyof

impro

vem

ent

in

ver

bal

fluen

cyaf

ter

20

Hz

Mose

ret

al.

(2002

)

9/1

0D

Lef

t

DL

PF

C

520

Hz

2s

60

sn.

a.80% (n

.a.)

TM

T(A

/B),

Str

oop,

WA

IS-R

,

CO

WA

T,

Bost

on

Nam

ing

Tes

t,

RA

VL

T,

JLO

Moto

rsp

eed/a

tten

tion,

WM

/

ExF

unct

ion,

vis

ual

asso

ciat

ive

lear

nin

g,

ver

bal

lear

nin

g/m

emory

,

vis

uosp

atia

lper

cepti

on/

anal

ysi

s

Impro

vem

ent

inE

xF

unct

ion

(cognit

ive

flex

ibil

ity)

Shaj

ahan

etal

.

(2002

)

15

DL

eft

DL

PF

C

10/2

wee

ks

5,

10

or

20

Hz

4,

2,

1s

60

s500

80% RM

T

Ver

bal

fluen

cy,

WM

S-R

,W

AIS

,

DS

ST

,A

VL

T,

Tes

tof

Ever

yday

Att

enti

on,

PA

G

WM

/ExF

unct

ion,

ver

bal

lear

nin

g/m

emory

,at

tenti

on,

reac

tion

tim

e

No

sign

effe

ct

B. Guse et al.

123

- 39 -

Ta

ble

1co

nti

nu

ed

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Hoppner

etal

.

(2003

)

20/1

0D

(1)

Lef

t

DL

PF

C

or

(2)

right

DL

PF

C

10/2

wee

ks

(1)

20

Hz

(2)

1H

z

(1)

2s

(2)

60

s

(1)

60

s

(2)

180

s

n.

a.(1

)90%

RM

T

(2)

110%

RM

T

d2-T

est

Moto

rsp

eed,

conce

ntr

atio

n

Sel

ecti

ve

impro

vem

ent

in

conce

ntr

atio

n

per

form

ance

(d2-

subsc

ore

)

Huber

etal

.

(2003

)

12

SZ

On

the

dom

inan

t

DL

PF

C

n.

a.H

igh-

freq

uen

cy

n.

a.n.

a.n.

a.n.

a.N

CT

Psy

chom

oto

rsp

eed

Impro

vem

ent

in

wom

en,

no

impro

vem

ent

in

men

Loo

etal

.

(2003

)

9/1

0D

Bil

ater

al

PF

C

15/3

wee

ks

15

Hz

5s

25

sn.

a.90% RM

T

MM

ST

,R

AV

LT

,V

PA

L,

EP

AT

,T

ow

erof

London,

CO

WA

T

Gen

eral

cognit

ive

stat

e,

vis

ual

(ass

oci

ativ

e)/

ver

bal

lear

nin

g/m

emory

,

ExF

unct

ion

Tre

nds

tow

ard

impro

vem

ent

in

ExF

unct

ion/v

erbal

lear

nin

gan

d

asso

ciat

ive

lear

nin

g;

det

erio

rati

on

in

rete

nti

on;

det

erio

rati

on

in

ExF

unct

ion/

pla

nnin

gin

acti

ve

and

impro

vem

ent

insh

amgro

up

Mar

tis

etal

.

(2003

)

15

D,

BD

Lef

tP

FC

10-2

0/2

–

4w

eeks

10

Hz

5s

30

s1,0

00–

2,0

00

110%

(n.a

.)

NA

RT

,S

imple

and

Choic

e

Rea

ctio

nT

ime,

Str

oop/

WA

IS/V

erbal

Flu

ency

,

WM

S-R

,G

rooved

Peg

boar

d,

Squir

eT

est

Inte

llig

ence

,at

tenti

on,

WM

/ExF

unct

ion,

Obj.

mem

ory

,fi

ne

moto

r

spee

d

Impro

vem

ent

in

WM

/ExF

unct

ion,

Obj.

mem

ory

and

fine

moto

rsp

eed

O’C

onnor

etal

.(2

003

)

14

DL

eft

DL

PF

C

10/2

wee

ks

10

Hz

8s

24

s1,6

00

90% (n

.a.)

WM

SII

I,R

AV

LT

,T

ransi

ent

New

sE

ven

tT

est

WM

/ExF

unct

ion,

ver

bal

lear

nin

g/m

emory

,

retr

ogra

de

mem

ory

Impro

vem

ent

inW

M

Fab

reet

al.

(2004

)

11

DL

eft

PF

C10/2

wee

ks

10

Hz

8s

52

s1,6

00

100%

RM

T

CV

LT

,T

MT

(A/B

),H

ive

Tes

t,

Dig

itS

pan

Tas

k,

MM

ST

,

Ver

bal

Flu

ency

Tas

k

Ver

bal

lear

nin

g/m

emory

,

moto

rsp

eed,

vis

uosp

atia

lsk

ills

,W

M/

ExF

unct

ion,

gen

eral

cognit

ive

stat

e

Impro

vem

ent

in

ExF

unct

ion/v

erbal

fluen

cy;

tren

d

tow

ard

impro

vem

ent

in

vis

uosp

atia

l

mem

ory

Cognitive effects of prefrontal rTMS

123

- 40 -

Ta

ble

1co

nti

nu

ed

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Hau

sman

n

etal

.(2

004

)

26/1

3D

(1)

left

DL

PF

Cor

(2)

bil

ater

al

DL

PF

C

(3)

sham

10/2

wee

ks

(1)

20

Hz

(2)

20

Hz

left

?1

Hz

right

10

s90

s(1

)2,0

00

(2)

2,0

00/

2,6

00

(1)

100%

RM

T

(2)

120%

RM

T

TM

T(A

/B),

Str

oop,

MV

G,

CO

WA

T

Moto

rsp

eed,

atte

nti

on,

Short

-/lo

ng-t

erm

mem

ory

,W

M/

ExF

unct

ion

Impro

vem

ent

in

colo

rnam

ing/

resp

onse

inhib

itio

n

(Str

oop);

moto

r

Spee

d/c

ognit

ive

flex

ibil

ity

(TM

T);

tren

dto

war

dbet

ter

ExF

unct

ion/v

erbal

fluen

cy

Huan

get

al.

(2004

)

24

HL

eft

DL

PF

C1

real

?1

sham

5H

z8

s23

s1,6

00

100%

(n.a

.)

TA

P(G

o/N

oG

o-

Tas

k)

Sel

ecti

ve

atte

nti

on

Nei

ther

impro

vem

ent

nor

det

erio

rati

on

in

cognit

ion

Jorg

eet

al.

(2004

)

10/1

0P

Str

DL

eft

PF

C10/2

wee

ks

10

Hz

5s

60

s1,0

00

100%

(n.a

.)

Bar

ona

Equat

ions,

MM

ST

,T

MT

(A/B

),S

troop,

CO

WA

T,

RA

VL

T,

BV

RT

,B

ost

on

Nam

ing

Tes

t,

Token

Tes

t,

WA

ISII

I,

Lin

eB

isec

tion

Tes

t

Pre

morb

id

inte

llig

ence

,gen

eral

cognit

ive

stat

e,

atte

nti

on,

ExF

unct

ion,

ver

bal

and

nonver

bal

lear

nin

g/m

emory

,

languag

e

com

pre

hen

sion/

repet

itio

n,

vis

uosp

atia

l/

vis

uoco

nst

ruct

ive

funct

ions/

neg

lect

Tre

nd

tow

ard

gen

eral

cognit

ive

impro

vem

ent;

no

dif

fere

nce

bet

wee

nac

tive

and

sham

gro

up

Mosi

man

n

etal

.(2

004

)

12/1

2D

(40–90

yea

rs)

Lef

tD

LP

FC

10/2

wee

ks

20

Hz

2s

28

s1,6

00

100%

(n.a

.)

MM

ST

,V

LT

,

Str

oop,

TM

T

A/B

,V

erbal

Flu

ency

Tas

k

Glo

bal

cognit

ive

funct

ion,

ver

bal

lear

nin

g/m

emory

,

atte

nti

on,

ExF

unct

ions

(flex

ibil

ity,

ver

bal

fluen

cy)

No

det

erio

rati

on,

no

signifi

cant

impro

vem

ent;

no

dif

fere

nce

bet

wee

n

acti

ve

and

sham

gro

up

Boggio

etal

.

(2005

)

13/1

2P

D?

DL

eft

DL

PF

C10/2

wee

ks

15

Hz

5s

n.

a.3,0

00

110%

(n.a

.)

WC

ST

,T

MT

(B),

CO

WA

T,

Str

oop,

HV

OT

,C

PM

,

Dig

itS

pan

Tes

t

WM

/ExF

unct

ion,

atte

nti

on,

vis

uosp

atia

lab

ilit

y,

reas

onin

g

Tre

nd

tow

ard

impro

vem

ent

in

ExF

unct

ion

(WC

ST

-

per

sever

atio

nan

d

Str

oop-

inte

rfer

ence

);no

dif

fere

nce

bet

wee

n

acti

ve

and

sham

gro

up

B. Guse et al.

123

- 41 -

Ta

ble

1co

nti

nu

ed

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Rek

toro

va

etal

.

(2005

)

7E

xD

ys

Lef

t

DL

PF

C

or

left

MC

1re

al?

1

sham

10

Hz

1s

10

s450

100%

(n.a

.)

TM

T(A

/B),

WA

IS-R

,

Str

oop,

VF

T,

Rey

-

Fig

ure

,W

MS

Moto

rsp

eed,

atte

nti

on,

WM

/

ExF

unct

ion,

vis

uoco

nst

ruct

ion/-

mem

ory

Sel

ecti

ve

impro

vem

ent

in

the

Str

oop-

inte

rfer

ence

afte

r

DL

PF

C

stim

ula

tion;

impro

vem

ent

in

dig

itsy

mbols

-

per

form

ance

indep

enden

tof

loca

tion

of

stim

ula

tion

Sac

hdev

etal

.

(2005

)

4S

ZL

eft

DL

PF

C

4w

eeks

15

Hz

5s

25

s1,8

00

90%

(n.a

.)M

MS

E,

Dig

itS

pan

,

TM

TA

/B,

Sym

bol-

Dig

it-C

odin

g,

Ver

bal

Flu

ency

,

WC

ST

Gen

eral

cognit

ive

stat

e,E

xF

unct

ion/

WM

(WM

,ver

bal

fluen

cy,

Cogn.

flex

ibil

ity),

psy

chom

oto

rsp

eed

No

signifi

cant

impro

vem

ent

Sch

ulz

e-

Rau

schen

bac

h

etal

.2005

16,

14/1

5D

,H

Lef

t

DL

PF

C

ca.

10

(2–3/

wee

k)

10

Hz

2s

5s

400–600

100%

(n.a

.)

AV

LT

,M

PT

,F

our-

Car

d-T

ask,

AM

I,

SS

MQ

,M

MS

T,

TM

T(A

/B),

WA

IS-

R,

Let

ter-

Num

ber

-

Span

-Tes

t,L

PS

Ver

bal

lear

nin

g/

mem

ory

,

subje

ctiv

e

mem

ory

,m

oto

r

spee

d,

WM

/

ExF

unct

ion

Impro

vem

ent

in

ver

bal

mem

ory

and

subje

ctiv

em

emory

inrT

MS

gro

up

Aver

yet

al.

(2006

)

35/3

3D

Lef

t

DL

PF

C

15/4

wee

ks

10

Hz

5s

25–30

s1,6

00

110%

RM

T

MM

ST

,R

AV

LT

,

WA

IS-R

,T

MT

(A/

B),

CO

WA

T,

Str

oop,

GO

AT

Gen

eral

cognit

ive

stat

e,ver

bal

lear

nin

g/m

emory

,

WM

/ExF

unct

ion,

moto

rsp

eed,

atte

nti

on,

ori

enta

tion

Impro

vem

ents

in

cognit

ive

funct

ions

atfo

llow

up

in

both

gro

ups

Kuro

da

etal

.

(2006

)

9D

Lef

t

DL

PF

C

10/2

wee

ks

10

Hz

5s

25

s1,0

00

100%

(n.a

.)

MM

ST

,W

MS

-R,

TM

T(A

/B)

Ass

oci

atio

n(v

erbal

)

lear

nin

g/m

emory

,

moto

rsp

eed,

ExF

unct

ion

(cognit

ive

flex

ibil

ity)

Impro

vem

ent

in

asso

ciat

ion

(ver

bal

)le

arnin

g/

mem

ory

(unre

late

d

word

s,del

ayed

reca

ll)

Cognitive effects of prefrontal rTMS

123

- 42 -

Ta

ble

1co

nti

nu

ed

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Rosa

etal

.

(2006)

20/1

5D

Lef

t

DL

PF

C

20/4

wee

ks

10

Hz

10

s20

s2,5

00

100%

(n.a

.)

WA

IS-R

,W

MS

-R,

RB

MT

ExF

unct

ion

(work

ing

mem

ory

),dif

fere

nt

com

ponen

tsof

mem

ory

No

signifi

cant

impro

vem

ent;

tren

dto

war

d

impro

vem

ent

in

RB

MT

inrT

MS

gro

up;

det

erio

rati

on

in

EC

Tgro

up

afte

r

2w

eeks

and

4w

eeks

Sole

-Pad

ull

es

etal

.(2

006

)

20/1

9M

CL

eft

PF

C1

5H

z10

s20

s500

80%

(n.a

.)F

ace-

Nam

e-M

emory

-

Tas

ks,

MM

ST

(Ass

oci

atio

n)

Lea

rnin

g/

mem

ory

,gen

eral

cognit

ive

stat

e

Impro

vem

ent

in

Ass

oci

ativ

e

Mem

ory

;no

dif

fere

nce

bet

wee

n

acti

ve

and

sham

gro

up

Van

der

has

selt

etal

.(2

006

)

28

HL

eft

DL

PF

C

1re

al?

1

sham

10

Hz

n.

a.26,

1s

1,5

60

110%

(n.a

.)

Str

oop

Pro

cess

ing

spee

d,

sele

ctiv

e

atte

nti

on

Impro

vem

ent

in

pro

cess

ing

spee

d,

i.e.

inse

lect

ive

atte

nti

on

over

all

tria

ls(c

ongru

ent/

inco

ngru

ent)

Wag

ner

etal

.

(2006)

17

HL

eft

DL

PF

C

1re

al?

1

sham

20

Hz

2s

28

s1,6

00

100%

(n.a

.)

Str

oop,

WC

ST

,T

AP

(Div

ided

Att

enti

on)

Sel

ecti

ve/

div

ided

atte

nti

on,

ExF

unct

ion

Det

erio

rati

on

in

vis

ual

reac

tion

tim

e(T

AP

)

30

min

.af

ter

stim

ula

tion;

no

(del

ayed

)ef

fect

in

ExF

unct

ion

Mogg

etal

.

(2008)

29/3

0D

Lef

t

DL

PF

C

10

10

Hz

5s

55

s1,0

00

110%

RM

T

CA

MC

OG

,W

AIS

-R,

Gro

oved

Peg

boar

dT

est

Gen

eral

cognit

ive

stat

e,

atte

nti

on,

ExF

unct

ion

(work

ing

mem

ory

),

moto

rfu

nct

ion

No

signifi

cant

effe

ct

atan

yti

me

poin

t

B. Guse et al.

123

- 43 -

Ta

ble

1co

nti

nu

ed

Auth

ors

Subje

cts

trea

ted/

sham

,

refe

rence

Dia

gnosi

sL

oca

tion

Whole

sess

ions/

wee

ks

Fre

quen

cyT

rain

dura

tion

Inte

rtra

in-

inte

rval

Puls

es

per

sess

ion

Moto

r

thre

shold

Cognit

ive

rati

ngs

Cognit

ive

dom

ain

Cognit

ive

effe

ct

Van

der

has

selt

etal

.(2

009

)

15

DL

eft

DL

PF

C

10/2

wee

ks

vs.

1se

ssio

n

(rea

l/sh

am)

10

Hz

3,

9s

26,

1s

1,5

60

110%

(n.a

.)

Com

pute

rize

dT

ask-

Sw

itch

ing-

Par

adig

m

ExF

unct

ion

(att

enti

onal

contr

ol/

cognit

ive

flex

ibil

ity)

Aft

er2

wee

ks:

impro

vem

ent

of

init

iati

on

tim

ein

vis

ual

tria

lsan

d

reac

tion

tim

ein

audit

ory

tria

ls

(res

ponder

s);

afte

r

1se

ssio

n:

Impro

vem

ent

in

init

iati

on

tim

e

(res

ponder

s);

no

effe

ctin

the

moto

r

com

ponen

tof

swit

chin

g

Dia

gnose

s:A

DA

lzhei

mer

dis

ease

,B

Dbip

ola

rdis

ord

er,

Ddep

ress

ion,

ExD

ysex

ecuti

ve

dysf

unct

ion,

Hhea

lthy,

MC

mem

ory

com

pla

ints

,P

D?

DP

arkin

son’s

dis

ease

?D

epre

ssio

n,

Pst

rD

post

stro

ke

dep

ress

ion,

SZ

schiz

ophre

nia

.S

ite

of

stim

ula

tion:

(DL

)P

FC

(dors

ola

tera

l)pre

fronta

lco

rtex

,P

Cpar

ieta

lco

rtex

.M

oto

rth

resh

old

:A

MT

acti

ve

moto

rth

resh

old

,R

MT

rest

ing

moto

rth

resh

old

.N

euro

cognit

ive

outc

om

era

tings:

AM

IA

uto

bio

gra

phic

alM

emory

Inte

rvie

w,

(R)/

(H)A

VL

T(R

ey)/

(Hopkin

s)A

udit

ory

Ver

bal

Lea

rnin

gT

est,

BSR

TB

usc

hke

Sel

ecti

ve

Rem

indin

gT

est,

BV

RT

Ben

ton’s

vis

ual

rete

nti

on

test

,C

NB

Colo

rado

neu

ropsy

cholo

gic

albat

tery

,C

OW

AT

Contr

oll

edO

ral

Word

Ass

oci

atio

nT

est,

CP

Mco

lore

dpro

gre

ssiv

em

atri

ces,

CP

TC

onti

nuous

Per

form

ance

Tes

t,C

VL

TC

alif

orn

iaV

erbal

Lea

rnin

gT

est,

DS

ST

Dig

itS

ym

bol

Subst

ituti

on

Tes

t,E

PA

TE

xpan

ded

Pai

red

Ass

oci

ate

Tes

t,G

OA

TG

alves

ton

Ori

enta

tion

and

Am

nes

iaT

est,

HV

OT

Hooper

Vis

ual

Org

aniz

atio

nT

est,

JLO

Judgem

ent

of

Lin

eO

rien

tati

on,

LP

SL

ernpru

fsyst

em,

MM

ST

Min

iM

enta

lS

tatu

sT

est,

MP

TM

emory

for

Pas

tT

est,

MV

GM

unch

ner

Ver

bal

erG

edac

htn

iste

st,

NA

RT

New

Adult

Rea

din

gT

est,

NC

TN

um

ber

Connec

tion

Tes

t,P

AG

‘tra

ffic

lights

test

’,SIL

SS

hip

ley

Inst

itute

of

Liv

ing

Sca

le,

SSM

QS

quir

eS

ubje

ctiv

eM

emory

Ques

tionnai

re,

Str

oop

Str

oop

Inte

rfer

ence

Tes

t,T

MT

(A/B

)T

rail

Mak

ing

Tes

t,V

FT

(Let

ter)

Ver

bal

Flu

ency

Tes

t,V

PA

LV

isual

Pai

red

Ass

oci

ates

Lea

rnin

g,

WA

IS(-

R)

Wec

hsl

erIn

tell

igen

ceS

cale

(Rev

ised

),W

MS(-

R)/

WM

SII

IW

echsl

erM

emory

Sca

le(R

evis

ed)/

3.

Ver

sion.

Cognit

ive

dom

ain:

ExF

unct

ion

exec

uti

ve

funct

ion,

WM

work

ing

mem

ory

Cognitive effects of prefrontal rTMS

123

- 44 -

Table 2 Differential cognitive effects of HF rTMS

Cognitive domain Improvement No effect (n. s.) Deterioration

Attention

Alertness/Simple reaction 3 (Padberg et al. 1999; Loo 2001; Shajahan et al.

2002)

Selective/Focused attention;

Response inhibition

3 (Martis et al. 2003;

Hausmann et al. 2004;

Rektorova et al. 2005)

9 (Speer et al. 2001; Moser et al. 2002; Huang

et al. 2004 (H); Jorge et al. 2004; Mosimann

et al. 2004; Boggio et al. 2005; Avery et al.

2006; Vanderhasselt et al. 2006 (H); Wagner

et al. 2006 (H))

Divided attention 1 (Wagner et al. 2006

(H))

Sustained attention/

Concentration

2 (Hoppner et al. 2003;

Rektorova et al. 2005)

2 (Speer et al. 2001; Mogg et al. 2008)

Executive functions/Working memory

Working memory (Short-

term storage/Manipulation/

Monitoring)

2 (Martis et al. 2003;

O’Connor et al. 2003)

10 (Triggs et al. 1999; Shajahan et al. 2002;

Fabre et al. 2004; Boggio et al. 2005;

Rektorova et al. 2005; Sachdev et al. 2005;

Schulze-Rauschenbach et al. 2005; Avery

et al. 2006; Rosa et al. 2006; Mogg et al. 2008)

Cognitive flexibility 2 (Moser et al. 2002;

Hausmann et al. 2004)

10 (Speer et al. 2001; Fabre et al. 2004; Jorge

et al. 2004; Mosimann et al. 2004; Boggio

et al. 2005; Sachdev et al. 2005; Schulze-

Rauschenbach et al. 2005; Avery et al. 2006;

Kuroda et al. 2006; Wagner et al. 2006 (H))

Verbal fluency/Retrieval 3 (Triggs et al. 1999; Martis

et al. 2003; Fabre et al. 2004)

14 (Little et al. 2000; Loo 2001; Speer et al.

