TMS in cognitive plasticity and thepotential for rehabilitationSimone Rossi1 and Paolo M. Rossini2,3,4

1Dipartimento di Neuroscienze, Sezione Neurologia, Universita di Siena, Policlinico Le Scotte, Viale Bracci, I-53100 Siena, Italy2Neurologia, Universita Campus Biomedico, Via Longoni 71, Roma, Italy3IRCCS Centro S.Giovanni di Dio-Fatebenefratelli, Via Pilastroni 4, Brescia, Italy4AFaR-Dip.Neuroscienze, Ospedale Fatebenefratelli, Isola Tiberina, Roma, Italy

Cognitive neuroscientists use transcranial magnetic

stimulation (TMS) in several ways, from aiming to

increase understanding of brain–behavior relationships

to transiently improving performance, both in normals

and in patients with neurological and neuropsycho-

logical deficits. Different types of TMS (single-pulse,

paired-pulse, repetitive) are able to interfere with higher

brain functions that require the cooperation of different

brain areas and complex neuronal networks. Currently,

behavioral TMS effects on the brain are usually short-

lived and their underlying mechanisms not yet wholly

understood. However, the aim of using TMS to deve-

lop rehabilitative strategies for motor, perceptive and

cognitive functions represents an intriguing challenge.

Transcranial magnetic stimulation (TMS), a non-invasiveand painless technique that allows researchers to stimu-late discrete brain areas, has been available since the mid1980s [1]. The technique involves delivering a briefmagnetic pulse to the scalp through a coil. This induceselectric currents that produce excitation or inhibition inrestricted pools of superficial cortical neurons underneaththe coil. When applied on the scalp overlying the primarymotor cortex (M1), single-pulse TMS allows routine evalu-ations of the excitability and conductivity of corticospinalmotor pathways. This approach has been largely appliedin investigating movement physiology in the healthy, inpatients with neurological disorders (see [2,3] for compre-hensive clinical reviews) and in post-lesional follow-upstudies of plastic cerebral readaptations [4]. Furthermore,paired-pulse TMS allows the investigation of intracorticalmechanisms of inhibition and facilitation (see Box 1).

In the late 1990s, a new generation of magnetic stimu-lators was introduced, able to deliver rhythmic trains ofseveral stimuli per second, and therefore called repetitiveTMS (rTMS). The terms ‘slow-frequency’ rTMS for rates#1 Hz, and ‘high-frequency’ for those $1 Hz (up to 30 ormore Hz) are generally used. The cut-off at 1 Hz is notentirely arbitrary and empirical, because there is evidencethat slow- and high-frequency stimulations produce rela-tively distinct effects, both on direct measures of brainactivity and on behavior, via psychophysical techniques(see Box 1; [5–7]). Cognitive neuroscientists therefore

have the opportunity to interfere transiently with behav-ior in several domains (i.e. motor, visual, sensory, memory,language). Such an approach can be used not only for abetter understanding of cortical functions (namely, toreveal the causal relationship between the targeted areaand the task under study), but also in attempts to modu-late a given brain function, in healthy people and thosewith pathology, thereby extending the concept of the‘virtual lesion’ patient previously introduced to depict theinterference effects of rTMS [8].

The existing literature indicates that these effects aregenerally short-lived (see Box 1). However, the possibilityof interfering with complex cognitive functions in the longterm opens new strategies for modifying brain–behaviorrelationships, making TMS a hypothetical rehabilitativetool in its own right. Currently, despite fascinating attemptsto use TMS in this way, large-scale applications in clinicalsettings are still lacking. The aim of this review, therefore,is not to encompass the traditional applications that TMShas had in the last ten years of rehabilitative research,namely predicting and following-up functional recoveryand helping to quantify other therapeutic interventions[23]. Rather, we aim to provide pointers towards a betterunderstanding of the current and future uses of TMSin promoting plastic changes that might eventually beexploited in rehabilitative functional recovery programs.

Motor functions

TMS and motor imagery

Neuroimaging has shown that the anatomical neuralsubstrates of motor imagery, a complex cognitive phenom-enon, partly coincide with those of actual movementexecution [24]. TMS provides clues about the temporaldynamics of the brain activity underlying motor imagery.Indeed, following single-pulse TMS over contralateralM1, the amplitude of the motor evoked potential (MEP) ofthose muscles acting as ‘prime movers’ within the motorprogram is increased, both when wrist movements [25,26]or more fine intrinsic hand movements are imagined [27].These effects have hemispheric specificity [26], and areless evident during other non-motor related cognitiveactivities [27,28], presumably owing to the underlyingdesynchronization of the resting EEG rhythm [29]. Suchcorticospinal facilitatory effects indicate that motor imag-ery can induce online synaptic adaptations of M1, leadingCorresponding author: Simone Rossi (Rossisimo@unisi.it).

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to rapid shifts in output representation patterns [30],which can be monitored online by TMS. Behavioral con-sequences are worth considering for rehabilitative strate-gies: for instance, not only does daily mental practice ofindividual finger movements such as when playing thepiano lead to an enlargement of the cortical representationof the muscles involved in the task, but improvements inthe execution on the keyboard are also observed [31]. Thissuggests a progressive ‘motor consolidation’ of the motorsequence, even in the absence of overt motor training.

TMS and ‘motor consolidation’

More direct evidence for a key role of M1 in consolidatingpractice-related performance comes from recent obser-vations: training of thumb movements in a directionopposite to TMS-elicited muscle twitch leads to transientinversion of the stimulus-related direction [32]. RepetitiveTMS applied at 1 Hz – which has inhibitory effects on thestimulated region – applied over M1 after actual practicedisrupts the retention of behavioral improvements in sucha simple motor skill [33]. However, when single-pulseTMS on the contralateral M1 was applied synchronouslywith each directionally specific (voluntarily performed)thumb movement, the encoding of the motor sequence wasenhanced, such that the ‘motor memory’ lasted longer thanafter motor training without TMS [34]. This finding hasclear rehabilitative implications because it suggests thatuse-dependent encoding of a motor task can be improvedby concomitant TMS.

A recent insightful paper [35], however, presents a lessintuitive picture. Here, the authors investigated the effectof a high-frequency, 5-Hz rTMS train over the left M1(of intensity below motor threshold) on force productionduring a contralateral finger-tapping test. The behavioralconsequence was a short-lived force increase, owing to thefact that M1 ipsilateral to the finger tapping probablyhelped to compensate for the transient ‘deficit’, as canhappen in the acute phase of a stroke [36]. However, whenboth motor cortices were simultaneously stimulated –with the aim of additionally disrupting the compensatoryipsilateral M1 activity – the increase in tapping force waseven larger and lasted longer. By investigating intracor-tical inhibition/intracortical facilitation (ICI/ICF) mech-anisms (see Box 1), the authors demonstrated that theeffect of bilateral M1 rTMS exceeded the algebraic sum ofthe separate stimulation of each motor cortex [35]. Hence,simultaneous interference of bilateral M1, as well asdisrupting the translation of the motor program into thedesired force (but surprisingly leaving unaltered the motorconsolidation), also led to a long-lasting overestimation ofthe force actually produced. In other words, the doublerTMS interference induced a sort of ‘trap’ for the brain,with unexpected positive behavioral consequences. Suchan approach, if replicable and applicable in a clinicalcontext, could open new avenues for interventional rehabi-litative strategies aimed at promoting compensatorymechanisms in unaffected cortical areas after stroke.

Slow-rate TMS and motor behavior

With a single exception [37], slow-frequency rTMS hasnot proved able to alter basic motor behavior as tested by

Box 1. Types of TMS stimuli

Single and paired-pulse TMS

A single TMS pulse applied over M1 produces a series of epidurally-

recordable corticospinal volleys (called ‘indirect waves’) that reflect

the trans-synaptic activation of superficial cortical neurons [9]. The

temporal summation of these waves at the spinal motoneuron level

generates the related motor evoked potential (MEP) in contralateral

target muscles. Each MEP, if recorded during a voluntary contraction

of the target muscle, is followed by a suppression of electromyo-

graphic (EMG) activity: a phenomenon known as the ‘silent period’,

which possibly reflects – following an early phase of spinal origin –

the activation of inhibitory (mainly GABAb) interneurons at cortical

level [9].

In the paired-shock method [10], a sub-threshold conditioning

TMS stimulus (CS) precedes a supra-threshold test stimulus (TS)

by a programmable interstimulus interval (ISI) (ranging between

1–15 ms). The amplitude modulation of the TS allows the evaluation

of inhibitory (at shorter intervals) and facilitatory (at longer ISIs)

phenomena taking place intra-cortically, which are probably GABAa

and glutamate-mediated, respectively. These effects are usually

referred to as ICI/ICF curves (intracortical inhibition/intracortical

facilitation) [10]. Putative underlying mechanisms are mostly based

on pharmaco/neurophysiological combined approaches, in which

drugs with experimentally identified mechanisms of action are

administered to volunteers, with the aim of producing specific,

physiologically detectable, changes of MEPs, slow potentials (SPs)

or ICI/ICF curves (see [11,12] for physiologically-oriented reviews).