2001; Moser et al. 2002; Shajahan et al. 2002;

Loo et al. 2003; Hausmann et al. 2004; Jorge

et al. 2004; Mosimann et al. 2004; Boggio

et al. 2005; Rektorova et al. 2005; Sachdev

et al. 2005; Schulze-Rauschenbach et al. 2005;

Avery et al. 2006)

Problem solving/Planning/

Reasoning

2 (Loo 2001; Boggio et al. 2005) 1 (Loo et al. 2003)

Learning ? Memory (Intermediate-/Long-term storage)

Verbal learning ? Memory 3 (Padberg et al. 1999; Little

et al. 2000 (recall); Schulze-

Rauschenbach et al. 2005)

12 (Triggs et al. 1999; Speer et al. 2001; Moser

et al. 2002; Shajahan et al. 2002; Loo et al.

2003 (Learning); O’Connor et al. 2003; Fabre

et al. 2004; Hausmann et al. 2004; Jorge et al.

2004; Mosimann et al. 2004; Avery et al.

2006, Rosa et al. 2006)

2 (Loo 2001; Loo et al.

2003 (Retention))

Spatial learning ? Memory/

Objective learning ?

Memory

1 (Martis et al. 2003) 5 (Little et al. 2000; Speer et al. 2001; Fabre

et al. 2004; Jorge et al. 2004, Rosa et al. 2006)

(Visual) Associative learning

? Memory

2 (Kuroda et al. 2006; Sole-

Padulles et al. 2006)

3 (Loo 2001; Moser et al. 2002; Loo et al. 2003)

Retrograde/Autobiographic

memory

1 (Schulze-Rauschenbach et al.

2005)

2 (Loo 2001; O’Connor et al. 2003)

Psychomotor speed

Psychomotor speed/

Processing speed

4 (Martis et al. 2003;

Hausmann et al. 2004; Huber

et al. 2003 (females);

Vanderhasselt et al. 2006

(H))

13 (Rollnik et al. 2000; Loo 2001; Speer et al.

2001; Moser et al. 2002; Hoppner et al. 2003;

Huber et al. 2003 (males); Fabre et al. 2004;

Rektorova et al. 2005; Sachdev et al. 2005;

Schulze-Rauschenbach et al. 2005; Avery

et al. 2006; Kuroda et al. 2006; Mogg et al.

2008)

Vanderhasselt et al. 2009 not included; (H) healthy sample

B. Guse et al.

123

- 45 -

to find a significant effect in this domain (Mogg et al.

2008; Speer et al. 2001).

Regarding the allocated studies, about 23 assessed

executive functions/working memory in patients (21) and/or

healthy subjects (2). Significant improvements were found

in the domains working memory, cognitive flexibility and

verbal fluency/retrieval (Fabre et al. 2004; Hausmann et al.

2004; Little et al. 2000; Martis et al. 2003; Moser et al.

2002; O’Connor et al. 2003; Triggs et al. 1999; Vander-

hasselt et al. 2009). Problem solving/reasoning remained

without any beneficial but one adverse effect (Boggio et al.

2005; Loo 2001; Loo et al. 2003). In a great amount of

studies improvements were slight and failed to reach sig-

nificance, but a variety of studies report on trends (for more

details see, Tables 1, 2).

Concerning the results of the learning and memory

section there are 19 studies quantifying this dimension.

Little et al. (2000), Padberg et al. (1999) and Schulze-

Rauschenbach et al. (2005) discovered verbal learning/

memory improvements, but a great range of authors did

not find such statistically relevant effects (see, Table 2).

Loo (2001) found an individual temporary deterioration

in verbal learning/memory, two years later the same

group manifested a selective deterioration in the retention

of verbal material (Loo et al. 2003). However, amelio-

rations were reported in spatial and objective learning/

memory (Little et al. 2000; Martis et al. 2003). In other

studies subjects did not exhibit any relevant objective

memory change (Fabre et al. 2004; Jorge et al. 2004;

Speer et al. 2001). Subjects of other studies reached high

scores in associative learning/memory (Kuroda et al.

2006; Sole-Padulles et al. 2006) and in autobiographic

memory (Schulze-Rauschenbach et al. 2005). Missing

effects in the latter categories are described by Loo et al.

(2001, 2003), Moser et al. (2002) and O’Connor et al.

(2003).

As much as 16 studies explicitly assessed psychomotor

speed/processing speed with the Trail-Making-Test (Ver-

sion A), the d2-Test or the Stroop-Paradigm. Overall, three

studies stated improved psychomotor speed in different

tasks (Hausmann et al. 2004; Martis et al. 2003; Vander-

hasselt et al. 2006), one found gender differences in terms

of improvements in women and no improvements in men

(Huber et al. 2003), the others did not find relevant effects

(for details see, Table 2).

Effect of clinical status and stimulation type

on cognitive changes

As mentioned above our review reports the results of 27

clinical studies (involving patients with distinct diseases)

and 3 non-clinical studies (including only healthy volun-

teers). At first, we compare the different groups with regard

to the cognitive stimulation effect. We then summarize the

stimulation parameters in terms of their relative cognitive

effect. Finally, we contrast the stimulation conditions ‘‘real

(verum)’’ and ‘‘placebo (sham)’’ to give an overview of

placebo- or real rTMS-induced effects.

Clinical versus non-clinical group

One of the non-clinical groups stimulating over the (left)

PFC showed ameliorations in processing speed (Vander-

hasselt et al. 2006), whereas the others did not exhibit

relevant improving effects (Huang et al. 2004; Wagner

et al. 2006). However, Wagner et al. (2006) found an

individual deterioration in divided attention (visual reac-

tion time was slowed). Over all non-clinical groups a single

amelioration (in processing speed) can be manifested.

Regarding the clinical groups, there are 22 reported ame-

liorations spanning the domains attention (selective, sus-

tained), executive functions (working memory, cognitive

flexibility and verbal fluency/retrieval), learning and

memory (verbal, nonverbal) and processing speed. Never-

theless, a great number of studies did not find significant

effects over these domains (Table 2). Deteriorations are

reported in verbal learning/memory (Loo 2001; Loo et al.

2003) and in planning (Loo et al. 2003).

Stimulation parameters

In the majority of studies (18) subjects had 10 stimulation

sessions in 2 weeks (see, Table 1). The frequencies range

between 10 Hz and 20 Hz, the motor threshold between 80

and 100%. There is a notable difference between intertrain

intervals ranging from 5 s over 24–28 s up to about 60–

90 s. In consideration of all positive cognitive outcomes

(15), those studies using stimulation frequencies of 10 Hz

up to 20 Hz over a period of 2 up to 4 weeks (22) seem to

be most effective. Two studies which attained significant

improving effects with 10–20 Hz assessed five rTMS ses-

sions only (Moser et al. 2002; Triggs et al. 1999), in the

two other studies participants received one sham and one

real rTMS session (Rektorova et al. 2005; Vanderhasselt

et al. 2006). Seven studies with abovementioned stimula-

tion parameters (10–20 Hz, 2–4 weeks) are lacking sig-

nificant cognitive improvement, but indicate a trend of

cognitive amelioration anyhow (Boggio et al. 2005; Jorge

et al. 2004; Loo et al. 2003; Mosimann et al. 2004; Rosa

et al. 2006; Speer et al. 2001). Three others do not report

on any improving effect at these stimulation conditions

(Loo 2001; Mogg et al. 2008; Shajahan et al. 2002). With

regard studies using frequencies at the lower end of the

high-frequency range (5 Hz), there were no marked

improvements in cognitive functions (Huang et al. 2004;

Shajahan et al. 2002), one study found a tendency of

Cognitive effects of prefrontal rTMS

123

- 46 -

cognitive ameliorations (Sole-Padulles et al. 2006), but,

except for the latter case, the studies are composed of

single stimulation sessions.

Onset of cognitive measure

We looked into the studies to identify the time interval

between last rTMS administration and test onset. All

studies performed baseline cognitive testing prior or one

day before the first rTMS session. Most studies (19)

reported on cognitive measures the day of completing all

sessions without specifying the exact onset (Avery et al.

2006; Boggio et al. 2005; Hausmann et al. 2004; Hoppner

et al. 2003; Huber et al. 2003; Jorge et al. 2004; Loo

2001; Loo et al. 2003; Mogg et al. 2008; Moser et al.

2002; Mosimann et al. 2004; O’Connor et al. 2003;

Padberg et al. 1999; Rollnik et al. 2000; Rosa et al. 2006;

Sachdev et al. 2005; Speer et al. 2001; Triggs et al. 1999;

Vanderhasselt et al. 2006). Among these studies 18 used

frequencies of 10–20 Hz over a longer period (10–20

sessions (n = 16), 5 sessions (n = 2)), but only 6 of them

described significant positive cognitive outcomes being

associated with rTMS intervention. The others mainly

showed either a trend of cognitive improvement in verum

group or did not detect differences between groups (see,

Sect. Discussion). Two further studies exhibited tempo-

rary deteriorations.

The other studies described adequately the delay

between stimulation and test onset ranging from immediate

testing (Huang et al. 2004; Rektorova et al. 2005; Shajahan

et al. 2002; Sole-Padulles et al. 2006), 10–30 min (Little

et al. 2000; Wagner et al. 2006; Vanderhasselt et al. 2009),

20–24 h (Fabre et al. 2004), one or 3 days (Kuroda et al.

2006; Martis et al. 2003) up to one week (Schulze-Raus-

chenbach et al. 2005). Five studies integrated follow-up

measures (Boggio et al. 2005; Hoppner et al. 2003; Mogg

et al. 2008; O’Connor et al. 2003; Triggs et al. 1999), eight

studies intermediate measures (Triggs et al. 1999; Loo

2001; Rollnik et al. 2000; Shajahan et al. 2002; Little et al.

2000; O’Connor et al. 2003; Rosa et al. 2006; Vander-

hasselt et al. 2009).

Verum versus sham stimulation

Overall, 19 studies are sham-controlled, among these

studies 7 are designed crossover and ‘‘within subject’’ or

‘‘within group’’. Two of these studies were excluded

because of a small sham-sample (Little et al. 2000) or of

only a single sham session crossover (Vanderhasselt et al.

2009). For the sham procedure there were 13 studies using

active coils angulated at 45� or 90� and 4 studies using

sham coils. Therefore, we did not perform a comparison of

the different sham procedures. In the presentation of results

we only considered the main outcome of each analysis. The

impact of clinical status and stimulation condition (real vs.

sham) is outlined in regard to the relative cognitive effect

in Table 3.

Thus, individual (may be opposing) results were not

listed separately, but integrated in the overall report.

According to the hypothesis, 7 studies confirm a signifi-

cantly greater improvement of cognition in verum than in

sham condition. Another 8 studies do not reveal relevant

differences in cognition between stimulation conditions (in

terms of no significant improvement in both conditions).

The latter studies include trends toward improvements as

well as significant improvements in individual domains

that are not reported in detail. For that reason a reclassifi-

cation of some cases into the last category (‘‘overall cog-

nitive improvement’’, see Table 3) can be argued. There is

no greater sham than verum effect, but interestingly, one

study implicates a selective advantage in a planning task of

sham over verum stimulation (Loo et al. 2003). Two

studies report on overall cognitive improvement, i.e.

ameliorations in both stimulation conditions (Avery et al.

2006; Sole-Padulles et al. 2006), that could be due to

practice or placebo effects.

High-frequency versus low-frequency stimulation

Low-frequency studies meeting the predefined criteria are

outlined in Table 4. To overview their cognitive outcome,

low-frequency stimulation (=1 Hz) seems to deteriorate

cognitive functioning in lieu of having improving effects.

Table 3 Comparison sham

versus verum stimulation in

high-frequency studies: main

outcome

Group specific cognitive effect Studies contrasting real and placebo stimulation

No significant improvement: Verum =

Sham

8 (Loo 2001; Loo et al. 2003; Hausmann et al. 2004; Huang et al.

2004; Jorge et al. 2004; Mosimann et al. 2004; Boggio et al.

2005; Mogg et al. 2008)

Selective improvement: Verum[Sham 7 (Padberg et al. 1999; Rollnik et al. 2000; Speer et al. 2001;

Moser et al. 2002; Hoppner et al. 2003; Vanderhasselt et al.

2006; Wagner et al. 2006)

Selective improvement: Sham[Verum n. a.

Overall improvement (placebo-/

practice effect): Verum = Sham

2 (Avery et al. 2006; Sole-Padulles et al. 2006)

B. Guse et al.

123

- 47 -

Ta

ble

4L

ow

-fre

qu

ency

rTM

San

dco

gn

itio

n

Au

tho

rsS

ub

ject

s

trea

ted

/

sham

,

refe

ren

ce

Dia

gn

osi

sL

oca

tio

nW

ho

le

sess

ion

s/

wee

ks

Fre

qu

ency

(Hz)

Tra

in

du

rati

on

(min

)

Inte

rtra

in-

inte

rval

Pu

lses

per

sess

ion

Mo

tor

thre

sho

ld

Co

gn

itiv

e

rati

ng

s

Co

gn

itiv

e

do

mai

n

Co

gn

itiv

e

effe

ct

Fit

zger

ald

etal

.

(20

05

)

17

/16

SZ

(au

dit

ory

hal

luci

nat

ion

s)

TP

3(1

0-

20

-EE

G-

Sy

stem

)

10

/2w

eek

s1

15

–n

.a.

90

%R

MT

HV

LT

,v

erb

al

flu

ency

,d

igit

span

(fo

rwar

ds,

bac

kw

ard

s/

vis

uo

spat

ial)

,

VS

MT

Ver

bal

lear

nin

gan

d

mem

ory

,W

M/

exec

uti

ve

fun

ctio

n

No

det

erio

rati

on

in

cog

nit

ive

test

ing

Fre

gn

i

etal

.

(20

06

)

12

/9M

CD

,

refr

acto

ry

epil

epsy

Sit

eo

f

lesi

on

51

20

–1

,20

07

0%

max

.

stim

ula

tor

ou

tpu

t

Dig

itsp

an(f

orw

ard

,

bac

kw

ard

),si

mp

le

reac

tio

n,

Str

oo

p

test

WM

/Ex

Fu

nct

ion

,

sim

ple

reac

tio

n

tim

e,se

lect

ive

atte

nti

on

Sig

nifi

can

t

imp

rov

emen

tin

sim

ple

reac

tio

n

tim

ean

dS

tro

op

Tas

k;

no

effe

ctin

sho

rtte

rm/w

ork

ing

mem

ory

Jan

uel

etal

.

(20

06

)

11

/16

DR

igh

t

DL

PF

C

16

/4w

eek

s:

1./

2.

wee

k

dai

ly,

3./

4.

wee

kev

ery

two

day

s

12

91

3m

inn

.a.

90

%(n

.a.)

Gro

ber

and

Bu

sch

ke’

sT

est,

Str

oo

pT

est,

TM

T,

WA

IS-R

,

Car

deb

at’s

Flu

ency

Tes

t

Ver

bal

lear

nin

gan

d

mem

ory

,

sele

ctiv

e

atte

nti

on

,

psy

cho

mo

tor

spee

d,

Ex

Fu

nct

ion

No

sig

n.

dif

fere

nce

s

(Bas

elin

e/D

ay1

4)

Tro

jan

o

etal

.

(20

06

)

16

/8H

P3

(n=

8)

or

P4

(n=

8)

(10

-20

-

EE

G-

Sy

stem

)

11

10

–6

00

80

%(n

.a.)

Co

ord

inat

eta

sk,

cate

go

rica

lta

sk

Pro

cess

ing

of

cate

go

rica

lan

d

coo

rdin

ate

spat

ial

rela

tio

ns

Sel

ecti

ve

det

erio

rati

on

of

fun

ctio

nin

gin

acti

ve

gro

up

(im

med

iate

lyaf

ter

rTM

San

d1

0m

in.

afte

rrT

MS

),

pro

gre

ssiv

e

imp

rov

emen

tin

con

tro

lg

rou

p

Dia

gn

ose

s:D

Dep

ress

ion

,E

xDys

exec

uti

ve

dy

sfu

nct

ion

,H

hea

lth

y,

MC

Dm

ild

cog

nit

ive

dis

ord

er,

SZ

sch

izo

ph

ren

ia.

Neu

roco

gn

itiv

eo

utc

om

era

tin

gs

(H)A

VL

T(H

op

kin

s)A

ud

ito

ryV

erb

al

Lea

rnin

gT

est,

TM

TT

rail

Mak

ing

Tes

t,V

SM

TV

isu

osp

atia

lM

emo

ryT

est.

Mo

tor

thre

sho

ld:

AM

Tac

tiv

em

oto

rth

resh

old

,R

MT

rest

ing

mo

tor

thre

sho

ld.C

og

nit

ive

do

mai

n:

ExF

un

ctio

nex

ecu

tiv

e

fun

ctio

n,

WM

wo

rkin

gm

emo

ry

Cognitive effects of prefrontal rTMS

123

- 48 -

One study described improved simple reaction times and

better scores in the Stroop Task, but this had been associ-

ated with a reduced seizure activity in epilepsy patients by

the authors (Fregni et al. 2006). Two studies report no

worsening cognitive effects (Fitzgerald et al. 2005; Januel

et al. 2006), and one study by Trojano et al. (2006) referred

a selective deterioration of functioning directly and after

10 min of 1-Hz stimulation.

Discussion

Overall results and limitations of the studies

To summarize the results, we can state that high-frequency

rTMS (10–20 Hz) is most likely to cause significant cog-

nitive improvement when applied over the left (dorsolat-

eral) prefrontal cortex, within a range of 10–15 successive

sessions and an individual motor threshold between 80 and

110%. Regarding the analyses of clinical status and stim-

ulation condition concerning the efficacy of rTMS, the

clinical group is superior to the non-clinical group and

verum stimulation is in general superior to sham stimula-

tion. All in all, many studies failed to demonstrate signif-

icant cognitive effects, but they could show trends toward

selective cognitive improvements. In comparison with

studies using 1-Hz stimulation, high-frequency studies

seem to be superior concerning the cognitive outcome.

However, the evaluation is limited due to partly method-

ological differences between and within studies or to the

marginal number of low-frequency studies. General limi-

tations concern the absence of healthy control groups as

well as sham conditions to some extent. Important to note

is the marginal number of studies using functional imaging

and integrating follow-up measures for the exploration of

long-term effects. The relative high number of studies

giving evidence of placebo or practice effects requires

future amendment of control conditions. There are dis-

crepancies concerning the onsets of cognitive testing after

rTMS administration being substantially relevant for the

outcome. Therefore, results seem to be inconsistent

throughout the literature and the particular biological

mechanism of rTMS for cognitive improvement seems to

be questionable until the underlying pathophysiology

remains unclear. We do not know how long the effects of

rTMS on cognitive function will persist. Studies investi-

gating systematically the duration of the induced cognitive

effects are lacking, but one can assume, based on the

remaining effects on psychopathology (e.g. improvement

of mood), that also the cognitive improvement will persist

for a certain period of time. Future work is needed to

systematically investigate the impact of different test

onsets after rTMS application.

It should also be further addressed that the correct

positioning of the coil is important for the effects of rTMS.

Most of the studies used the method of Pascual-Leone

(placing the coil 5 cm rostrally from the hot spot of pri-

mary motor cortex) to identify the DLPCF or localized the

left DLPFC by the 10-20 EEG-system. While recent

studies on neuronavigation for TMS have shown that ste-

reotactically neuronavigated TMS results in stronger and

more robust TMS effects, neuronavigation may be impor-

tant for inducing long-lasting cognitive improvement. For

example, one study demonstrated a systematic difference in

the behavioral effect size due to the way of localization.

Individual fMRI-guided TMS neuronavigation yielded the

strongest and the 10-20 EEG-system stimulation approach

the smallest behavioral effect size (Sack et al. 2009). There

was a nearly tenfold increase in the needed number of

probands to induce the same behavioral effect when using

the 10-20 system compared to fMRI-guided neuronaviga-

tion. In addition, a previous study demonstrated clearly that

in most cases the DLPFC was not targeted correctly when

compared to the commonly used method of Pascual-Leone

with neuronavigated coil positioning (Herwig et al. 2001).

Effects on different cognitive domains

To discuss the effect of rTMS on attention, one has to

consider the different elements that build attentional pro-

cesses. A basal part of attention is the alertness, which is

generally separated in tonic alertness, representing the

enduring alert state over the day, and phasic alertness,

implying the temporary enhancement of this state due to an

internal or external stimulus (Posner 1975). The mainte-

nance of concentration over a longer period of time under

monotonous stimulus conditions is called sustained atten-

tion (Davies et al. 1984), whereas divided attention is

commonly characterized by keeping on line two or more

currently relevant (classes of) stimuli or mental operations

at the same time. Therefore, divided attention requires the

simultaneous monitoring of different information channels

to quickly detect relevant events and to execute actions

according to the actual demand (Posner and Boies 1971).

The essential function of selective or focused attention is

the selection of a particular subset of the available stimuli

for preferential processing and, consequently, the simulta-

neous suppression of currently irrelevant information

(Kinchla 1992). Important to note is that the concept of

divided and selective attention is closely connected to the

concept of executive functions. The studies reviewed in our

work mainly found improvements in selective and sus-

tained attention, not in alertness. The concept of executive

function describes higher cognitive processes like problem

solving, mental planning, initiation and inhibition of

behavior as well as action control. The main function of the

B. Guse et al.

123

- 49 -

executive system is monitoring cognitive (sub-) processes

and their flexible dynamic regulation due to changing

environments. Such adaptive behavior necessitates a flex-

ible mind, which maintains and updates currently relevant

information and exerts top–down control over the percep-

tion of incoming information and execution of outgoing

behavior. This control is most commonly associated with

the anterior pole of the brain, the prefrontal cortex (PFC)

(Fuster 1987; Miller and Cohen 2001; Chao and Knight

1995). For successfully using executive control the ability

of dynamic attentional shifting is necessary. Working

memory consists of the short-term storage of incoming

information and a set of executive processes. Short-term

storage involves the active maintenance of a limited

amount of information for a matter of seconds and is a

necessary component of many higher cognitive functions

mediated in part by the prefrontal cortex (PFC). The

executive component implies the mental manipulation of

maintained information (Carpenter et al. 1990; Fuster

1987; Goldmann-Rakic (1997); Stuss and Benson 1986).

Therefore, working memory is often operationalized by

continuous performance tasks requiring the permanent

maintenance and manipulation of incoming information.

As executive function and working memory were attrib-

uted to prefrontal cortex, one could expect a significant

influence of rTMS on these cognitive domains. Neverthe-

less, the presented studies do not exhibit high significances.

They mainly report on improvements in ‘‘working mem-

ory’’, ‘‘cognitive flexibility’’ or ‘‘verbal fluency’’, but there

are no effects in problem solving, planning or reasoning.

Maybe such higher cognitions require too specific modu-

lations of activity than they could be effectively modified

by rTMS. We do not know whether executive improve-

ments underlie alterations in basic functions like attention

or concentration.

Concerning the learning and memory section, memory

refers to intermediate- and long-term storage of informa-

tion and has to be distinguished from short-term storage or

working memory described above. It contains the encod-

ing, consolidation and retention of verbal and nonverbal

material. Therefore, tasks used are requiring the immediate

and delayed free recall or cued recognition of information.

With regard to the well known memory complaints after

electroconvulsive therapy (ECT), it is important to note

that no marked memory deficits have been found after

rTMS. In addition to this outcome beneficial therapeutic

(e.g. antidepressant) effects have been the consequence.

RTMS (compared to ECT) seems to be a more sensitive

technique while exhibiting therapeutic and even improving

cognitive effects.

Psychomotor speed/processing speed describes the time

a person needs to process incoming stimuli and to ade-

quately react to them or initiate behavior, e. g. connecting

numbers as fast as possible in ascending order. Only a few

studies indicate significant increase in processing/motor

speed when measured solely.

All in all, there are inconsistencies between results that

may be attributed to differences in methodology (e.g.

stimulation protocols, number of sessions, for details see,

Table 1) or sample constitution. Missing statistical power

in some cases may be due to marginal psychometric

test properties. The evaluation of results is difficult on

account of the sometimes overlapping contents of cognitive

domains.

What kind of cerebral changes due to rTMS may result

in improving behavioral outcomes?

Regarding the differential rTMS effects throughout the

literature, evidence is growing about the modification of

cerebral blood flow, glucose metabolism and neuronal

excitability in the stimulated area as well as in intercon-

nected brain regions (Conca et al. 2002; Fox et al. 1997).

Moreover, short-/long-term potentiation of synapses and

rapid dynamic alterations in gray matter (GM) density are

reported (Esser et al. 2006; May et al. 2007). The latter

result resembles structural changes in normal learning

mechanisms that could be triggered by high-frequency

rTMS pulses. The reported dynamic shift of gray matter

density after about 5 days of stimulation is attended by

clinical ameliorations within the same time. The occur-

rence of structural alterations mirrored by changes in

functional processing exemplifies structural neuroplastic-

ity as a counterpart of function. Furthermore, there is a

large body of literature suggesting an association of

hypofrontality in schizophrenia with negative symptoms

and cognitive deficits (Dolan et al. 1993; George and

Belmaker 2000; Weinberger et al. 1988). High-frequency

rTMS (especially at 10 Hz) seems to be a promising

technique to improve such negative symptoms (Hajak

et al. 2004; Cordes et al. 2005; Jin et al. 2006). Conse-

quently, high-frequency rTMS can be suggested to be able

to evoke improvements in both negative symptoms and

cognition. The herein reviewed rTMS studies assessing

cognition in schizophrenia did not show convincing

effects toward a cognitive improvement. Additionally, it

remains unclear whether structural changes, alterations in

metabolism or neurotransmission under the stimulated

area or in the connected neuronal network (or the com-

bination of all) may produce behavioral outcomes (e.g.

May et al. 2007; Strafella et al. 2001). Regarding the

stimulation location (PFC) one could expect improve-

ments in most of the abovementioned cognitive functions,

because they all underlie (at least in part) this area.

Nevertheless, the results of the studies do not exhibit such

consistent pattern.

Cognitive effects of prefrontal rTMS

123

- 50 -

The mechanism how rTMS may lead to an improvement

of cognitive function is rather complex and raises some

difficulties in interpretation. TMS-induced enhancement of

performance might be the result of the excitation of a

functionally relevant task-supporting activation, the exci-

tation of an area that inhibits competing functions, the

inhibition of an area that suppresses the execution of the

task, or the inhibition of an area that promotes competing

functions (Sack and Linden 2003). This is complicated by

the fact that the same stimulation pattern (e.g. supra-

threshold rTMS with 10 Hz) could lead to different effects

on cerebral blood flow depending on the stimulation site

(e.g. increase when stimulating the frontal eye field and

decrease during rTMS of the primary motor cortex) (Sack

and Linden 2003). The effects of rTMS also depend on the

history of synaptic activity in the stimulated region. For

example, if 6-Hz rTMS is applied for a short period (below

the threshold for any lasting after-effects), then the sup-

pressive effect of a subsequent period of 1-Hz rTMS is

enhanced (Ridding and Rothwell 2007). Generally, a prior

history of increased activity seems to increase the effec-

tiveness of rTMS protocols that decrease excitability,

whereas a prior history of reduced activity increases the

effect of facilitatory rTMS.

Further differential investigations are necessary to

expand knowledge of rTMS functioning and the under-

lying biological mechanisms by linking structural and

functional imaging data (including spectroscopy data)

with behavioral outcome variables. For a detailed analysis

of functional cerebral alterations, the rTMS procedure

could be conducted during fMRI-scanning. Such a

simultaneous approach provides the opportunity to

investigate the local response to TMS at a neurophysio-

logical level with high spatial resolution, thus helping to

determine in vivo the brain areas that are directly or

transsynaptically affected by TMS. Nevertheless using

fMRI tends to create also problems with interpretation;

for example, whether changes in perfusion or BOLD

signal reflect changes in excitatory, inhibitory or com-

bined neural activity.

An interesting topic in this context could also be to

evaluate and compare the contrast of brain alterations and

differences in activated neuronal networks in diseased

and healthy people to explore different coping strategies.

All in all, investigations have to prove the efficacy of

rTMS in randomized sham-controlled trials with higher

statistical power using larger sample sizes and improved

methodology. This may even become more interesting

while stimulation protocols inducing longer-lasting

effects like theta-burst stimulation (TBS) have been

developed. Currently studies are underway to test these

TBS in terms of affecting not only motor response, but

also cognition.

Acknowledgments T. Wobrock is a member of a speakers’ bureau

for AstraZeneca, Eli Lilly and Janssen-Cilag, and has accepted paid

speaking engagements in industry-sponsored symposia from Astra-

Zeneca, Bristol-Myers-Squibb, Eli-Lilly, Janssen Cilag and Pfizer,

and travel or hospitality not related to a speaking engagement from

Astra Zeneca, Bristol-Myers-Squibb, Eli Lilly, Janssen Cilag, and

Sanofi-Synthelabo, and received a research grant from Astra Zeneca.

B. Guse reports no competing interests.

References

Avery DH, Hotzheimer PE, Fawaz W, Russo J, Neumaier J, Dunner

DL, Haynor DR, Claypoole KH, Wajdik C, Roy-Byrne P (2006)

A controlled study of repetitive transcranial magnetic stimula-

tion in medication-resistant major depression. Biol Psychiatry

59:187–194

Barker AT, Jalinous R, Freeston IL (1985) Non-invasive magnetic

stimulation of human motor cortex (letter). Lancet 1:1106–1107

Ben-Shachar D, Belmaker RH, Grisaru N, Klein E (1997) Transcra-

nial magnetic stimulation induces alternations in brain mono-

amines. J Neural Transm 104:191–197

Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, Rumi DO,

Barbosa ER, Rosa MO, Pascual-Leone A, Rigonatti SP, Marc-

olin MA, Silva MTA (2005) Effect of repetitive TMS and

fluoxetine on cognitive function in patients with Parkinson’s

disease and concurrent depression. Brief reports. Mov Disord

20(9):1178–1219

Burt T, Lisanby SH, Sackheim HA (2002) Neuropsychiatric appli-

cations of transcranial magnetic stimulation: a meta analysis. Int

J Neuropsychopharmacol 5:73–103

Carpenter PA, Just MA, Shell P (1990) What one intelligence test

measures: a theoretical account of the processing in the Raven

Progressive Matrices Test. Psychol Rev 97:404–431

Chao LL, Knight RT (1995) Human prefrontal lesions increase

distractibility to irrelevant sensory inputs. Neuroreport 21:1605–

1610

Conca A, Koppi S, Konig P, Swoboda E, Krecke N (1996)

Transcranial magnetic stimulation: a novel antidepressive strat-

egy? Neuropsychobiology 34:204–207

Conca A, Peschina W, Konig P, Fritzsche H, Hausmann A (2002)

Effect of chronic repetitive transcranial magnetic stimulation on

regional cerebral blood flow and regional glucose uptake in drug

treatment-resistant depressives: a brief report. Neuropsychobi-

ology 45:27–31

Cordes J, Mobascher A, Arends M, Agelink MW, Klimke A (2005)

A new method for the treatment of depression: Transcranial

magnetic stimulation. Dtsch Med Wochenschr 130:889–892

Davies DR, Jones DM, Taylor A (1984) Selective and sustained-

attention tasks: Individual and group differences. In: Parasur-

aman R, Davies DR (eds) Varieties of Attention. Academic,

Orlando

Dolan RJ, Bench CJ, Liddle PF (1993) Dorsolateral prefrontal cortex

dysfunction in the major psychoses: symptoms or disease

specificity? J Neurosurg Psychiatr 56:1290–1294

Esser SK, Huber R, Massimini M, Peterson MJ, Ferrarelli F, Tononi

G (2006) A direct demonstration of cortical LTP in humans: A

combined TMS/EEG study. J Brain Res Bull 69(1):86–94

Fabre I, Galinowski A, Oppenheim C, Gallarda T, Meder JF, de

Montigny C, Olie JP, Poirier MF (2004) Antidepressant efficacy

and cognitive effects of repetitive transcranial magnetic stimu-

lation in vascular depression: an open trial. Int J Geriatr

Psychiatry 19:833–842

Fitzgerald PB, Benitez J, Daskalakis JZ, Brown TL, Marston N, de

Castella A, Kulkarni J (2005) A double-blind sham-controlled

B. Guse et al.

123

- 51 -

trial of repetitive transcranial magnetic stimulation in the

treatment of refractory auditory hallucinations. J Clin Psycho-

pharmacol 25(4):358–362

Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J, Martin

C, Jerabek P (1997) Imaging human intra-cerebral connectivity

ba PET during rTMS. Neuroreport 8:2787–2791

Fregni F, Otachi P, do Valle A, Boggio PS, Thut G, Rigonatti S,

Pascual-Leone A, Valente KD (2006) A randomized clinical trial

of repetitive transcranial magnetic stimulation in patients with

refractory epilepsy. Ann Neurol 60:447–455

Fuster JM (1987) The prefrontal cortex: anatomy, physiology, and

neuropsychology of the frontal lobe. Lippincott-Raven, New

York

George MS, Belmaker RH (2000) Transcranial magnetic stimulation

in neuropsychiatry. American Psychiatric Association,

Washington

Gershon AA, Dannon PN, Grunhaus L (2003) Transcranial magnetic

stimulation in the treatment of depression. Am J Psychiatry

160:835–845

Goldmann-Rakic PS (1997) Circuitry of primate prefrontal cortex and

regulation of behaviour by representational memory. In: Plum F

(ed) Handbook of physiology. Nervous system, vol 5. Higher

functions of the brain. American Physiological Society,

Bethesda, pp 373–417

Hajak G, Marienhagen J, Langguth B, Werner S, Binder H,

Eichhammer P (2004) High frequency transcranial magnetic

stimulation in schizophrenia: a combined treatment and neuro-

imaging study. Psychol Med 34:1157–1163

Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G (2004) Transcra-

nial magnetic stimulation in the investigation and treatment of

schizophrenia: a review. Schizophr Res 71:1–16

Hausmann A, Pascual-Leone A, Kemmler G, Rupp CI, Lechner-

Schoner T, Kramer-Reinstadler K, Walpoth M, Mechtcheriakov

S, Conca A, Weiss EM (2004) No deterioration of cognitive

performance in an aggressive unilateral and bilateral antidepres-

sant rTMS add-on trial. J Clin Psychiatry 65(6):772–782

Herwig U, Padberg F, Unger J, Spitzer M, Schonfeldt-Lecuona C

(2001) Transcranial magnetic stimulation in therapy studies:

examination of the reliability of ‘‘standard’’ coil positioning by

neuronavigation. Biol Psychiatry 50(1):58–61

Hoffmann RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros

NN, Wu YT, Caroll K, Krystal JH (2005) Temporoparietal

transcranial magnetic stimulation for auditory hallucinations:

safety, efficacy and moderators in a fifty patients sample. Biol

Psychiatry 58:97–104

Hoppner J, Schulz M, Mau R, Schlafke D, Richter J (2003)

Antidepressant efficacy of two different rTMS procedures. Eur

Arch Psychiatry Clin Neurosci 253:103–109

Huang CC, Su TP, Shan IK, Wei IH (2004) Effect of 5 Hz repetitive

transcranial magnetic stimulation on cognition during a Go/

NoGo task. J Psychiatr Res 38:513–520

Huber TJ, Schneider U, Rollnik J (2003) Gender differences in the

effect of repetitive transcranial magnetic stimulation in schizo-

phrenia. Psychiatry Res 120(1):103–105

Jandl M, Bittner R, Sack A, Weber B, Gunther T, Maurer K, Kaschka

WP (2004) Effects of rTMS on negative symptoms and EEG-

topography in schizophrenic patients. Eur Psychiatry 19(Suppl

1):164

Jandl M, Bittner R, Sack A, Weber B, Gunther T, Pieschl D, Kaschka

WP, Maurer K (2005) Changes in negative symptoms and EEG

in schizophrenic patients after repetitive transcranial magnetic

stimulation (rTMS): an open-label pilot study. J Neural Transm

112:955–967

Januel D, Dumortier G, Verdon CM, Stamatiadis L, Saba G, Cabaret

W, Benadhira R, Rocamora JF, Braha S, Kalalou K, Vicaut PE,

Fermanian J (2006) A double-blind sham controlled study of

right prefrontal repetitive transcranial magnetic stimulation

(rTMS): Therapeutic and cognitive effect in medication free

unipolar depression during 4 weeks. Prog Neuropsychopharma-

col Biol Psychiatry 30(1):126–130

Jin Y, Potkin SG, Kemp AS, Huerta ST, Alva G, Thai TM, Carreon

D, Bunney WE Jr (2006) Therapeutic effects of individualized

alpha frequency transcranial magnetic stimulation (alpha rTMS) on

negative symptoms of schizophrenia. Schizophr Bull 32:556–561

Jorge RE, Robinson RG, Tateno A, Narushima K, Acion L, Moser L,

Arndt S, Chemerinski E (2004) Repetitive transcranial magnetic

stimulation as treatment of poststroke depression: a preliminary

study. Biol Psychiatry 55:398–405

Kinchla RA (1992) Attention. Annu Rev Psychol 43:711–742

Kuroda Y, Motohashi N, Ito H, Ito S, Takano A, Nishikawa T, Suhara

T (2006) Effects of repetitive transcranial magnetic stimulation

on [11C] raclopride binding and cognitive function in patients

with depression. J Affect Disord 95:35–42

Little JT, Kimbrell TA, Wassermann EM, Grafman J, Figueras S,

Dunn RT, Danielson A, Repella J, Huggins T, George MS, Post

RM (2000) Cognitive effects of 1- and 20-Hertz repetitive

transcranial magnetic stimulation in depression: preliminary

report. Neuropsychiatry Neuropsychol Behav Neurol 13(2):

119–124

Loo C (2001) Effects of a 2- to 4-week course of repetitive

transcranial magnetic stimulation (rTMS) on neuropsychologic

functioning, electroencephalogram, and auditory threshold in

depressed patients. Biol Psychiatry 49:615–623

Loo C, Mitchell PB, Croker VM, Malhi GS, Wen W, Gandevia SC,

Sachdev PS (2003) Double-blind controlled investigation of

bilateral prefrontal transcranial magnetic stimulation for the

treatment of resistant major depression. Psychol Med 33:33–40

Martis B, Alam D, Dowd SM, Hill SK, Sharma RP, Rosen C, Pliskin

N, Martin E, Carson V, Janicak PG (2003) Neurocognitive

effects of repetitive transcranial magnetic stimulation in severe

major depression. Clin Neurophysiol 114:1125–1132

May A, Hajak G, Gansbauer S, Steffens T, Langguth B, Kleinjung T,

Eichhammer P (2007) Structural brain alterations following 5

days of intervention: dynamic aspects of neuroplasticity. Cereb

Cortex 17:205–210

Miller EK, Cohen JD (2001) An integrative theory of prefrontal

cortex function. A Rev Neurosci 24:167–202

Mogg A, Pluck G, Eranti SV, Landau S, Purvis R, Brown RG, Curtis

V, Howard R, Philpot M, McLoughlin DM (2008) A randomized

controlled trial with 4-month follow-up of adjunctive repetitive

transcranial magnetic stimulation of the left prefrontal cortex for

depression. Psychol Med 38(3):323–333

Moser DJ, Jorge RE, Manes MD, Paradiso S, Benjamin BS, Robinson

RG (2002) Improved executive functioning following repetitive

transcranial magnetic stimulation. Neurology 58:1288–1290

Mosimann UP, Schmitt W, Greenberg BD, Kosel M, Muri RM,

Berkhoff M, Hess CW, Fisch HU, Schlaepfer TE (2004)

Repetitive transcranial magnetic stimulation: a putative add on

treatment for major depression in elderly patients. Psychiatr Res

126:123–133

O’Connor M, Brenninkmeyer C, Morgan A, Bloomingdale K, Thall

M, Vasile R, Pascual Leone A (2003) Magnetic stimulation and

electroconvulsive therapy on mood and memory: a neurocogni-

tive risk-benefit-analysis. Cogn Behav Neurol 6(2):118–127

Padberg F, Zwanzger P, Thoma H, Kathmann N, Haag C, Greenberg

BD, Hampel H, Moller HJ (1999) Repetitive transcranial

magnetic stimulation (rTMS) in pharmacotherapy-refractory

major depression: comparative study of fast, slow and sham

rTMS. Psychiatry Res 88(3):163–171

Posner MI (1975) The psychology of attention. In: Gazzaniga MS,

Blakemore C (eds) Handbook of psychology. Academic,

New York

Cognitive effects of prefrontal rTMS

123

- 52 -

Posner MI, Boies SW (1971) Components of attention. Psychol Rev

78:391–408

Post A, Keck ME (2001) Transcranial magnetic stimulation as a

therapeutic tool in psychiatry: what do we know about the

neurobiological mechanism? J Psychiatr Res 35:193–215

Poulet E, Brunelin J, Bediou B, Forgeard L, Daleru J, D’Amato T,

Saoud M (2005) Slow transcranial magnetic stimulation can

rapidly reduce resistant auditory hallucinations in schizophrenia.

Biol Psychiatry 57:188–191

Rektorova I, Megova S, Bares M, Rektor I (2005) Cognitive

functioning after repetitive transcranial magnetic stimulation in

patients with cerebrovascular disease without dementia: a pilot

study of seven patients. J Neurol Sci 229–230:157–161

Ridding MC, Rothwell JC (2007) Is there a future for therapeutic

use of transcranial magnetic stimulation? NatRevNeurosci 8(7):

559–567

Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R,

Emrich HM, Schneider U (2000) High frequency repetitive

transcranial magnetic stimulation (rTMS) of the dorsolateral

prefrontal cortex in schizophrenic patients. NeuroReport 11:

4013–4015

Rosa MA, Gattaz WF, Pascual-Leone A, Fregni F, Rosa MO, Rumi

DO, Myczkowski M, Silva MF, Mansur C, Rigonatti SP,

Teixeira MJ, Marcolin MA (2006) Comparison of repetitive

transcranial magnetic stimulation and electroconvulsive therapy

in unipolar non-psychotic depression: a randomized single-blind

study. Int J Neuropsychopharmacol 9(6):667–676

Sachdev P, Loo C, Mitchell P, Malhi G (2005) Transcranial magnetic

stimulation for the deficit syndrome of schizophrenia: A pilot

investigation. Psychiatry Clin Neurosci 59(3):354–357

Sack AT, Linden DE (2003) Combining transcranial magnetic

stimulation and functional imaging in cognitive brain research:

possibilities and limitations. Brain Res Brain Res Rev 43(1):

41–56

Sack AT, Cohen Kadosh R, Schumann T, Moerel M, Walsh V,

Goebel R (2009) Optimizing functional accuracy of TMS in

cognitive studies: a comparison of methods. J Cogn Neurosci

21(2):207–221

Sackeim HA, Portnoy S, Neeley P, Steif BL, Decina P, Malitz S

(1986) Cognitive consequences of low-dosage electroconvulsive

therapy. Ann NY Acad Sci 462:326–340

Schulze-Rauschenbach SC, Harms U, Schlaepfer TE, Maier W,

Falkai F, Wagner M (2005) Distinctive neurocognitive effects of

repetitive transcranial magnetic stimulation and electroconvul-

sive therapy in major depression. Br J Psychiatry 186:410–416

Shajahan PM, Glabus MF, Steele JD, Doris AB, Anderson K, Jenkins

JA, Gooding PA, Ebmeier KP (2002) Left dorso-lateral repet-

itive transcranial magnetic stimulation affects cortical

excitability and functional connectivity, but does not impair

cognition in major depression. Prog Neuropsychopharmacol Biol

Psychiatry 26(5):945–954

Sole-Padulles C, Bartres-Faz D, Junque C, Clemente IC, Molinuevo

JL, Bargallo N, Sanchez-Aldeguer J, Bosch B, Falcon C, Valls-

Sole J (2006) Repetitive transcranial magnetic stimulation

effects on brain function and cognition among elders with

memory dysfunction. A randomized sham-controlled study.

Cereb Cortex 16:1487–1493

Speer AM, Repella JD, Figueras S, Demian NK, Kimbrell TA,

Wasserman EM, Post RM (2001) Lack of adverse cognitive

effects of 1 Hz and 20 Hz repetitive transcranial magnetic

stimulation at 100% of motor threshold over left prefrontal

cortex in depression. J ECT 17(4):259–263

Squire LR (1982) Memory and electroconvulsive therapy (Letter).

Am J Psychiatry 139:1221

Strafella A, Paus T, Barrett J, Dagher A (2001) Repetitive transcranial

magnetic stimulation of the human prefrontal cortex induces

dopamine release in the caudate nucleus. J Neurosci 21(157):1–4

Stuss DT, Benson DF (1986) The frontal lobes. Raven, New York

Triggs WJ, McCoy KJM, Greer R, Rossi F, Bowers D, Kortenkamp S,

Nadeau SE, Heilman KM, Goodman WK (1999) Effects of left

frontal transcranial magnetic stimulation on depressed mood,

cognition, and corticomotor threshold. Biol Psychiatry 45(11):

1440–1446

Trojano L, Conson M, Maffei R, Grossi D (2006) Categorial and

coordinate spatial processing in the imagery domain investigated

by rTMS. Neuropsychologia 44(9):1569–1574

Vanderhasselt MA, De Raedt R, Baeken C, Leyman L, D’haenen H

(2006) The influence of rTMS over the left dorsolateral

prefrontal cortex on Stroop task performance. Exp Brain Res

169:279–282

Vanderhasselt MA, De Raedt R, Leyman L, Baeken C (2009) Acute

effects of repetitive transcranial magnetic stimulation on atten-

tional control are related to antidepressant outcomes. J Psychi-

atry Neurosci 34(2):119–126

Wagner W, Rihs TA, Mosimann UP, Fisch HU, Schlaepfer TE (2006)

Repetitive transcranial magnetic stimulation of the dorsolateral

prefrontal cortex affects divided attention immediately after

cessation of stimulation. J Psychiatr Res 40:315–321

Weinberger DR, Berman KF, Chase TN (1988) Mesocortical

dopaminergic function and human cognition. Ann NY Acad

Sci 537:330–338

Weiner RD, Rogers HJ, Davidson JR, Squire LR (1986) Effects of

stimulus parameters on cognitive side effects. Ann NY Acad Sci

462:315–325

Zimmermann P, Fimm B (1997) Test for Attentional Performance

(TAP), version 1.5. Psytest Press, Freiburg

B. Guse et al.

123

- 53 -

2.3 The effect of long-term high frequency repetitive transcranial magnetic

stimulation on working memory in schizophrenia and healthy controls – a

randomized placebo-controlled, double-blind fMRI study

This uni-centric rTMS and fMRI study investigates schizophrenia patients and

healthy controls. We ask whether a three-week excitatory 10 Hz rTMS applied to the

left DLPFC can improve verbal WM and modulate brain activation. We suppose that

patients’ probable benefit in working memory performance would be higher compared

to healthy controls due to ceiling effects in healthy controls. In addition, we hypothesize

that patients’ WM activations would approximate those of controls in the sense of

“normalized” system recruitment due to rTMS intervention. As in the first described

main study (see 2.1), rTMS is conducted over a period of 15 total sessions at 10 Hz,

110% of the individual resting motor threshold, with 1000 stimuli per session (15.000 in

total) and an inter-train interval of 30 seconds. In the placebo condition the same coil is

positioned 5 cm latero-caudal to F3 and distorted 45° away from the skull. Patients

(n=25) and healthy controls (n= 22) are assigned to either placebo or active stimulation

and compared to each other at every time point. Additional cognitive tasks are

administered targeting domains other than working memory. Contrary to our

hypothesis, functional imaging results indicate no statistical significant activity change

in the WM network over time in any contrast or sample. According to the ANOVAs for

repeated measures, cognitive performance remains without statistically relevant

alteration in all groups. As no analysis reveals relevant interaction effects, outlasting

after-effects following long-term high-frequency rTMS on brain activity or WM

performance can not be confirmed.

- 54 -

R

Tsr

BKa

b

c

d

e

f

h

����

a

ARRAA

KrfMSHLWC

a3

0h

Behavioural Brain Research 237 (2013) 300– 307

Contents lists available at SciVerse ScienceDirect

Behavioural Brain Research

j ourna l ho me pa ge: www.elsev ier .com/ locate /bbr

esearch report

he effect of long-term high frequency repetitive transcranial magnetictimulation on working memory in schizophrenia and healthy controls—Aandomized placebo-controlled, double-blind fMRI study

irgit Gusea,b,∗, Peter Falkaia, Oliver Grubera, Heather Whalleyc, Lydia Gibsond, Alkomiet Hasana,atrin Obste, Peter Dechent f, Andrew McIntoshc, Boris Suchanb, Thomas Wobrocka

University Medical Centre, Department of Psychiatry and Psychotherapy, Georg August University Göttingen, von-Siebold-Str. 5, D-37075 Göttingen, GermanyInstitute of Cognitive Neuroscience, Department of Neuropsychology, Ruhr University Bochum, Universitätsstr. 150, D-44780 Bochum, GermanyDivision of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Kennedy Tower, Morningside, Edinburgh EH10 5HF, UKInstitute of Psychology, Department of Experimental Psychology, Georg-August-University Göttingen, Goßlerstraße 14, D-37073 Göttingen, GermanyInstitute of Psychology, Department of Social Psychology, University Jena, Humboldtstr. 26, D-07743 Jena, GermanyMR-Research in Neurology and Psychiatry, University Medical Center Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany

i g h l i g h t s

3-week HF rTMS does not alter brain activation during working memory.Schizophrenia patients do not significantly differ from controls after treatment.Long-term HF rTMS does not change cognitive performance.Active rTMS is not superior to placebo rTMS.

r t i c l e i n f o

rticle history:eceived 31 May 2012eceived in revised form 29 August 2012ccepted 17 September 2012vailable online xxx

eywords:TMSMRI

iddle frontal gyruschizophreniaealthy controlsong term effect

orking memoryognition

a b s t r a c t

In schizophrenia patients negative symptoms and cognitive impairment often persist despite treatmentwith second generation antipsychotics leading to reduced quality of life and psychosocial functioning.One core cognitive deficit is impaired working memory (WM) suggesting malfunctioning of the dorso-lateral prefrontal cortex. High frequency repetitive transcranial magnetic stimulation (rTMS) has beenused to transiently facilitate or consolidate neuronal processes. Pilot studies using rTMS have demon-strated improvement of psychopathology in other psychiatric disorders, but a systematic investigation ofworking memory effects outlasting the stimulation procedure has not been performed so far. The aim ofour study was to explore the effect of a 3-week high frequency active or sham 10 Hz rTMS on cognition,specifically on working memory, in schizophrenia patients (n = 25) in addition to antipsychotic therapyand in healthy controls (n = 22). We used functional magnetic resonance imaging (fMRI) to compare acti-vation patterns during verbal WM (letter 2-back task) before and after 3-weeks treatment with rTMS.Additionally, other cognitive tasks were conducted. 10 Hz rTMS was applied over the left posterior middlefrontal gyrus (EEG electrode location F3) with an intensity of 110% of the individual resting motor thresh-

old (RMT) over a total of 15 sessions. Participants recruited the common fronto- parietal and subcorticalWM network. Multiple regression analyses revealed no significant activation differences over time inany contrast or sample. According to the ANOVAs for repeated measures performance remained withoutalterations in all groups. This is the first fMRI study that has systematically investigated this topic withina randomized, placebo-controlled, double-blind design, contrasting the effects in schizophrenia patientsand healthy controls.

∗ Corresponding author at: University Medical Centre, Department of Psychiatrynd Psychotherapy, Georg-August-University Göttingen, Von-Siebold-Straße 5, D-7075 Göttingen, Germany. Tel.: +49 0 551 39 10114; fax: +49 0 551 39 9337.

E-mail address: bguse@gwdg.de (B. Guse).

166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.bbr.2012.09.034

- 55

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Schizophrenia is a major mental illness characterized by posi-tive symptoms (e.g. delusions, hallucinations), negative symptoms(e.g. apathy, blunted affect, emotional/social withdrawal) and cog-nitive dysfunction. Research from the last twenty years indicates

-

ain Re

ttdmawdtttgvfimmigta(

smp(atwfvtartrcucolbcqce(cthDcaidrmAir

rsfs

B. Guse et al. / Behavioural Br

hat these impairments in cognition are one of the main predic-ors for poor social and functional outcome and a main reason forisability in schizophrenia patients [16,18,24]. Cognitive impair-ent in schizophrenia generally includes the domains of attention

nd concentration, psychomotor speed, learning and memory asell as executive functions [30,32]. One of the core cognitiveeficits is working memory (WM) as part of a disturbed cen-ral executive system [6,53]. Working memory implies the shorterm retention of information that is no longer accessible inhe environment and the manipulation of this information foruiding behavior [9]. Over the past few decades, studies have pro-ided a substantial body of evidence supporting a critical roleor bilateral prefrontal, anterior cingulate and parietal regionsn mediating WM performance (e.g. [50]; for review [54]). The

iddle frontal gyrus (Brodmann area (BA) 9/46) is known to beainly activated during the manipulation and executive monitor-

ng of incoming stimuli (e.g. [55]), whereas the inferior frontalyrus (BA 44) and parts of the superior frontal gyrus (premo-or and supplementary motor area, BA 6) as well as parietalssociation cortices are most sensitive for maintenance processese.g. [38]).

These results are in line with functional and cytoarchitecturaltudies pointing to a tightly knit and specific network of frontal-ediated working memory functions (for review [35,40,56]). The

refrontal cortex, especially the dorsolateral prefrontal cortexDLPFC, BA 9/46), has an important role in working memorynd is, above all, well located for transcranial magnetic stimula-ion (TMS) [27]. In this context, Mull and Seyal [33] investigatedhether transient functional disruption of the dorsolateral pre-

rontal cortex (DLPFC) with TMS would impair performance in aerbal WM task. Participants were presented sequences of let-ers and asked to decide if the letter just displayed was the sames the letter presented three trials back (n-back task). The studyevealed an effect on task accuracy when TMS was applied tohe left DLPFC between letter presentations. Thus, as inhibitoryepetitive TMS (rTMS) induces virtual lesion in the prefrontalortex interfering with cognitive performance, facilitatory stim-lation has been discussed to have the potential to improveognitive performance and memory functions [41]. The applicationf transcranial magnetic stimulation is one possibility to modu-ate activity states and to interfere with the function of certainrain areas. Physiological studies of the primary motor cortexonducted in healthy subjects indicate that, dependent on the fre-uency and pattern of the stimulation protocol, repetitive TMSan induce a long-lasting enhancement or reduction of corticalxcitability (for review see [20,61]). In general, low frequency<1 Hz) rTMS reduces and high frequency rTMS (>5 Hz) enhancesortical excitability, but the recently introduced theta-burst pro-ocol (TBS, a modified repetitive TMS protocol) applied at veryigh-frequencies (50 Hz) does not follow this frequency-rule [44].ependent on whether the TBS is applied in an intermittent orontinuous pattern, the effects are facilitatory or inhibitory. Inddition to that, we also know from recently published stud-es that the effects of TBS and rTMS are dependent on manyifferent factors, like history of synaptic plasticity, the interneu-on networks recruited by the TMS pulse, current activity of theembrane potential, and pharmacological modulation [44,21,22].ll these factors contribute to the high interindividual variabil-

ty of physiological and behavioral responses following TBS andTMS.

However, there is emerging evidence that some establishedepetitive TMS protocols have the capacity to induce plasticity

hifts of the stimulated and interconnected brain areas and, there-ore, to modulate behavioral and cognitive functions (for reviewee [41,61,44,48]).

- 56 -

search 237 (2013) 300– 307 301

Based on these physiological findings, repetitive TMS has beensuccessfully used to improve motor performance and motor learn-ing [4,11,37,41]. Beyond the influence on the motor system there isgrowing evidence showing transient neuronal facilitation and cog-nitive process enhancement due to rTMS in healthy subjects. Everset al. [12] studied visually evoked event-related potentials (ERP)and mean choice reaction time measured before and after 20 HzrTMS (compared to sham and 1 Hz single TMS) applied to the leftand right prefrontal cortex in healthy subjects. Results revealed asignificant decrease of P3 latencies and reaction time due to 20 HzrTMS of the left but not right PFC. In a combined study using TMSand near-infrared spectroscopy, Yamanaka et al. [60] administered5 Hz or sham TMS to the left or right parietal cortex of healthy sub-jects during the delay period of a spatial WM task (control task:visuospatial attention task). Reaction times improved in the spa-tial WM task only after active stimulation of the right parietalcortex. This effect was attended by significantly increased frontaloxygenated hemoglobin (oxy-Hb) levels during the WM task andreduced levels during the control task reflecting a selectively facil-itating effect on spatial WM. Klimesch et al. [29] could show thatrTMS at individual upper alpha frequency (IAF + 1 Hz) delivered tothe mesial frontal (Fz) and right parietal (P6) cortex can enhancethe performance in a mental rotation task.

However, most studies raise limitations concerning the focuson direct cognitive effects of single sessions. Repeated sessiondesigns applying daily rTMS to test gradual or cumulative alter-ations in after-effects should be proven for therapeutic purposes.Until now, some circumscribed outlasting or consolidation effectsof rTMS and other non-invasive brain stimulation techniques havebeen described in the human motor system indicating long-lastingbehavioral effects (e.g. [41,42,61], see above). The transfer of thesemotor-system findings to prefrontal regions and the increase ofstimulation sessions is essential for treatment application in neu-ropsychiatric diseases associated with working memory and othercognitive deficits.

We have recently reviewed the effects of high-frequencyrepetitive TMS (>1 Hz) on cognitive functions and revealed thatstimulation protocols using frequencies between 10 Hz and 20 Hzand 80–110% of the individual resting motor threshold are mostlikely to result in an improvement of cognitive functions. Fur-thermore, our review indicates that improvements depend on therepetition rate of rTMS sessions and that patients with neuropsy-chiatric disorders do show usually greater improvements thanhealthy controls [19]. In schizophrenia patients, facilitatory rTMSapplied to the frontal lobe has been discussed to be effective inthe treatment of negative symptoms (Meta-Analysis and review[10]). Within some of these studies targeting negative symptomsvia frontal repetitive TMS, cognitive effects of the stimulationwere additionally investigated, whereas only one of five random-ized controlled trials showed a beneficial effect in schizophreniapatients [8].

To explore the neurobiology underlying non-invasive brainstimulation related functional changes in the frontal lobe, placebo-controlled, randomized and double-blind studies using techniquesof experimental neurophysiology and functional brain imaging arenecessary.

In particular, multimodal studies contrasting effects on the dis-eased versus healthy brain are needed to get a better understandingof process in the frontal cortex. Therefore, the aim of our combinedlong-term rTMS and fMRI study was to investigate whether long-term rTMS is a promising tool to modulate working memory inhealthy subjects and in schizophrenia patients that outlasts the

stimulation procedure. In this context, we were interested in func-tional cerebral alterations of the frontal lobe evaluated by fMRI aswell as behavioral performance effects due to rTMS treatment.

302 B. Guse et al. / Behavioural Brain Research 237 (2013) 300– 307

Table 1Demography of the sample.

SZ active SZ sham HC active HC sham SZ all HC all

Number 13 12 11 11 25 22Sex (m:f) 10:3 9:3 8:3 8:3 19:6 16:6Educational level (mean years) 15.5 12.6 16.4 12.5 14.1 14.5

H

2

2

piSdaMbpprs

mtdjptBta

2

motmfdi

s3(b1tmswttr

TF

Er

Age average (range) 37 (22–58) 36 (20–51)

C = healthy controls, SZ = schizophrenia, f = female, m = male.

. Methods

.1. Subjects

We studied 25 right-handed in- and out-patients (real/active, n = 13,lacebo/sham, n = 12) with an ICD-10 diagnosis of schizophrenia with predom-

nant negative symptoms (>20 points according to the Positive and Negativeyndrome Scale (PANSS) [28]) and with an illness duration for at least 6 months (foremography see Table 1). All patients were on stable doses of second generationntipsychotics and had stable PANSS scores 2 weeks before inclusion in the study.edication was not changed throughout the study. Anticonvulsive or high-dose

enzodiazepine treatment was prohibited. This experimental fMRI-study is a sub-roject of a large randomized multicenter clinical trial (NCT00783120). Therefore,atients were centrally randomized to placebo or real intervention group (designeported in [7]). Rater, investigators and patients were blind across all parts of thetudy.

22 healthy right-handed comparison subjects (active, n = 11, sham, n = 11), pair-atched for age (maximal difference of 2 years), gender and educational level were

reated in the same stimulation condition as their equivalent patient. Three subjectsropped out before stimulation due to withdrawal of their consent. Comparison sub-

ects were excluded if they had a first-degree relative with schizophrenia or anothersychiatric disorder. A history of neurologic illness (especially epileptic seizures) orhose with contraindications to MRI scanning e.g. magnetic implants were excluded.efore inclusion subjects signed written informed consent after complete descrip-ion of the study. The study was in accordance with the Declaration of Helsinki andpproved by the local ethic committee of the University Medical Center Göttingen.

.2. Stimulation procedure

rTMS was performed with a MagProX100 (Medtronic/Denmark) magnetic sti-ulator according to international safety guidelines [46,58]. For the determination

f the individual resting motor threshold (RMT), single pulse TMS was appliedhrough a standard figure-of-eight coil to the hand area of the left motor cortex and

otor-evoked potentials (MEPs) were recorded via electromyography (EMG) sur-ace electrodes from the right first-dorsal interosseus muscle (FDI). The RMT wasefined as the lowest intensity that produced a motor evoked potential of <50 �V

n the relaxed FDI in at least five of ten trials [47].rTMS intervention was then conducted over a period of 3 weeks (15 total ses-

ions, 1 session/weekday) at 10 Hz, 110% of the individual RMT, inter-train interval0 s with 1000 stimuli per session, delivering 15,000 stimuli per patient in totalTable 2). Coil position over the left DLPFC was guaranteed in active and sham groupy a coil positioning method using the 10–20-EEG system. In brief, the standard0–20 EEG electrode positions were individually measured and marked. The posi-ion of the coil center was then located at the electrode position F3 (left posterior

iddle frontal gyrus, BA 46) [14,49]. For active stimulation the coil was placed at theame point tangentially to the scull oriented posterior to anterior. Sham stimulation

as delivered at the same parameters but with the coil positioned 5 cm laterocaudal

o F3 and with one wing angulated 45◦ away from the scull. This method was usedo evoke slight temporal skull sensations without effective stimulation of the targetegion.

able 2low chart.

EG: Electroencephalography; fMRI: functional magnetic resonance imaging; RMT:esting motor threshold; rTMS: repetitive transcranial magnetic stimulation.

- 57

36 (20–58) 36 (21–52) 36 (20–58) 36 (20–58)

2.3. fMRI scanning procedure

For functional MRI, axial gradient-echo echo planar images (EPI) were acquiredon a 3 T Siemens Magnetom Tim Trio scanner. Images were obtained using a standard8-channel-head-coil. The head was stabilized with small cushions to minimizemovement during scanning. Functional imaging was performed with the follow-ing parameter settings: echo time 36 ms, repetition time 2000 ms, flip angle 70◦ ,field of view 256 mm, voxel size 2 mm × 2 mm × 4 mm, 22 axial slices parallel to theAC–PC plane acquired in ascending order. Acquisition was run for 400 volumes inone single session, of which the first six volumes were discarded for the analysis.Triggering of the stimulation by the scanner pulses was conducted using Presen-tation Software. Before functional scanning, T1-weighted anatomical imaging wasperformed for each subject (voxel size 1 mm × 1 mm × 1 mm).

2.4. Neuropsychological assessment

During the fMRI session, subjects performed a verbal n-back working memorytask with parametrically varied WM load among 0, 1 and 2 items [39]. Subjectsviewed sequences of capital letters (A–E) displayed in the middle of a visual screen(700 ms each letter; 1800 ms inter-stimulus interval, offset to onset) and provideddominant hand button press at every stimulus. In the 0-back (control) condition, thetarget was any letter that matched the pre-specified letter “X”. In the 1- and 2-backcondition, the target was any letter that corresponded to the one presented one ortwo trials preceding it, respectively. Demands of stimulus encoding and responseremained constant across conditions, only requirements of maintenance and manip-ulation differed with increasing amounts of information. Subjects responded to eachrandomly presented letter, pressing one button for targets (33%) and another fornon-targets. Conditions were run block-wise in the same order (0-1-2-0-1-2. . .),with 18 blocks à 15 stimuli. Prior to each trial, subjects were given short instructions(e.g. “1-back”, presented 3500 ms on the screen).

Additional “off-line” neuropsychological ratings were conducted prior to thefirst and at least one hour after the last rTMS session. Neuropsychological tests wereadministered in a fixed order by the same blinded rater. All tests were designed toindicate deficits in parts of the dorsolateral prefrontal cortex and interconnectedbrain regions, respectively. The Trail Making Test (TMT-A/B) requires complex visualscanning, motor speed (Version A) and the ability of flexible shifting (Version B) (e.g.[43]). The Tübinger Aufmerksamkeitsprüfung (TAP) is a computer based test batteryand its subtests “selective attention” and “divided attention” were conducted tomeasure basal attention processes [62]. The divided attention task comprises anauditory and a visual component requiring keeping both sensory inputs on line. Thecomputer based Wisconsin Card Sorting Test (WCST) is commonly used to assesscognitive flexibility and abstract reasoning [17].

2.5. Psychopathological baseline assessment

Psychopathological assessment at baseline was conducted using the PANSS

(Table 3). This scale is standardized for typical and dimensional assessment ofschizophrenia symptoms and evaluates positive, negative and other dimensions onbasis of a formal semi-structured clinical interview [28]. Additional validated ratingscales were conducted to assess other psychopathological symptoms: the CalgaryDepression Rating Scale for Schizophrenia (CDSS) [1], the Montgomery and Asberg

Table 3Schizophrenia sample. Baseline results of the clinical ratings.

Clinical rating scales Baseline

M (SD) active M (SD) sham p

PANSSTotal score 81.7 (11.9) 72.1 (12.0) 0.08Psychopathology 42.3 (7.2) 37.2 (8.2) 0.14Positive scale 15.3 (4.4) 11.9 (3.1) 0.06Negative scale 23.9 (3.5) 23.3 (2.2) 0.62

MADRS 12.4 (3.1) 14.1 (7.3) 0.48CDSS 2.2 (1.8) 3.8 (4.7) 0.33CGI 4.1 (0.5) 3.7 (0.95) 0.37GAF 56.9 (7.0) 60.1 (7.8) 0.35

Means (M) and standard deviations (SD) of test scores at baseline.

-

ain Re

Dtdo

2

2

rpMicnMwfi

gwortamc

anafdpe

rccoopae

2

Cfii

2Eousiei(stthbic

2s

3

3

3

r

B. Guse et al. / Behavioural Br

epression Rating Scale (MADRS) [31], the Clinical Global Impression (CGI) [34] andhe Global Assessment Scale of Functioning (GAF) [59] (Table 3). Ratings were con-ucted by the same experienced and blinded investigator. The psychopathologicalutcome over all subjects will be published within the multicenter trial.

.6. Data analysis

.6.1. Functional imaging dataFor movement correction the reconstructed and converted EPI images were

ealigned to the mean functional image using SPM5 (Statistical Parametric Map-ing; http://www.fil.ion.ucl.ac.uk/spm/) running in Matlab (MathWorks, Natick,assachusetts). Slice time correction was then carried out to minimize differences

n acquisition times. The source (structural) and reference (functional) image wereo-registered, the anatomic image was segmented. This output file was then used toormalize the realigned functional data into standard stereotactic space (using theontreal Neurologic Institute (MNI) template provided by SPM5). Finally, the EPIsere smoothed with an 8 mm × 8 mm × 8 mm full-width half-maximum Gaussianlter.

Statistical analyses were conducted using the General Linear Model in SPM,enerating a matrix that allowed mapping brain activity alterations associatedith different experimental task demands. The design comprised three conditions,

ne for each task difficulty (0-, 1-, 2-back). In order to produce the hemodynamicesponse for each experimental condition (sustained activity over the whole blocks),he vectors were convolved with a canonical hemodynamic response function using

box-car function. For additional movement correction at the first-level the realign-ent output file was fitted in as regressor. Linear t-contrasts were then defined

omprising vectors for 1-back vs. 0-back, 2-back vs. 0-back and 2-back vs. 1-back.The resulting single-subject images were taken to a second-level random effects

nalysis. First, we were interested in whether all groups recruited the common WMetwork reported in the literature and whether groups differed in WM activationt baseline. Initially, one-sample t-tests were performed for each group (SZ, HC)or WM demand (2-back vs. 0-back, 1-back vs. 0-back). We then looked for groupifferences and calculated different two factorial analyses of variance (ANOVA) com-rising “diagnostic group” (SZ, HC) and “stimulation condition” (active, sham) forach contrast of interest.

In order to study the effect of stimulation pre- to post-treatment within aepeated measure design we performed a multiple regression analysis for eachontrast constructing a vector for each subject (n = 47) and condition (n = 8) asovariate. This vector specifically encoded which scores in different conditions werebtained from the same subject. Thus, every subject was assigned to schizophreniar healthy group, to active or sham stimulation and to both time points (pre- andost-treatment). Therefore, the row component of variance was obtained to evalu-te activation differences pre- to post-treatment within groups and their interactionffects.

.6.2. Behavioral dataBehavioral data were analyzed using SPSS software (version 18.0, SPSS Inc.,

hicago, IL, USA). Since active and sham group had been centrally randomized, werstly explored whether educational level, gender, age, medication and stimulation

ntensity (RMT) were balanced at baseline.

.6.2.1. Neuropsychology. Accuracy data and reaction times (RTs) were aggregated.rror and omission trials were excluded from the reaction time analysis. Meansf active and sham groups were compared for schizophrenia patients and controlssing Student’s t-tests. Data of the schizophrenia and control sample were theneparately pooled and compared with each other to increase test power and tonvestigate the effect of psychopathological symptoms on baseline measures. Wexpected that schizophrenia patients would perform worse than healthy controlsn all neurocognitive measures. For treatment effects data were submitted to a 2time of measurement: pre-treatment vs. post-treatment) × 2 (diagnostic group:chizophrenia vs. healthy controls) × 2 (stimulation condition: active vs. sham) fac-orial design with time of measurement as within-subjects factor. Thus, for eachest variable an ANOVA for repeated measures was performed with additional postoc analyses using paired, two tailed t-tests in case of significant results indicatedy interactions in the ANOVA with all p-values corrected for multiple compar-

sons. Moreover, Cohen’s d for repeated measures was calculated for all relevantomparisons.

.6.2.2. Psychopathology. Means of active and sham groups were compared forchizophrenia patients using Student’s t-tests.

. Results

.1. Functional imaging data

.1.1. BaselineIn line with previous studies within group analyses (SZ/HC)

evealed recruitment of bilateral fronto-parietal regions during

- 58 -

search 237 (2013) 300– 307 303

2-back WM performance (Fig. 1) with some activation in subcor-tical regions such as insula, caudate nucleus and thalamus (e.g.[35,40]). For detailed activation coordinates see SupplementaryTables 1 and 2. Between group analysis yielded no main effectof diagnostic group (HC/SZ), no main effect of stimulation con-dition (active/sham) and no interaction effect of diagnosticgroup × stimulation condition at a threshold of p < .001 uncor-rected. At the 1-back difficulty all participants activated the samenetwork to a lower extent than in the 2-back condition, so werestricted to report the 2-back vs. 0-back contrast.

3.1.2. Treatment effectsThe multiple regression analyses were performed regarding

each diagnostic group (healthy controls and schizophreniapatients) in each condition (active and sham stimulation) at bothtime points (before and after stimulation). Contrary to our initialhypothesis, the multiple regression analysis revealed no statisti-cally significant activation difference pre- to post- treatment withineither the schizophrenic or the control sample and no relevantinteraction effect over all contrasts of interest at a threshold ofp < .001, uncorrected. Post hoc t-tests confirmed a lack of activa-tion difference between these groups after stimulation at p < .001uncorrected. MNI activation coordinates including correspondingcluster sizes and T-values at pre- and post- treatment during the2-back condition can be found in Supplementary Tables 1 and 2.

Overall, results revealed no significant activation differencesbetween schizophrenia patients and healthy controls at baselineor at post-treatment and no differences between or within groupsover time. The same is the case for both stimulation conditions,active and sham groups did not differ significantly.

3.2. Behavioral data

3.2.1. BaselineDemographic parameters were balanced across groups, but

active stimulation groups had higher mean educational levels thansham groups (Table 1). There were also more male individualsin both the active and sham groups. Regarding the stimulationintensity in the active samples, RMT was marginally higher in theschizophrenia than healthy group. Antipsychotic dosage (chlor-promazine equivalents) was balanced across sub-samples. Activeand sham stimulated patients differed significantly in the numberof correct trials in the 2-back condition of the verbal working mem-ory task (n-back) with a higher number of correct trials in the activegroup (t(23) = 3.11, p = .01). All remaining neuropsychological com-parisons between sham and active groups were non-significant.No significant clinical differences emerged between active andsham stimulated patients. Between-group comparisons demon-strated a decreased number of correct responses and increasedreaction times in the 0-back condition of the verbal WM taskin the schizophrenia group compared to the healthy controlgroup (t(29.5) = −2.47, p < .05 and t(36.7) = 2.52, p < .05, respec-tively). Further, a decreased number of correct responses in the1-back and 2-back working memory demand of the WM task inschizophrenia patients has been revealed (t(30.1) = −2.86, p < .05and t(44) = −2.80, p < .05, respectively) but no increase in reactiontimes. Schizophrenia patients had significantly increased reactiontimes than healthy controls in the TMT-B (t(34) = 2.09, p < .05) aswell as in the WCST (t(29) = 3.56, p = .001) and in the selectiveattention task (t(38) = 2.86, p < .05). No differences emerged in theremaining neurocognitive measures. Neuropsychological baselineresults can be found in Supplementary Tables 3 and 4.

3.2.2. Treatment effects, neuropsychologyVerbal working memory (n-back task). For the 0-back task an

ANOVA for repeated measures revealed a significant main effect

304 B. Guse et al. / Behavioural Brain Research 237 (2013) 300– 307

Fig. 1. Overview of the activations in the 2-back working memory condition. Brain regions activated in the 2-back vs. 0-back WM contrast, p < 0.001 (uncorrected) forillustration purposes. HC: healthy controls; SZ: schizophrenic patients.

otttmoto4e4i

rA3(ntbadgoaagsaa

f diagnostic group on accuracy (F(1, 42) = 9.66, p < .01) and reac-ion times (F(1, 42) = 6.89, p < .05) (Table 4). The same ANOVA forhe 1-back task demonstrated a significant main effect of diagnos-ic group on accuracy (F(1, 42) = 8.42, p < .01), further a significant

ain effect of time of measurement (F(1, 42) = 10.26, p < .01) andf diagnostic group on reaction times (F(1, 42) = 4.72, p < .05). Inhe accuracy ANOVA of the 2-back task significant main effectsf diagnostic group (F(1, 42) = 12.24, p < .01) and stimulation (F(1,2) = 13.60, p < .01) were found. Additionally, a significant mainffect of time of measurement on reaction times was revealed (F(1,2) = 14.22, p < .01). All in all, no significant interactions could be

dentified in the working memory domain.Visual scanning/motor speed, flexible shifting (TMT). The ANOVA

evealed a main effect of time of measurement for both the TMT- (F(1, 32) = 5.90, p < .05) and the TMT-B in “reaction times” (F(1,2) = 10.94, p < .01), but no interaction effects. Selective attentionTAP). Analysis on the selective attention task did not reveal any sig-ificant effects for accuracy. In contrast, for reaction times of correctrials a main effect for diagnostic group (F(1, 36) = 7.68, p < .01) coulde found and a time of measurement × stimulation interaction at

trend level (F(1, 36) = 3.09, p < .10). However, post hoc analysesid not indicate significant changes in reaction times in neitherroup and thus could not confirm this interaction effect. Resultsf the post hoc t-Tests can be found in Supplementary Tables 3nd 4. Divided attention (TAP). Accuracy data analysis of the dividedttention task indicated a significant main effect of diagnostic

roup (F(1, 35) = 6.95, p < .05) and a significant time of mea-urement × stimulation interaction (F(1, 35) = 5.13, p < .05). Furthernalysis of these effects did not indicate any significant changes inccuracy. The ANOVA on reaction times revealed significant main

- 59

effects of time of measurement (F(1, 35) = 4.53, p < .05) and of stimu-lation (F(1, 35) = 5.52, p < .05). Furthermore, a significant diagnosticgroup × stimulation interaction was found (F(1, 35) = 4.39, p < .05).Again, this interaction effect could not be confirmed by subsequentt-tests as no significant differences over time could be found. Cogni-tive flexibility, abstract reasoning (WCST). In regard to the accuracy,the ANOVA indicated no significant differences. For reaction times(correct responses) in the WCST main effects could be found fortime of measurement (F(1, 26) = 24.62, p < .001) and for diagnos-tic group (F(1, 26) = 9.31, p < .01). Additionally, the ANOVA revealeda significant time of measurement × diagnostic group interaction(F(1, 26) = 5.30, p < .05). Subsequent analysis indicated that reactiontimes decreased in schizophrenic patients in both stimulation con-ditions (t(6) = 3.25, p < .05 for the active group, t(5) = 3.06, p = .056for the sham group).

4. Discussion

This is the first multimodal study investigating the cognitiveeffect and the underlying brain activations of long-term rTMS inhealthy subjects and schizophrenia patients. We asked whether athree-week excitatory 10 Hz rTMS applied to the left DLPFC canimprove verbal working memory and modulate brain activationin healthy controls and schizophrenia patients. Furthermore, wesupposed that patients’ probable benefit in working memory per-formance would be higher compared to healthy controls due to

ceiling effects in healthy controls. In addition, we hypothesizedthat patients’ WM activations would approximate those of con-trols in the sense of “normalized” system recruitment due to rTMSintervention.

-

B. Guse et al. / Behavioural Brain Re

Table 4Analysis of Variance (ANOVA) for repeated measures. Neurocognitive measures,treatment effects.

Neurocognitive tests Df, error F- value p-value

Verbal WM (0-back)Group AC 1, 42 9.66 0.003b

Group RT 1, 42 6.89 0.017a

Verbal WM (1-back)Group AC 1, 42 8.42 0.008b

Group RT 1, 42 4.72 0.052b

Time RT 1, 42 10.26 0.004b

Verbal WM (2-back)Group AC 1, 42 12.24 0.002b

Stimulation AC 1, 42 13.60 0.001b

Time RT 1, 42 14.22 0.001b

TMT-ATime RTd 1, 32 5.90 0.021a

TMT-BTime RTd 1, 32 10.94 0.002b

Selective attention (TAP)Group RT 1, 36 7.68 0.009b

Stimulation × time RT 1, 36 3.09 0.088c

Divided attention (TAP)Group AC 1, 35 6.95 0.012a

Stimulation RT 1, 35 5.52 0.025a

Time RT 1, 35 4.53 0.041a

Time AC 1, 35 3.37 0.075a

Stimulation × time AC 1, 35 5.13 0.030a

Group × time RT 1, 35 4.39 0.043a

WCSTGroup RT 1, 26 9.31 0.005b

Time AC 1, 26 3.38 0.077c

Time RT 1, 26 24.62 < 0.001b

Group × time RT 1, 26 5.30 0.03a

ANOVA for repeated measures (group × stimulation × time), with time as within-subjects factor. For illustration purposes this table includes statistically significant(p < .05) and trend level results (p < .10). AC: accuracy, RT: reaction time (correctresponses).

a p < .05.b p < .01.c p < .10.

4

tststafihs(dbdeCmttspsAoo

d RT: total time needed.

.1. Functional imaging and behavioral neuropsychology

Imaging results were contrary to our initial hypothesis. Mul-iple regression analyses for each contrast revealed no statisticalignificant activity change in the working memory network overime, neither in the schizophrenia nor in the healthy controlsample. As analyses did not reveal relevant main effects or interac-ions, after-effects following high-frequency rTMS on frontal brainctivity during working memory performance could not be con-rmed in our study. In line with current literature, patients andealthy controls activated a network including fronto- parietal andubcortical regions during verbal working memory performancee.g. [35,40]). These regions demonstrated increased activationsuring the 2-back condition of the task compared to the 1-ack condition. Thus, participants enhanced activation at higheremands requiring maintenance and manipulation abilities. Thisffect was equivalent for all groups over all stimulation conditions.oncerning the behavioral data, the initial ANOVAs for repeatedeasures either remained either without interaction effects, or

hese interactions were not confirmed by post hoc t-tests. Reac-ion times in the WSCT significantly improved in the schizophreniaample after active stimulation, but to a minor extent also afterlacebo stimulation. Most of the main effects were “time of mea-

urement” and can be explained by training effects over all groups.lterations over time could not be clearly attributed to the kindf stimulation or group. Thus, the impact of high frequency rTMSn neuronal activation or cognitive enhancement outlasting the

- 60 -

search 237 (2013) 300– 307 305

stimulation procedure remains questionable at this time. How-ever, there is some evidence that reaction time is more likely tobe modulated as performance accuracy.

One recently published randomized double-blind, placebo-controlled study investigated the effect of a single 20 Hz rTMSsession applied to the DLPFC on gamma-oscillatory activityevoked during the execution of an n-back working memory taskin schizophrenia patients and healthy controls [3]. This singlesession reduced frontal gamma-oscillatory activity in schizophre-nia patients, but enhanced it in healthy subjects in particularduring the three-back part of the n-back task [3]. The authorsexplained these effects by a complex interplay between inhibitorygamma–aminobutric acid (GABA) neurotransmission and homeo-static metaplasticity. One open-label study showed that theconsecutive 5-day application of 10 Hz rTMS over the left DLPFCimproves negative symptoms in schizophrenia patients andchanged EEG frequency bands in various cortical regions [26].

However, despite these findings of rTMS induced modulationsin EEG frequency bands, our study has not been able to revealchanges in fMRI-based network activations of the frontal lobe. Inthis context, various models for explanation can be discussed. Oneimportant fMRI study conducted on schizophrenia patients andhealthy controls indicated that the variance of prefrontal cortexactivation during the execution of an n-back task may be asso-ciated with differences in performance levels [5]. In this study,the activation pattern was dependent on the task-performanceand schizophrenia patients with a poor performance showed areduced frontal activation. On the other hand, patients with ahigh performance which was closer to that of the healthy controlgroup demonstrated an enhanced activation. These findings sup-port the hypotheses that working memory deficits in schizophreniapatients, as also observed in our study, cannot exclusively beexplained by a hypo- or hyperactivation of frontal lobe networks[5].

Though revealing performance differences in working memorybetween groups, we were not able to detect differences in BOLDactivation, at baseline. Thus, assuming that rTMS can only mod-ulate cortical networks with an abnormal activation pattern, thelacking baseline difference in BOLD activity might explain our neg-ative finding. Finally, it can be discussed that the activity differencesof the 2-back paradigms are not pronounced enough to be modu-lated by long-term rTMS. As discussed above, one study revealedrTMS-induced differences in gamma-oscillations, which were mostpronounced in the 3-back paradigm [3].

In general, the inclusion rate of patients exhibiting more severesymptoms was low due to the long intervention phase. This factmay contribute to a statistical ceiling effect in the schizophreniagroup. Furthermore, the sensitivity of instruments measuring these(slight) effects is important. Though TMS has been demonstratedto modulate local field potentials and BOLD-responses [2,51], long-lasting after-effects may be more difficult to map as they arelikely to be smaller than direct effects. Moreover, there is stillno clear knowledge about the time period that rTMS treatmenteffects would be detectable. It is possible that other techniques,like e.g. EEG, MEG or multimodal imaging would be more suit-able to detect smaller changes in brain activity. Also, computerizedcognitive performance tests may be more sensitive for the detec-tion of subtle alterations (e.g. several subtests of the TAP system).One final methodological limitation in our study is that sam-ple sizes differed between subtests with consequent effects onstatistical power. Assuming that high frequency rTMS has thepotential to facilitate and consolidate neural processing to a cer-

tain extent, one should consider concomitant cognitive trainingsor other interventions (e.g. application of d-cycloserin) to improvethe modulation of complex cognitive functions by a metaplasticapproach.

3 ain Re

C

r

A

aANoPt

G

A

t

R

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

06 B. Guse et al. / Behavioural Br

onflict of interest

The authors report no actual or potential conflicts of interest aselated to this report.

cknowledgments

This work was supported by the University Medical Centernd the MR-Research in Neurology and Psychiatry, Georg-ugust-University Goettingen and by the Institute of Cognitiveeuroscience, Ruhr-University Bochum, further by the Departmentf Psychology, University of Edinburgh, UK. We specially thank I.fahlert, U. Engelhardt and M. Keil for their individual contributiono this study.

This work is a subproject of a multicenter trial funded by theerman Research Foundation (DFG: grant FA 241/10-1).

ppendix A. Supplementary data

Supplementary data associated with this article can be found, inhe online version, at http://dx.doi.org/10.1016/j.bbr.2012.09.034.

eferences

[1] Addington D, Addington J, Maticka-Tyndale E. Assessing depression inschizophrenia: the Calgary Depression Scale. British Journal of Psychiatry(Suppl) 1993;22:39–44.

[2] Allen EA, Pasley BN, Duong T, Freeman RD. Transcranial magnetic stim-ulation elicits coupled neural and hemodynamic consequences. Science2007;317:1918–21.

[3] Barr MS, Farzan F, Arenovich T, Chen R, Fitzgerald PB, Daskalakis ZJ. The effectof repetitive transcranial magnetic stimulation on gamma oscillatory activityin schizophrenia. PLoS ONE 2011;6(7):1–11.

[4] Butefisch CM, Khurana V, Kopylev L, Cohen LG. Enhancing encoding of a motormemory in the primary motor cortex by cortical stimulation. Journal of Neu-rophysiology 2004;91:2110–6.

[5] Callicott JH, Mattay VS, Verschinski BA, Marenco S, Egan MF, Weinberger DR.Complexity of prefrontal cortical dysfunction in schizophrenia: more than upor down. American Journal of Psychiatry 2003;160:2209–15.

[6] Cannon TD, Glahn DC, Kim J, Van Erp TGM, Karlsgodt K, Cohen MS, et al. Dor-solateral prefrontal cortex activity during maintenance and manipulation ofinformation in working memory in patients with schizophrenia. Archives ofGeneral Psychiatry 2005;62:1071–80.

[7] Cordes J, Falkai P, Guse B, Hasan A, Schneider-Axmann T, Arends M, et al. Repet-itive transcranial magnetic stimulation for treatment of negative symptoms inresidual schizophrenia: rationale and design of a sham-controlled, randomizedmulticenter study. European Archives of Psychiatry and Clinical Neuroscience2009;259(Suppl. 2):189–97.

[8] Demirtas-Tatlidede A, Vahabzadeh-Hagh A, Pascual-Leone A. Can noninvasivebrain stimulation enhance cognition in neuropsychiatric disorders? Neu-ropharmacology 2012 [PMID: 22749945, epub ahead of print].

[9] D’Esposito M, Postle BR, Rypma B. Prefrontal cortical contributions to work-ing memory: evidence from event-related fMRI studies. Experimental BrainResearch 2000;133:3–11.

10] Dlabac-de Lange J, Knegtering R, Aleman A. Repetitive transcranial magneticstimulation for negative symptoms of schizophrenia: review and meta-analysis. Journal of Clinical Psychiatry 2010;71(4):411–8.

11] Duque J, Mazzocchio R, Stefan K, Hummel F, Olivier E, Cohen LG. Memoryformation in the motor cortex ipsilateral to a training hand. Cerebral Cortex2008;18:1395–406.

12] Evers S, Böckermann I, Nyhuis PW. The impact of transcranial magnetic stimu-lation on cognitive processing: an event-related potential study. NeuroReport2001;12:2915–8.

14] Fitzgerald PB, Maller JJ, Hoy KE, Thomson R, Daskalakis ZJ. Exploring the optimalsite for the localization of dorsolateral prefrontal cortex in brain stimulationexperiments. Brain Stimulation 2009;2:234–7.

16] Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophre-nia. Pharmacology Biochemistry and Behavior 2011;99(2):245–53.

17] Grant DA, Berg EA. Wisconsin card sorting test. Göttingen: Hofgrefe-Verlag;1993.

18] Green MF. What are the functional consequences of neurocognitive deficits inschizophrenia? American Journal of Psychiatry 1996;153(3):321–30.

19] Guse B, Wobrock T, Falkai P. Cognitive effects of high frequency repetitivetranscranial magnetic stimulation: a systematic review. Journal of NeuralTransmission 2010;117(1):105–22.

20] Hallett M. Transcranial magnetic stimulation – a primer. Neuron 2007;55(2):187–99.

[

[

- 61

search 237 (2013) 300– 307

21] Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC. The role of interneu-ron networks in driving human motor cortical plasticity. Cerebral Cortex 2012[epub ahead of print, PMID: 22661405].

22] Hasan A, Hamada M, Nitsche MA, Ruge D, Galea JM, Wobrock T,et al. Direct-current-dependent shift of theta-burst-induced plasticity inthe human motor cortex. Experimental Brain Research 2012;217(1):15–23.

24] Hoe M, Nakagami E, Green MF, Brekke JS. The causal relationships betweenneurocognition, social cognition and functional outcome over time inschizophrenia: a latent difference score approach. Psychological Medicine2012;5::1–13.

26] Jandl M, Bittner R, Sack A, Weber B, Günther T, Pieschl D, et al. Changes innegative symptoms and EEG in schizophrenic patients after repetitive transcra-nial magnetic stimulation (rTMS): an open-label pilot study. Journal of NeuralTransmission 2005;112(7):955–67.

27] Kaminski JA, Korb FM, Villringer A, Ott DVM. Transcranial magnetic stimulationintensities in cognitive paradigms. PLoS 2011;6(9):1–11.

28] Kay S, Fiszbein A, Opler L. The positive and negative syndrome scale (PANSS)for Schizophrenia. Schizophrenia Bulletin 1987;13:261–76.

29] Klimesch W, Sauseng P, Gerloff C. Enhancing cognitive performance with trans-cranial magnetic stimulation at human individual alpha frequency. EuropeanJournal of Neuroscience 2003;17:1129–33.

30] Mesholam-Gately RI, Giulliano AJ, Goff KP, Faraone SV, Seidman LJ. Neurocogni-tion in first-episode schizophrenia: a meta-analytic review. Neuropsychology2009;23(3):315–36.

31] Montgomery SA, Asberg M. A new depression scale designed to be sensitive tochange. British Journal of Psychiatry 1979;134:382–9.

32] Mueser KT, McGurk SR. Schizophrenia: review article. Lancet 2004;363:2063–72.

33] Mull BR, Seyal M. Transcranial magnetic stimulation of left prefrontal corteximpairs working memory. Clinical Neurophysiology 2001;112:1672–5.

34] NIMH. Clinical Global Impression (CGI). 1976.35] Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory

paradigm: a meta-analysis of normative functional neuroimaging studies.Human Brain Mapping 2005;25:46–59.

37] Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain1994;117:847–58.

38] Paulesu E, Frith CD, Frackowiak RS. The neural correlates of the verbal compo-nent of working memory. Nature 1993;362:342–5.

39] Perlstein WM, Dixit NK, Carter CS, Noll DC, Cohen JD. Prefrontal cortex dys-function mediates deficits in working memory and prepotent responding inschizophrenia. Biological Psychiatry 2003;53:25–38.

40] Petrides M. Lateral prefrontal cortex: architectonic and functional organization.Philosophical Transactions of the Royal Society of London, Series B: BiologicalSciences 2005;360:781–95.

41] Reis J, Robertson E, Krakauer JW, Rothwell J, Marshall L, Gerloff C, et al. Consen-sus: can tDCS and TMS enhance motor learning and memory formation? BrainStimulation 2008;1(4):363–9.

42] Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E, et al. Noninva-sive cortical stimulation enhances motor skill acquisition over multiple daysthrough an effect on consolidation. Proceedings of the National Academy ofSciences, United States of America 2009;106:1590–5.

43] Reitan RM. The relation of the trail making test to organic brain damage. Journalof Constructivist Psychology 1958;19:393–4.

44] Ridding MC, Ziemann U. Determinants of the induction of cortical plasticityby non-invasive brain stimulation in healthy subjects. Journal of Physiology2010;588(13):2291–304.

46] Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS ConsensusGroup. Safety, ethical considerations, and application guidelines for the useof transcranial magnetic stimulation in clinical practice and research. ClinicalNeurophysiology 2009;120(12):2008–39.

47] Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al.Non-invasive electrical and magnetic stimulation of the brain, spinal cord androots: basic principles and procedures for routine clinical application. Reportof an IFCN committee. Electroencephalography and Clinical Neurophysiology1994;91:79–92.

48] Rothwell JC. Using transcranial magnetic stimulation methods to probe con-nectivity between motor areas of the brain. Human Movement Science2011;30(5):906–15.

49] Rusjan PM, Barr MS, Farzan F, Arenovich T, Maller JJ, Fitzgerald PB, DaskalakisZJ. Optimal transcranial magnetic stimulation coil placement for targeting thedorsolateral prefrontal cortex using novel magnetic resonance image-guidedneuronavigation. Human Brain Mapping 2010;31:1643–52.

50] Rypma B, Berger JS, D’Esposito M. The influence of working-memory demandand subject performance on prefrontal cortical activity. Journal of CognitiveNeuroscience 2002;14:721–31.

51] Sarfeld AS, Diekhoff S, Wang LE, Liuzzi G, Uludag K, Eickhoff SB, et al. Con-vergence of human brain mapping tools: neuronavigated TMS parametersand fMRI activity in the hand motor area. Human Brain Mapping 2011,http://dx.doi.org/10.1002/hbm.21272.

53] Silver H, Feldman P, Bilker W. Working memory deficit as a core neu-ropsychological dysfunction in schizophrenia. American Journal of Psychiatry2003;160:1809–16.

54] Smith EE, Jonides J. Storage and executive processes in the frontal lobes. Science1999;283:1657–61.

-

ain Re

[

[

[

[

[

[

B. Guse et al. / Behavioural Br

55] Smith EE, Jonides J, Koeppe RA. Dissociating verbal and spatial working memoryusing PET. Cerebral Cortex 1996;6:11–20.

56] Wager TD, Smith EE. Neuroimaging studies of working memory: a meta-analysis. Cognitive, Affective, and Behavioral Neuroscience 2003;3:255–74.

58] Wassermann EM. Risk and safety of repetitive transcranial magnetic stim-

ulation: report and suggested guidelines from the International Workshopof Repetitive Transcranial Magnetic Stimulation. Electroencephalography andClinical Neurophysiology 1998;108(1):1–16.

59] Wittchen, Kohler, Zauding (dt. Bearbeitung). Global assessment scale of func-tioning (GAF); 1989.

[

- 62 -

search 237 (2013) 300– 307 307

60] Yamanaka K, Yamagata B, Tomioka H, Kawasaki S, Mimura M. Trans-cranial magnetic stimulation of the parietal cortex facilitates spatialworking memory: near-infrared spectroscopy study. Cerebral Cortex 2010;20:1037–45.

61] Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, Berardelli

A, et al. Consensus: motor cortex plasticity protocols. Brain Stimulation2008;1:164–82.

62] Zimmermann, P, Fimm, B. Neuropsychologische Testbatterie zur Erfassung vonAufmerksamkeitsdefiziten. Freiburg: Psychologisches Institut der Universität;1989.

3 Discussion

Prior to submission of the thesis, recruitment and data acquisition for the first

described trial (see 2.1.) was completed while data analysis for all centres is still

ongoing. Nevertheless, a first insight into the unpublished psychopathological findings

from our sub-sample will be provided in the following discussion. This chapter is

subdivided into a brief introduction, followed by a question-based discussion of our

results, some general study limitations and a conclusion including future perspectives.

Regarding the scientific basis, negative symptoms in schizophrenia have been closely

linked to DLPFC dysfunction due to deficient neuronal integrity and brain metabolism.

Inefficient dynamic modulation of DLPFC activity has been shown to impair working

memory performance in schizophrenia. TMS is a non-invasive method that is able to

modulate activity states in the brain and to evoke focal plasticity shifts (Esser et al.,

2006; Reis et al., 2008). rTMS has further been proven to produce outlasting

consolidation effects in the human motor system that indicate behavioural changes (e.g.

Reis et al., 2008, 2009; Ziemann et al. 2008). According to the “Hebbian”

characteristics of synaptic plasticity, long-term potentiation (LTP) can be triggered

using repetitive TMS (Hebb, 1949; Esser et al., 2006). However, these mechanisms

have been mainly studied in the motor cortex (Ilic & Ziemann, 2005). Vorel and

Lisanby (2008) provided an issue of the potential clinical relevance of synaptic

plasticity in the prefrontal cortex: LTP could selectively strengthen specific inputs into

the PFC, thereby filtering other inputs and thus representing a cellular mechanism of

attention. Alternatively, LTP could strengthen neuronal circuits within the PFC or boost

PFC metabolism and function overall, including executive, planning and motor

function. Single session rTMS studies have demonstrated transient cognitive

enhancement at higher frequencies (see 1.2.3.2). The cognitive effect of repeated

sessions has been rather unexplored in the field. However, for therapeutic purposes

outlasting rTMS effects would be essential. So far, long-term rTMS has been

successfully applied in clinical settings aiming at psychopathological improvement (see

1.2.3.1). But systematic investigations in larger samples with improved methodology

- 63 -

are lacking. Furthermore, the outlasting effect on cognition and brain physiology has to

be studied systematically.

Therefore, the major aim of this thesis was to establish if 1.) high frequency long-

term rTMS is able to improve psychopathology, specifically negative symptoms, in

patients with schizophrenia, if 2.) high frequency long-term rTMS has a beneficial

effect on cognition, and if 3.) high frequency long-term rTMS can improve WM

dysfunction in patients with schizophrenia compared to healthy controls. A further

objective was to investigate whether this kind of brain stimulation influences brain

activation within the WM network effectively.

3.1 Does rTMS improve Psychopathology in Patients with Schizophrenia?

Below, preliminary psychopathological findings are provided from our sub-sample

(see 2.3). To date this data is unpublished as it is the main objective of the multicentre-

trial outlined in chapter 2.1.

Psychopathological results indicate a tendency to selective psychopathological

improvement due to long-term rTMS treatment. No deterioration has been found.

Firstly, with regard to the primary outcome variable, analysis on the negative symptom

subscale of the PANSS demonstrated a significant main effect of time of measurement

(F(1, 23) = 33.12, p < .001) and no statistically relevant interactions. The PANSS

negative symptoms improved in both stimulation conditions and thus, cannot be

attributed to rTMS intervention. More interestingly, an improvement in the PANSS

positive symptoms score emerged after active stimulation. The ANOVA revealed a

significant main effect of time of measurement (F(1, 20) = 9.96, p < .01) and a time of

measurement x stimulation interaction at a trend level (F(1, 20) = 2.99, p < .10). Further

analysis revealed a significant improvement only for the active stimulation group (t(11)

= 3.05, p < .05) and thus confirmed this interaction. A similar pattern was found for the

general psychopathology subscale of the PANSS. The ANOVA indicated a significant

main effect for the time of measurement (F(1, 20) = 7.50, p < .05) but the time of

measurement x stimulation interaction did not reach significance (F(1, 20) = 2.42, p <

.14). For the PANSS total score an ANOVA revealed a significant main effect of time

of measurement (F(1, 20) = 20.96, p < .001) and a time of measurement x stimulation

- 64 -

interaction at a trend level (F(1, 20 = 3.08, p < .10). The PANSS total score

improvement can be explained by selective subscale improvement. Depressive

symptoms (MADRS) decreased after active stimulation compared to sham stimulation.

An ANOVA performed for the MADRS revealed a significant main effect for the time

of measurement (F(1, 22) = 8.87, p < .01) and a time of measurement x stimulation

interaction at a trend level (F(1, 22) = 3.73, p < .10). Post-hoc t-tests demonstrated a

significant decrease in the MADRS score for schizophrenia patients in the active

stimulation group (t(12) = 3.16, p < .01). With respect to the remaining measures

(CDSS, CGI, GAF), active stimulation could not be shown to be superior to sham

stimulation. Results point to a general clinical benefit for schizophrenia patients from a

3-week 10 Hz rTMS intervention over the DLPFC as it has been shown that certain

depressive and positive psychotic symptoms (MADRS, PANSS) selectively improved.

However, most of the above results remain on a trend level but point to symptom

improvement. These results are only preliminary and evaluation with more statistical

power is indispensable.

Nevertheless, in the event of replication in a larger sample, the effect on the

PANSS positive symptoms is amazing as we initially targeted negative symptoms with

prefrontal stimulation. However, since sum scores of the positive syndrome scale were

analyzed, there is no clear evidence about which kind of positive symptoms exactly

improved. Further investigations are necessary to subsume a specific cluster or

symptom.

Auditory hallucinations, as part of the positive syndrome scale, have been mostly

targeted using inhibitory rTMS applied to the left temporo-parietal cortex (e.g. Hoffman

et al, 2000, 2003; 2005; Poulet et al., 2005; for a review see Fitzgerald & Daskalakis,

2008 or Poulet et al., 2010). Based on this preliminary finding one should take into

account that prefrontal stimulation may trigger similar processes, possibly via inhibition

of clinically relevant remote areas. Therefore, it seems more likely that prefrontal

stimulation enhances some kind of control or coping mechanisms with consequent

effects on individual symptom management.

- 65 -

3.2 Does rTMS influence Cognition?

Our review article (see 2.2) aimed to cope with this objective and investigated the

impact of rTMS on cognition for a potential therapeutic application. We therefore

reviewed long-term high frequency rTMS studies between 1999 and 2009 stimulating

the prefrontal cortex of patients suffering from neuropsychiatric illnesses or healthy

volunteers, where the effects on cognitive functions were measured. The behavioural

outcome, subdivided in different cognitive domains, was analyzed with regard to the

impact of clinical status (patient/healthy volunteer) and stimulation type (active/sham).

The results indicate that rTMS applied at 10 Hz up to 20 Hz, over the left DLPFC,

within a range of 10-15 successive sessions at the intensity of 80-110% of the individual

motor threshold, seems to be most effective in improving cognition. In comparison,

patients (generally independent of the kind of diagnosis) tend to reach greater

improvement than healthy subjects. One of the non-clinical (healthy) groups showed

ameliorations in processing speed, all the others did not show any significant alteration.

When contrasting the clinical groups, 22 studies reported improvements spanning the

domains of attention (selective, sustained), executive functions (working memory,

cognitive flexibility and verbal fluency/ retrieval), learning and memory (verbal,

nonverbal) and processing speed. However, many studies failed to demonstrate

significant cognitive effects, but in some of them trends towards selective cognitive

improvement emerged. One can speculate as to whether healthy subjects generally

respond to a minor extent due to ceiling effects. But the amount of studies explicitly

contrasting patients with healthy controls is rare. In general, most of the clinical trials

studied the effect in depression. 3 studies stimulated patients with schizophrenia with

non-significant results for cognitive enhancement. While in 7 studies a superiority of

active stimulation towards placebo stimulation emerged in terms of significantly greater

improvement in the active condition. One limitation concerns the unanswered question

about the onset of neurocognitive testing. Most studies did not quote their exact onset

times. The delay period is important as immediate measures would record direct after-

effects rather than cumulative effects of the whole series. Taken together, results give

reason to extend research in this field as long-term high frequency rTMS has been

shown to selectively enhance cognitive processing. However, the impact of rTMS on

- 66 -

cognition has to be evaluated within systematic investigations taking into consideration

the neurobiological basis of cognitive improvement. Our third study (see 2.3) explicitly

used the combination of rTMS and fMRI to assess rTMS induced activity changes. The

results are discussed in the following section.

3.3 Does rTMS improve WM Dysfunction in Patients with Schizophrenia? Does

rTMS alter Brain Activation within the WM Network?

To address this twofold question we performed a combined rTMS and fMRI study

(see 2.3) and tried to find out whether a three-week excitatory 10 Hz rTMS applied to

the left DLPFC can improve verbal WM and modulate brain activation in schizophrenia

patients compared to healthy controls. We supposed that patients’ probable benefit in

WM performance would be higher compared to healthy controls due to ceiling effects in

healthy controls. Further, we hypothesized that patients’ WM activations would

approximate those of controls in the sense of “normalized” system recruitment due to

the intervention.

Looking at the behavioural baseline results, patients performed relatively well over

all cognitive subtests but differed from healthy subjects in several tasks. Comparisons

demonstrated a decreased number of correct responses and increased reaction times in

the 0-back condition of the verbal WM task in the schizophrenia group. Further,

decreased accuracy in the 1-back and 2-back demand of the WM task in schizophrenia

patients has been revealed. Patients showed significantly increased reaction times in the

Trail-Making Test (TMT-B, Reitan, 1958), in the Wisconsin Card Sorting Test (WCST,

Grant & Berg, 1993) and in the selective attention task of the “Tübinger

Aufmerksamkeitsbatterie” (TAP, Zimmermann & Fimm, 1989). This was expected

according to the literature (e.g. Heinrichs & Zakzanis 1998). Regarding the stimulation

effect on cognitive performance over time, the initial ANOVAs for repeated measures

remained either without interaction effects, or the interactions could not be confirmed

by post-hoc t-tests. Reaction times in the WCST significantly improved in the

schizophrenia sample after active stimulation, but to a minor extent also after placebo

stimulation. Most of the occurring effects can be explained by training effects.

Alterations over time could not be clearly attributed to type of stimulation or group.

- 67 -

Thus, an effect of real rTMS on cognitive performance cannot be confirmed in this

study. However, there is some evidence in our study that reaction time rather than

accuracy can be modulated. A recent near-infrared spectroscopy study (Yamanaka et al.

2010) shares this observation. In this single session study 5 Hz or sham TMS was

administered to the left or right parietal cortex of healthy subjects during the delay

period of a spatial WM task (control task: visuospatial attention task). Reaction times

improved in the spatial WM task after active stimulation of the right parietal cortex,

whereas accuracy did not improve. Another current rTMS/ fMRI crossover study on

healthy subjects identified neuroplastic alterations in prefrontally connected networks as

a substrate of behavioural changes (Esslinger et al., 2012). They administered once 5 Hz

real and sham rTMS to the right DLPFC and could show that reaction times after real

stimulation were significantly shorter. In our study, we aimed to improve performance

accuracy with repeated rTMS and our study failed to demonstrate accuracy effects.

However, reaction time decreases at unchanged accuracy may also reflect an

improvement in performance.

Regarding the fMRI results, multiple regression analyses revealed no statistical

significant activity change in the WM network over time, neither in the schizophrenia

nor in the healthy control sample. Active stimulation did not significantly differ from

placebo stimulation. As analyses did not reveal relevant main effects or interactions,

outlasting after-effects in the prefrontal region following high-frequency rTMS could

not be confirmed in this study.

However, consistent with the literature patients and healthy controls activated a

network including fronto- parietal and some subcortical regions during verbal WM

performance (e.g. Owen et al., 2005; Petrides, 2005). These regions demonstrated

increased activations during the 2-back condition of the task compared to the 1-back

condition. Thus, all participants enhanced activation at higher demands requiring

maintenance and manipulation abilities. The effect was equivalent for all groups over all

stimulation conditions and time points. For an overview of cortical activations in the 2-

back condition of the WM task see Figure 5 (in supplement material, 2.3).

- 68 -

Post-Treatment Pre-Treatment

HC, Sham

HC, active

SZ, sham

SZ, active

Figure 5: Brain regions activated in the 2- vs. 0-back WM contrast, p<0.001 (uncorrected) for illustration purposes. HC: healthy controls; SZ: schizophrenic patients.

The outcome is divergent from the model introduced by Callicott et al. (2003). They

assumed an inverted U-shaped BOLD-response curve during WM performance that

would be left-shifted in patients compared to controls (see 1.1.2, Figure 2A). Contrary

to this theory, patients and controls in our study seemed to follow a similar activity

curve but with some differences in performance accuracy and speed.

Our baseline results indicated performance differences in WM between groups, but

we were not able to detect differences in BOLD activation. Different explanations for

our negative findings can be discussed. Assuming that rTMS can only modulate cortical

networks with an abnormal activation pattern, the lacking baseline difference in BOLD

activity between groups might explain our results. It can be discussed that the activity

differences of the 2-back paradigms are not pronounced enough to be modulated by

long-term rTMS. One randomized double-blind, placebo-controlled study investigated

the effect of a single 20 Hz rTMS session applied to the DLPFC on gamma-oscillatory

activity evoked during the execution of an n-back WM task in schizophrenia patients

and healthy controls (Barr et al. 2011). This single session reduced frontal gamma-

- 69 -

oscillatory activity in schizophrenia patients, but enhanced it in healthy subjects, in

particular during the 3-back part of the n-back task. In line with this, a recently

published study from the same group (Barr et a., 2012) investigated, similarly to our

study, the cumulative behavioural effect of high-frequency rTMS on WM performance

in schizophrenia patients. The stimulation procedure was a little different to ours as they

stimulated over 4 weeks with 20 Hz rTMS, at 90% of the individual RMT, sequentially

over the left and right DLPFC. Performance differences between active and sham

treated patients were measured between 1- and 3-back verbal WM tasks pre- to post-

treatment. Behavioural data were compared with a non-stimulated healthy control

group. They hypothesized that rTMS intervention would normalize patients’ WM

performance to levels comparable to healthy subjects. Interestingly, they could

demonstrate that active rTMS significantly improved the accuracy in the 3-back task.

Performance levels increased in patients with active stimulation and approximated those

of controls. Reaction times and psychopathology did not improve. Apart from some

differences in methodology or samples, it seems likely that the higher demanding 3-

back condition or the sequential bilateral stimulation has been the essential factor for

this beneficial outcome. Unfortunately, the authors did not quote the exact onset of

cognitive testing after the last rTMS session. Further, additional structural/functional

MRI or neurophysiological recordings have not been conducted. However, this is an

important finding opening future perspectives in the field of neuropsychiatry which has

to be replicated in a larger sample with additional brain functional measures as the

question about whether long-term rTMS treatment is able to modulate brain activity in a

sustainable manner remains unanswered here.

Another important issue may be the possibility of diagnosis unspecific but ability

specific differences. Following this hypothesis, Callicott et al. (2003) conducted a study

on schizophrenia patients and healthy controls indicating that the variance of prefrontal

cortex activation during the execution of an n-back WM task may be associated with

differences in performance levels. In that study, the activation pattern was dependent on

the task-performance and schizophrenia patients with poor performance showed

reduced frontal activation. On the other hand, high performing patients, close to healthy

controls, demonstrated enhanced activation. These findings support the hypotheses that

WM deficits in patients with schizophrenia, as also observed in our study, cannot

exclusively be explained by a hypo- or hyperactivation of frontal lobe networks in

- 70 -

patients (Callicott et al., 2003). In our study we could not compare high- with low-

performers afterwards since groups were not adequately balanced after cut-off scoring.

Allen et al. (2007) and Sarfeld et al. (2011) have demonstrated for example that TMS

is able to modulate local field potentials and BOLD-responses. But it seems possible

that outlasting after-effects are more difficult to map than direct effects. Moreover, there

is still no clear knowledge about the time period that rTMS treatment effects would be

detectable. An optimal time schedule is substantially relevant for the outcome. Our

review indicates, as also mentioned in 3.1, discrepancies throughout the literature

concerning the onsets of cognitive testing after rTMS administration. Studies

investigating systematically the duration of the induced cognitive effects were lacking,

but one can assume, based on the effects on psychopathology (e.g. improvement of

mood), that also the cognitive improvement persists for a certain period of time. Bäumer

et al. (2003) systematically evaluated the after-effects of two premotor 1 Hz rTMS on

motor cortex excitability in healthy humans. Direct effects after the first session lasted

for less than 30 min., whereas after the second session at day 2 this effect lasted for at

least 2 hours. Stimulation on day 1 and 7 (with increased decay) only led to a 30 min.

after-effect again. The authors concluded that rTMS evokes cumulative plastic changes

of motor cortex excitability when repeated within 24h but not after 1 week, implying

memory formation after the first train lasting more than a day but less than a week.

Based on these and other results we conducted our fMRI and neuropsychological post-

measure around 1-2 hours after the last rTMS session. However, it is possible that

neuroplastic alterations, as it has been shown for the motor cortex, are not directly

transferable into other brain areas. Results of an rTMS study stimulating over the left

superior temporal area in healthy volunteers indicate dynamic alterations of gray matter

(GM) density after 5 days of real rTMS (1 Hz, 110% of RMT) (May et al., 2007).

These effects were not attended by differences in pure tone audiometry (behavioural

outcome) rather pointing to alterations in auditory processing. Selective gray matter

increase in the target region could not be clearly confirmed to be behaviorally relevant.

Nevertheless, the authors concluded that this period of time corresponds to the onset of

therapeutic effects in neuropsychiatric diseases following rTMS or antipsychotic agents

(Stahl et al., 2001; Tergau et al., 1999). The results underline the cumulative effect of

consecutive rTMS out of the motor cortex and indicate a similar onset of

- 71 -

psychopathological changes and neuroplastic alterations which generally confirms our

methodology.

It still remains possible, that there are no neuroplastic effects following rTMS

intervention in our study. However, given that subtle functional-behavioural changes

due to rTMS occurred but just remained undetected in our study, one should consider

the application of other techniques like EEG, MEG, NIRS or multimodal imaging being

more suitable to detect subtle changes in brain activity. Further, it would be promising

to introduce more specific cognitive performance tests which are more sensitive for

subtle alterations (e.g. computerized tests such as the subtests of the TAP-system,

Zimmermann & Fimm, 1989).

Assuming that high frequency rTMS generally has the potential to facilitate and

consolidate neural processing to a certain extent, it could be worth adding concomitant

cognitive trainings to improve the modulation of complex cognitive functions. A study

by Bentwich et al. (2011) supports the potential of synergistic effects. Results indicate

beneficial effects of rTMS combined with cognitive training (COG) in Alzheimer’s

disease (AD). Patients, treated with cholinesterase inhibitors, were subjected to daily

rTMS-COG sessions for 6 weeks, followed by maintenance sessions (2/week) for 3

months. Six brain regions were stimulated, three of them separately each day. COG

tasks fitted these regions and comprised different verbal, spatial or executive domains

(see Alzheimer Disease Assessment Scale-cognition/ ADAS-cog, Rosen et al., 1984).

Task difficulty was individually adjusted once a week. Overall results showed

significant improvement of about 4 points for ADAS-cog scores after 6 weeks and 4.5

months. An average improvement of less than 2.6 points in ADAS-cog scores was

recorded in studies with the same treatment periods but using COG alone (e.g. Orrell et

al., 2005; Tárraga et al., 2006). Moreover, the average improvement with the currently

approved drugs for AD are about 2.7 ADAS-cog points for a similar time condition

(Birks et al., 2009; for an overview see Bentwich et al., 2011). These results reflect the

impact of rTMS on the potentiation or fascilitation of cognitive training effects. If

replicated in other contexts or disorders results provide future perspectives for target-

oriented cognitive modulation.

In short, the impact of high frequency rTMS on neuronal activation or cognitive

enhancement outlasting the stimulation procedure remains questionable at this time.

However, data are convincing that we should take into account higher cognitive

- 72 -

demands in future studies. Furthermore, we should prove systematically whether

(sequential) bilateral stimulation would be superior to unilateral stimulation with regard

to cognitive improvement. Methodology has to be advanced, measuring instruments to

be more sensitive towards subtle alterations. Importantly, the synergistic effect of rTMS

and cognitive training should be refined in future studies.

3.4 General Limitations

A general limitation concerns the quite low inclusion rate of patients exhibiting more

severe symptoms that is possibly due to the long intervention phase. This may have

contributed to a statistical ceiling effect in the schizophrenia group (as well as minor

task difficulty). Further, sample sizes differed between cognitive subtests with

consequent effects on statistical power. Fortunately, some of the tests will be evaluated

multi-centrically providing increased power. Another restriction may be the relatively

short period of medication stability of 2 weeks before inclusion in our trial.

Nevertheless, active and sham group had balanced medication levels (chlorpromazine

adjusted) at baseline and their doses were stable in the course of the study. A further

limitation may concern the question about optimal stimulation parameters for the

induction of neuroplastic changes. Apart from the stimulation frequency or intensity, it

might be essential to set the optimal inter-train-interval (time between TMS trains/

relaxation time) for plasticity induction. One unresolved issue is our still limited

knowledge about whether these parameters are transferable from the motor cortex to

prefrontal areas.

- 73 -

3.5 Conclusion and Future Perspective

Overall, it still remains possible that repeated rTMS is not able to influence cognitive

performance or underlying activation pattern effectively. However, it seems likely that

some limitations in our study concerning the sample (e.g. size, severity of symptoms/

duration of illness) or some kind of methodology (e.g. sensitivity of measuring

instruments, task difficulty) have contributed to this negative cognitive outcome. In

comparison with the recently published study from Barr et al. (2012), one main point

explaining our negative finding could be the relative ceiling effect of patients and

controls at the task difficulties 1- and 2-back. Given that only deviant activation pattern

and deficient behaviour are able to be modulated with rTMS, it seems possible that the

task demand has to be increased to get more pronounced activation and behavioural

differences. In line with Barr et al. (2012) we therefore assume, that an additional 3-

back task would have been beneficial for the outcome. Further, a (sequential) bilateral

stimulation may provide a promising perspective. Most of the pilot studies investigating

psychopathological or cognitive effects stimulated unilaterally (see 1.2.3, Table 1 or see

2.2 for the review article). However, in the study from Barr et al. (2012) the cognitive-

behavioural effects were not attended by psychopathological improvement. With

respect to our psychopathological results, we were able to show preliminary but trend-

setting findings towards improvement in depressive symptoms and some positive

symptoms. These have to be proven in a larger sample. An important consideration for

future studies could be the systematic investigation of synergistic effects. rTMS has

been shown to facilitate cognitive processes to a certain extent and might thus be able to

potentiate or strengthen specific cognitive training effects.

However, it is obvious that brain stimulation itself is not able to modulate the

complex interplay of functional networks in such a way that would be necessary e.g. for

social interactions. Thus, regarding the spectrum and complexity of psychosis

symptoms, one should take into account psychotherapeutic interventions such as

training of social and emotional competence, interpersonal therapy and training of

problem solving strategies. Another essential part could be anti-stigmatism or

empowerment programs to increase self-esteem in patients. Combining different

interventions may increase the effectiveness.

- 74 -

References

Abi-Dargham A (2004). Do we still believe in the dopamine hypothesis? New data bring

new evidence. Int J Neuropsychop 7(Supplement 1):1-5.

Addington D, Addington J, Maticka-Tyndale E (1993) Assessing depression in

schizophrenia: the Calgary Depression Scale. Br J Psychiatry (Suppl.) 22: 39-44.

Aleman A, Hijman R, de Haan EH, Kahn RS (1999). Memory impairment in schizophrenia:

a meta-analysis. Am J Psychiatry 156:1358-66.

Allen EA, Pasley BN, Duong T, Freeman RD (2007). Transcranial magnetic stimulation

elicits coupled neural and hemodynamic consequences. Science 317:1918-21.

Arnsten AF, Goldman-Rakic PS (1998). Noise stress impairs prefrontal cortical cognitive

function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen

Psychiatry 55(4):362-8.

Baddeley A (1986). Working Memory. Oxford: Oxford University Press.

Baddeley A (2000). The episodic buffer: a new component of working memory? Trends in

Cognitive Science 4:417-23.

Bajbouj M (2007). Psychiatrische Erkrankungen. In H Siebner, U Ziemann (eds.), Das TMS-

Buch. Transkranielle Magnetstimulation (pp 297-303). Heidelberg: Springer Verlag.

Barker AT, Jalinous R, Freeston IL (1985). Non - invasive magnetic stimulation of human

cortex. Lancet 1 (8437):1106-7.

Barr MS, Farzan F, Arenovich T, Chen R, Fitzgerald PB, Daskalakis ZJ (2011). The effect

of repetitive transcranial magnetic stimulation on gamma oscillatory activity in

schizophrenia. PLoS ONE 6(7):1-11.

Barr MS, Farzan F, Rajji TK, Voineskos AN, Blumberger DM, Arenovich T et al. (2012).

Can Repetitive Magnetic Stimulation Improve Cognition in Schiophrenia? Pilot Data

from a Randomized Controlled Trial. Biol Psychiatry.doi:pii: S0006-3223(12)00730-

.10.1016/j.biopsych.2012.08.020. [Epub ahead of print] .

- 75 -

Bäumer T, Lange R, Liepert J, Weiller C, Siebner HR, Rothwell JC et al. (2003). Repeated

premotor rTMS leads to cumulative plastic changes of motor cortex excitability in

humans. NeuroImage 20:550-60.

Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, Khaigrekht M, et al.

(2011). Beneficial effect of repetitive transcranial magnetic stimulation combined with

cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J

Neural Transm 118:463-71.

Boroojerdi B, Phipps M, Kopylev L, Wharton CM, Cohen LG, Grafman J (2001).

Enhancing analogic reasoning with rTMS over the left prefrontal cortex. Neurology

56:526-8.

Burt T, Lisanby SH, Sackheim HA (2002). Neuropsychiatric applications of transcranial

magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol 5:73-103.

Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R et al. (2000).

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia

revisited. Cereb Cortex 10:1078–92.

Callicott JH, Mattay VS, Verschinski BA, Marenco S, Egan MF, Weinberger DR (2003).

Complexity of Prefrontal Cortical Dysfunction in Schizophrenia: More than Up or

Down. American Journal of Psychiatry 160: 2209-15.

Cannon TD, Glahn DC, Kim J, Van Erp TGM, Karlsgodt K, Cohen MS et al. (2005).

Dorsolateral prefrontal cortex activity during maintenance and manipulation of

information in working memory in patients with schizophrenia. Arch Gen Psychiatry

62:1071-80.

Cohen LG, Roth BJ, Nilsson J (1990). Effects of coil design on delivery of focal magnetic

stimulation. Technical considerations. Electroencepahlogr Clin Neurophysiol 75, 350-

57.

Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole et al. (1999). Repetitive

transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a

pilot study. J Neurol Neurosurg Psychiatry 67(1): 129-30.

Cordes J, Brinkmeyer J, Kotrotsios G, Arends M, Mobascher A, Agelink MW et al. (2005)

.The effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on

- 76 -

negative symptoms and electrophysiological correlates of facial affect recognition in

schizophrenia. Schizophr Bull 31(2):510.

Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN)

(Hrsg.) (2006) S3 – Praxisleitlinien in Psychiatrie und Psychotherapie. Band 1,

Behandlungsleitlinie Schizophrenie. Leitlinienprojektgruppe: W. Gaebel, P. Falkai, S.

Weinmann, T. Wobrock. Darmstadt: Steinkopff- Verlag.

D’Esposito M, Postle BR, & Rypma B (2000). Prefrontal cortical contributions to working

memory: Evidence from event-related fMRI studies. Experimental Brain Research 133,

3–11.

Epstein CM, Schwartzberg DG, Davey KR (1990). Localizing the site of magnetic brain

stimulation in human. Neurology 40, 666 – 70.

Epstein CM (2008). TMS stimulation coils. In EM Wassermann, CM Epstein, U Ziemann,

V Walsh, T Paus, SH Lisanby (eds.), The Oxford Handbook of Transcranial Magnetic

Stimulation (pp 24-32). New York: Oxford University Press.

Esser SK, Huber R, Massimini M, Peterson MJ, Ferrarelli F, Tononi G (2006). A direct

demonstration of cortical LTP in humans: a combined TMS/EEG study.

Esslinger C, Schüler N, Sauer C, Gass D, Mier D, Braun U et al., (2012). Induction and

Quantification of Prefrontal Cortical Network Plasticity Using 5 Hz rTMS and fMRI.

Hum Brain Mapp. doi: 10.1002/hbm.22165. [Epub ahead of print].

Evers S, Böckermann I, Nyhuis PW (2001). The impact of transcranial magnetic stimulation

on cognitive processing: an event-related potential study. Neuroreport 12:2915-8.

Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Möller HJ. WFSBP Task Force

on Treatment Guidelines for Schizophrenia (2005) Guidelines for biological treatment

of schizophrenia, part 1: acute treatment of schizophrenia. World J Biol Psychiatry 6

(3): 132-91.

Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Moller HJ. WFSBP Task Force

on Treatment Guidelines for Schizophrenia (2006) Guidelines for biological treatment

of schizophrenia, part 2: long-term treatment of schizophrenia. World J Biol Psychiatry

7(1): 5-40.

- 77 -

Fitzgerald PB, Benitez J, de Castella A, Daskalakis ZJ, Brown TL, Kulkarni J (2006). A

randomized, controlled trial of sequential bilateral repetitive transcranial magnetic

stimulation for treatment-resistant depression. American Journal of Psychiatry 163:88-

94.

Fitzgerald PB, Daskalakis ZJ (2008). A review of repetitive transcranial magnetic

stimulation use in the treatment of schizophrenia. Can J Psychiatry 53(9):567-76.

Floresco SB, Grace AA (2003). Gating of hippocampal-evoked activity in prefrontal cortical

neurons by inputs from the mediodorsal thalamus and ventral tegmental area. J Neurosci

21:2851-60.

Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J et al. (1997). Imaging human

intra-cerebral connectivity by PET during TMS. NeuroReport 8: 2787-91.

Funahashi S (2007). The general purpose working memory system and functions of the

dorsolateral prefrontal cortex. In N Osaka, RH Logie, M D’Esposito (eds.), The

Cognitive Neuroscience of Working Memory (pp. 213-229). New York: Oxford

University Press.

Goff DC, Evins AE (1998) Negative symptoms in schizophrenia: neurobiological models

and treatment response. Harv Rev Psychiatry 6(2): 59-77.

George MS, Belmaker RH (2000) Transcranial magnetic stimulation in neuropsychiatry.

APA, Washington DC.

Green MF, Kern RS, Braff DL, Mintz J (2000). Neurocognitive deficits and functional

outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 26:119-

36.

Grant DA, Berg EA (1993). Wisconsin card sorting test. Göttingen, Hogrefe-Verlag.

Hajak G, Marienhagen J, Langguth B, Werner S, Binder H, Eichhammer P (2004). High-

frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined

treatment and neuroimaging study. Psychol Med 34 (7):1157-63.

Hallett M. (2007). Transcranial magnetic stimulation: a primer. Neuron 55(2):187-99.

Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G (2004). Transcranial magnetic

stimulation in the investigation and treatment of schizophrenia: a review. Schizophr Res

71:1-16.

- 78 -

Hebb DO (1949). The Organization of Behaviour. Wiley, New York.

Heinrichs RW, Zakzanis KK (1998). Neurocognitive deficit in schizophrenia: a quantitative

review of the evidence. Neuropsychol 12(3):426-45.

Henry JD, Crawford JR (2005). A meta-analytic review of verbal fluency deficits in

schizophrenia relative to other neurocognitive deficits. Cogn Neuropsychiatry 10:1-33.

Herold C, Diekamp B, Güntürkün O (2008). Stimulation of dopamine D1 receptors in the

avian fronto-striatal system adjusts daily cognitive fluctuations. Behav Brain Res

194:223-9.

Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS (2000). Transcranial

magnetic stimulation and auditory hallucinations in schizophrenia. Lancet 355:1073-5.

Hoffman RE, Cavus I (2002). Slow transcranial magnetic stimulation, long-term

depotentiation, and brain hyperexcitability disorders. Am J Psychiatry 159: 1093-102.

Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, et al. (2005).

Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety,

efficacy and moderators in a fifty patient sample. Biol Psychiatry 58(2):97-104.

Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F, Carrol K et al. (2003).

Transcranial magnetic stimulation of the left temporoparietal cortex and medication-

resistant auditory hallucinations. Arch Gen Psychiatry 60(1):49-56.

Huber TJ, Schneider U, Rollnik JD (2003). Gender differences in the effect of repetitive

transcranial magnetic stimulation in schizophrenia. J Psychiatry Res 30, 120(1): 103-5.

Huettel SA, Song AW, McCarthy G (eds.) (2004). Functional Magnetic Resonance

Imaging. Sinauer Associates, Inc. Publishers Sunderland, Massachusetts, U.S.A.

Ilic TV, Ziemann U (2005). Exploring motor cortical plasticity using transcranial magnetic

stimulation in humans. Annals of the New York Academy of Sciences 1048:175-84.

Jandl M, Bittner R, Sack A, Weber B, Günther T, Maurer K et al. (2004). Effects of rTMS

on negative symptoms and EEG-topography in schizophrenic patients. European

Psychiatry 19 (Suppl. 1):164.

- 79 -

Jin Y, Potkin SG, Kemp AS, Huerta ST, Alva G, Thai TM et al. (2006). Therapeutic effects

of individualized alpha frequency transcranial magnetic stimulation ({alpha}TMS) on

the negative symptoms of schizophrenia. Schizophr Bull 32(3):556-61.

Johnson MR, Morris NA, Astur RS, Calhoun VD, Mathalon DH, Kiehl KA et al. (2006). A

Functional Magnetic Resonance Imaging Study of Working Memory Abnormalities in

Schizophrenia. Biological Psychiatry 60: 11-21.

Johnson-Selfridge M, Zalewski C (2001). Moderator variables of executive functioning in

schizophrenia: meta-analytic findings. Schizophr Bull 27:305-16.

Kay SR, Fiszbein A, Opler LA (1987). The Positive and Negative Syndrome Scale (PANSS)

for schizophrenia. Schizophrenia Bulltin 13:261-76.

Kellermann T (2007). Evaluation von Gruppenunterschieden bei fMRI- Daten an einem

Beispiel aus der psychiatrischen Forschung (S 13-17). Dissertationsschrift, Rheinisch-

Westfälische Technische Hochschule Aachen.

Kellermann T, Stöcker T, Shah NJ (2008). Methodik der funktionellen

Magnetresonanztomographie. In T Kircher, S Gauggel (Hrsg.), Neuropsychologie der

Schizophrenie. Symptome, Kognition, Gehirn (S 20-35). Heidelberg: Springer-Verlag.

Kimbrell TA, Dunn RT, George MS, Danielson AL, Willis MW, Repella JD et al. (2002).

Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional

cerebral glucose metabolism in normal volunteers. Psychiatry Res 115:101-13.

Klein E, Kolsky Y, Puyerovsky M, Koren D, Chistyakov A, Feinsod M (1999). Right

prefrontal slow repetitive magnetic stimulation in schizophrenia: a double-blind sham-

controlled pilot study. Biol Psychiatry 46: 1451-4.

Klimesch W, Sauseng P, Gerloff C (2003). Enhancing cognitive performance with

transcranial magnetic stimulation at human individual alpha frequency. Eur. J.

Neurosci. 17:1129-33.

Lisanby SH (2008).Therapeutic applications of TMS. In EM Wassermann, CM Epstein, U

Ziemann, V Walsh, T Paus, SH Lisanby (eds.), The Oxford Handbook of Transcranial

Magnetic Stimulation (p 609). New York: Oxford University Press.

- 80 -

Lisanby SH, Luber B, Perera T, Sackeim HA (2000). Transcranial magnetic stimulation:

Applications in basic neuroscience and neuropsychopharmacology. Int J

Neuropsychopharm 3: 259-73.

Maccabee PJ, Amassian VE (2008). Lessons learned from magnetic stimulation of physical

models and peripheral nerve in vitro. In EM Wassermann, CM Epstein, U Ziemann, V

Walsh, T Paus, SH Lisanby (eds.), The Oxford Handbook of Transcranial Magnetic

Stimulation (pp 47-56). New York: Oxford University Press.

Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E et al. (1999).

Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory

task, as measured by fMRI. Biol Psychiatry 45:1128–37.

Maroun M, Richter-Levin G (2003). Exposure to acute stress blocks the induction of long-

term potentiation of amygdale-prefrontal cortex pathway in vivo. J Neurosci 23:4406-9.

Martin JL, Barbanoj MJ, Schlaepfer TE, Clos S, Pérez V, Kulisevsky J, Gironell A (2002).

Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev

2:CD003493.

May A, Hajak G, Gänßbauer S, Steffens T, Langguth B, Kleinjung T, et al. (2007).

Structural Brain Alterations following 5 Days of Intervention: Dynamic Aspects of

Neuroplasticity. Cereb Cortex 17:205-10.

Menon V, Anagnoson RT, Mathalon DH, Glover GH, Pfefferbaum A (2001). Functional

Neuroanatomy of Auditory Working Memory in Schizophrenia: Relation to Positive

and Negative Symptoms. NeuroImage 13:433-46.

Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to

change. Br J Psychiatry 134: 382-9.

Mottaghy FM, Hungs M, Brügmann M, Sparing R, Boroojerdi B,, Foltys H, et al. (1999).

Facilitation of picture naming after repetitive transcranial magnetic stimulation.

Neurology 53:1806-12.

Nahas Z, Molloy M, Risch SC, George MS (2000). TMS in schizophrenia. In: George MS,

Belmaker RH (eds.): Transcranial magnetic stimulation in neuropsychiatry.

Washington, DC: American Psychiatric Press 237– 52.

NIMH. Clinical Gloabal Impression (CGI). 1976.

- 81 -

Novak T, Horacek J, Mohr P, Kopecek M, Rodriguez M, Spaniel F et al. (2006). The

double-blind sham-controlled study of high-frequency rTMS (20Hz) for negative

symptoms in schizophrenia: negative results. Neuro Endocrinol Lett 27(1-2):209-13.

Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al. (1997). Decreased

prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature

385(6617):634-6.

Orrell M, Spector A, Thorgrimsen L, Woods B (2005). A pilot study examining the

effectiveness of maintenance Cognitive Stimulation Therapy (MCST) for people with

dementia. Int J Geriatr Psychiatr 20:446-51.

Overall JE, Gorham DR (1962). The brief psychiatric rating scale. Psychological Reports

1962 vol. 10, 799-812.

Owen AM, McMillan KM, Laird AR, Bullmore E (2005). N-back working memory

paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain

Mapp 25:46-59.

Padberg F, Großheinrich N, Schläpfer TE (2007). Depressive Erkrankungen. In H Siebner,

U Ziemann (eds.), Das TMS-Buch. Transkranielle Magnetstimulation (pp 609-619).

Heidelberg: Springer Verlag.

Paulesu E, Frith CD, Frackowiak RS (1993). The neural correlates of the verbal component

of working memory. Nature (362):342-5.

Paus T, Castro-Alamancos MA, Petrides M (2001). Cortico-cortical connectivity of the

human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial

magnetic stimulation. Eur J Neurosci 14: 1405-11.

Paus T, Jech R, Thompson CJ, Comeau R, Peters T, Evans AC (1997). Transcranial

magnetic stimulation during positron emission tomography: a new method for studying

connectivity of the human cerebral cortex. J Neurosci 17:3178-84.

Perlstein WM, Carter CS, Noll DC, Cohen JD (2001). Relation of prefrontal cortex

dysfunction to working memory and symptoms in schizophrenia. American Journal of

Psychiatry 158:1105-13.

- 82 -

Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J et al. (2005). Slow

transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in

schizophrenia. Biol Psychiatry 57(2):188-91.

Poulet E, Haesebaert F, Saoud M, Suaud-Chagny MF, Brunelin J (2010). Treatment of

schizophrenia patients and rTMS. Psychiatr Danub Suppl 1: 143-6.

Reichenberg A (2010). The assessment of neuropsychological functioning in schizophrenia.

Dialogues Clin Neurosci 12:383-92.

Reis J, Robertson E, Krakauer JW, Rothwell J, Marshall L, Gerloff C et al. (2008).

Consensus: Can tDCS and TMS enhance motor learning and memory formation? Brain

Stimul. 1(4):363-9.

Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E et al. (2009). Noninvasive

cortical stimulation enhances motor skill acquisition over multiple days through an

effect on consolidation. PNAS 106:1590-5.

Reitan RM (1958). The relation of the trail making test to organic brain damage. J of Constr

Psychol. 19:393-4.

Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R et al. (2000). High

frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral

prefrontal cortex in schizophrenic patients. Neuroreport 11(18): 4013 – 5.

Rollnik JD, Seifert J, Huber TJ, Becker H, Panning B, Schneider U, Emrich HM (2001)

Repetitive transcranial magnetic stimulation and electroconvulsive therapy in a patient

with treatment-resistant schizoaffective disorder. Depress Anxiety 13(2): 103-4.

Rosen WG, Mohs RC, Davis KL (1984). A new rating scale for Alzheimer’s disease. Am J

Psychiatr 141(11):1356-64.

Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ et al. (1994).

Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots:

basic principles and procedures for routine clinical application. Report of an IFCN

committee. Electroenceph Clin Neurophysiol 91:79-92.

Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W (1999). Magnetic

stimulation: motor evoked potentials. The International Federation of Clinical

Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 52:97-103.

- 83 -

Rypma, B., Berger, J. S., & D’Esposito, M. (2002). The influence of working-memory

demand and subject performance on prefrontal cortical activity. Journal of Cognitive

Neuroscience, 14, 721–31.

Sachdev P, Loo C, Mitchell P, Malhi G (2005). Transcranial magnetic stimulation for the

deficit syndrome of schizophrenia: a pilot investigation. Psychiatry Clin Neurosci 59(3):

354-7.

Sandbrink F (2008). The MEP in clinical neurodiagnosis. In EM Wassermann, CM Epstein,

U Ziemann, V Walsh, T Paus, SH Lisanby (eds.), The Oxford Handbook of

Transcranial Magnetic Stimulation (pp 24-32). New York: Oxford University Press.

Sarfeld AS, Diekhoff S, Wang LE, Liuzzi G, Uludag K, Eickhoff SB et al. (2011).

Convergence of human brain mapping tools: Neuronavigated TMS parameters and

fMRI activity in the hand motor area. Hum Brain Mapp. Doi: 10.1002/hbm.21272.

Shajahan PM, Glabus MF, Steele JD, Doris AB, Anderson K, Jenkins JA et al. (2002). Left

dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and

functional connectivity, but does not impair cognition in major depression. Prog Neuro-

Psychoph 26:945-54.

Siebner HR, Rothwell J (2003). Transcranial magnetic stimulation: new insights into

representational cortical plasticity. Exp Brain Res148:1-16.

Silver H, Feldman P, Bilker W (2003). Working memory deficit as a core

neuropsychological dysfunction in schizophrenia. Am J Psychiatry 160: 1809–16.

Smith EE, Jonides J (1999). Storage and executive processes in the frontal lobes. Science

283:1657-61.

Smith EE, Jonides J, Koeppe RA (1996). Dissociating verbal and spatial working memory

using PET. Cereb. Cortex 6:11-20.

Speer AM, Kimbrell TA, Wassermann EM, Repella JD, Willis MW, Herscovitch P, Post

RM (2000). Opposite Effects of High and Low Frequency rTMS on Regional Brain

Activity in Depressed Patients. Society of Biological Psychiatry 48:1133-41.

Stahl SM, Nierenberg AA, Gorman JM (2001). Evidence of early onset of antidepressant

effect in randomized controlled trials. J Clin Psychiatry 62(Suppl4):17-23, discussion

37-40.

- 84 -

Strafella AP, Paus T, Barrett J, Dagher A (2001). Repetitive transcranial magnetic

stimulation of the human prefrontal cortex induces dopamine release in the caudate

nucleus. J Neurosci 21 (15):RC 157.

Tárraga L, Boada M, Modinos G, Espinosa A, Diego S, Morera A, et al. (2006). A

randomised pilot study to assess the efficacy of an interactive, multimedia tool of

cognitive stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatr

77(10):1116-21.

Teneback CC, Nahas Z, Speer AM., Molloy M, Stallings LE, Spicer KM et al. (1999).

Changes in prefrontal cortex and paralimbic activity in depression following two weeks

of daily left prefrontal TMS. J Neuropsychiatry Clin Neurosci 11: 426-35.

Tergau F, Naumann U, Paulus W, Steinhoff BJ (1999). Low-frequency repetitive

transcranial magnetic stimulation improves intractable epilepsy. Lancet 353:2209.

Töpper R, Mottaghy FM, Brügmann M, Noth J, Huber W (1998). Facilitation of picture

naming by focal transcranial magnetic stimulation of Wernicke’s area. Exp. Brain Res.

121:371-8.

Ueno S, Tashiro T, Harada K (1988). Localized stimulation of neural tissues by means of a

paired configurationof time-varying magnetic fields. Journal of Applied Physiology 64,

5862-4.

Volz H, Gaser C, Hager F, Rzanny R, Ponisch J, Mentzel H et al. (1999). Decreased frontal

activation in schizophrenics during stimulation with the Continuous Performance Test -

a functional magnetic resonance imaging study. Eur Psychiatry14:17–24.

Vorel SR, Lisanby SH (2008). Therapeutic potential of TMS-induced plasticity in the

prefrontal cortex. In EM Wassermann, CM Epstein, U Ziemann, V Walsh, T Paus, SH

Lisanby (eds.), The Oxford Handbook of Transcranial Magnetic Stimulation (pp 611-

20). New York: Oxford University Press.

Wassermann EM, Lisanby SH (2001). Therapeutic application of repetitive transcranial

magnetic stimulation: a review. Clin Neurophysiol 112: 1367-77.

Winterer G, Weinberger DR (2004). Schizophrenia: Genes, dopamine and cortical signal-

to-noise ratio in schizophrenia. Trends in Neurosci 27:683-90.

- 85 -

Williams GV, Castner SA (2006). Under the curve: critical issues for elucidating D1

receptor function in working memory. Neuroscience 139:263–76.

Wittchen, Kohler, Zauding (1998) (dt. Bearbeitung). Global Assessment Scale of

Functioning (GAF).

Yamanaka K, Yamagata B, Tomioka H, Kawasaki S, Mimura M (2010). Transcranial

magnetic stimulation of the parietal cortex facilitates spatial working memory: near-

infrared spectroscopy study. Cereb Cortex 20:1037-45.

Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, Berardelli A et al.

(2008). Consensus: motor cortex plasticity protocols. Brain Stim 1:164-82.

Zimmermann, P. & Fimm, B. (1989): Neuropsychologische Testbatterie zur Erfassung von

Aufmerksamkeitsdefiziten. Freiburg: Psychologisches Institut der Universität.

Internet Sources:

http://www.bci2000.org/wiki/index.php/User_Tutorial:EEG_Measurement_Setup

- 86 -

Abbreviations ADAS-cog = Alzheimer Disease Assessment Scale-cognition BA = Brodmann area BOLD = blood-oxygen-level-dependent BPRS = Brief Psychiatric Rating Scale CDSS = Calgary Depression Rating Scale for Schizophrenia CGI = the Clinical Global Impression COG = cognitive training DA(1) = dopamine dHb = deoxygenated haemoglobin DLPFC = dorsolateral prefrontal cortex ECT = electroconvulsive therapy EEG = Electroencephalography EF = electric field EMG = electromyography EPSP = excitatory postsynaptic potential ERP = Event-related potential FDI = first-dorsal interosseus muscle fMRI = functional magnetic resonance imaging GABA = gamma-aminobutyric acid GAF = the Global Assessment Scale of Functioning Hb = haemoglobin HC = healthy controls HF = high frequency Hz = Hertz (frequency) ICD-10 = International Statistical Classification of Diseases and Related Health Problems LTD = long-term depression LTP = long-term potentiation MADRS = the Montgomery and Asberg Depression Rating Scale MEG = Magnetoencephalography NIRS = Near Infrared Spectroscopy PANSS = Positive and Negative Syndrome Scale for Schizophrenia PET = Positron-Emission-Tomography PFC = prefrontal cortex rCBF = regional cerebral blood flow RMT = resting motor threshold rTMS = repetitive transcranial magnetic stimulation SGAs = second generation antipsychotics SPECT = single photon emission computed tomography SZ = schizophrenia TAP = Tübinger Aufmerksamkeitsprüfung (a test battery, by Zimmermann & Fimm, 1989) TE = echo time TR = repetition time WHO = World Health Organization WM = working memory

- 87 -

Acknowledgements

Research on working memory and the underlying cerebral network in schizophrenia

would not be possible without the aid of many participating patients and healthy

volunteers. I would like to thank all those participants who supported this work. I am

particularly indebted to PD Dr. Thomas Wobrock and Prof. Dr. Peter Falkai for

providing the opportunity to study this interesting field in combination with TMS and

fMRI. I have very much appreciated their advice, encouragement and support during the

whole phase of this thesis. I thank Prof. Dr. Boris Suchan for his external support and

supervision. For their individual contribution to this thesis and to my emotional

wellbeing I am deeply grateful to Alkomiet Hasan, Petra Bellmann-Knieps, Katrin

Radenbach, Katja Jamrozinski, Maria Keil and last but not least to my dear family. My

special thanks is also extended to all the others who contributed to this work.

- 88 -

Curriculum Vitae

Name Birgit Guse

Date of birth August 15, 1980

Place of birth Duisburg, NRW, Germany

04/11 Lab visit, University of Edinburgh, Scotland

since 2008 Ph.D. student, Institute of Cognitive Neuroscience, Ruhr-

University Bochum and University Medical Centre Goettingen,

Graduate student, Graduate Institute for Clinical Behavioural Therapy

(AWKV Kassel), Cognitive Behavioural Therapy,

Clinical associate, Dpt. for Psychiatry and Psychotherapy, University

Medical Centre, Georg-August-University Goettingen

since 2007 Research assistant, Dpt. for Psychiatry and Psychotherapy,

University Medical Centre, Georg-August-University Goettingen

2007 Diploma

2000-2007 Undergraduate student of Psychology, Ruhr-University Bochum

1991-2000 Secondary school, Geschwister-Scholl Gymnasium Marl

1987-1991 Elementary school, August-Doehr Grundschule Marl

- 89 -

List of Publications

2009

Cordes J, Falkai P, Guse B, Hasan A, Schneider-Axmann T, Arends M, et al. (2009).

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in

residual schizophrenia: rationale and design of a sham-controlled, randomized

multicenter study. European Archives of Psychiatry and Clinical Neuroscience 259

Suppl 2: S189-97.

2010

Guse B, Falkai P, Wobrock T (2010). Cognitive effects of high-frequency repetitive

transcranial magnetic stimulation: a systematic review. Journal of Neural Transmission

117(1): 105-22.

Wobrock T, Hasan A, Malchow B, Wolff-Menzler C, Guse B, Lang N, Schneider-

Axmann T, Ecker UK, Falkai P (2010). Increased cortical inhibition deficits in first-

episode schizophrenia with comorbid cannabis abuse. Psychopharmacology (Berl)

208(3): 353-63.

2011

Hasan A, Kremer L, Gruber O, Schneider-Axmann T, Guse B, Reith W, Falkai P,

Wobrock T (2011). Planum temporale asymmetry to the right hemisphere in first-

episode schizophrenia. Psychiatry Research 193(1): 56-9.

Hasan A, Nitsche MA, Rein B, Schneider-Axmann T, Guse B, Gruber O, Falkai P,

Wobrock T (2011). Dysfunctional long-term potentiation-like plasticity in

schizophrenia revealed by transcranial direct current stimulation. Behavioural Brain

Research 224(1):15-22.

Hasan A, Wobrock T, Falkai P, Schneider-Axmann T, Guse B, Backens M, Ecker UK,

Heimes J, Galea JM, Gruber O, Scherk H (2011). Hippocampal integrity and

neurocognition in first-episode schizophrenia: A multidimensional study. World J Biol

Psychiatry (Epub. ahead of print).

- 90 -

2013

Birgit Guse, Peter Falkai, Oliver Gruber, Heather Whalley, Lydia Gibson, Alkomiet

Hasan et al. (2013). The effect of long-term high frequency repetitive transcranial

magnetic stimulation on working memory in schizophrenia and healthy controls – a

randomized placebo-controlled, double-blind fMRI study. Behavioural Brain Research,

Jan 15, 237:300-7.

- 91 -