Slow-frequency rTMSOf potential relevance for rehabilitative purposes is that slow-

frequency rTMS produces several inhibitory effects that can outlast

the period of stimulation for minutes or hours [13,14], although with

inter-individual variability [15]. Long-term depression (LTD) seems a

likely candidate for such relatively long-lasting inhibition of M1 [16],

although direct evidence is still required. Inhibitory changes in

parietal [17] and visual [18] cortices have also been described

following rTMS in healthy subjects, pointing indirectly to similar

mechanisms of action at different cortical levels. However, the oppo-

site happens in migraineurs [19], a finding in line with the concept

that individual ‘reactivity’ to rTMS – and in turn behavioral effects –

might depend on the basal degree of cortical excitability [20].

High-frequency rTMS

Rapid-rate rTMS of M1 mainly shifts cortical excitability towards

excitation [21], to an extent that EMG after-discharges in the target

muscle, or spread to more proximal muscles, can be detected. This

makes rapid-rate rTMS, especially of high intensities and prolonged

trains, potentially epileptogenic. Hence, safety guidelines should be

adhered to both for clinical and research use of TMS [22]. Behavi-

orally, rapid-rate rTMS can be used to transiently interfere with an

ongoing cognitive task by inducing ‘neural noise’,which is random

(or non-synchronous) with respect to the goal-state of the area

stimulated, into the process under study, thereby disrupting task

performance [5]. Attempts to explain how rapid-rate TMS can

transiently enhance some cognitive functions are provided in

the main text.

Sham stimulationThe use of rTMS is associated with several sensory sensations and

sources of distraction potentially able to interfere with the cognitive

task demands [20]. Therefore, it is mandatory to compare any

behavioral effects induced by rTMS of the target brain area with other

stimulation sites (presumed to be mechanistically excluded by the

task demands), or with a sham stimulation. This could be obtained

either by specially-designed coils producing the same physical

effects (i.e. noise) without delivering any energy into the brain, or

by keeping the coil oriented perpendicularly to the targeted area,

therefore minimizing the cortical activation.

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finger tapping or pinching in normal subjects [38–42], butit can modify cortical excitability for a time outlasting theperiod of stimulation (Box 1). Converging evidence fromneuroimaging [42] and brain electrophysiology [39] indi-cates that 15–30 min of 1-Hz rTMS of M1 depresses localsynaptic activity and induces widespread changes in

homologous motor and premotor areas (see Box 2). Thissuggests that rapid rTMS-induced remapping of M1 couldprovide a neural substrate for acute compensatory plas-ticity in response to focal motor lesions. Similarly, slow-frequency rTMS-induced inhibition might also have apotential ‘therapeutic’ counterpart for controlling excessive,

Box 2. Electrophysiological and PET evidence of acute M1 remapping following rTMS

Figure I represents the time course of the movement-related cerebral

potentials (MRCPs) accompanying voluntary right thumb abductions

in different, randomly administered, experimental conditions [39]:

basal, after rTMS over left M1, and after a sham rTMS. Repetitive

TMS consisted of 900 stimuli at 1 Hz, each one producing a muscle

twitch with kinetic characteristics similar to those of the actually

executed movement. A further control condition included 900 voluntary

thumb movements paced at 1 Hz by a metronome (not shown here).

MRCPs reflect the overall excitatory and inhibitory synaptic activity

required for the sequential planning and execution of the move-

ment, in which both SMA (in the initial part) and M1 (close to the

movement onset) are involved. The application of 1-Hz rTMS led to a

significant reduction of ipsi- and contralateral M1 activity, without

changes of kinematics of the produced movements (indeed, for

MRCP computation, only movements with same spatio/temporal

characteristics were selected). A possible interpretation of these

findings is that prolonged rTMS-related muscle twitches might

have induced a sort of motor consolidation, thereby reducing the

demands on motor areas during voluntary production of the same

movement.

At higher spatial resolution, Lee et al. [42] examined how 1-Hz rTMS

changes regional excitability and how the motor system compensates

for these changes. They stimulated left M1 (1800 stimuli, either real or

sham) just below motor threshold; the eight subjects were then scanned

by PET in a block design alternating a baseline ‘rest’ condition with free-

choice movements of the right hand fingers, the frequency of which was

paced by a sound. Regional cerebral blood flow (CBF) – thought to

reflect mainly inhibitory synaptic activity [42], which is metabolically

demanding – significantly increased locally at the stimulation site

and extended to the unstimulated hemisphere, mainly involving the

premotor cortex. Movement-related CBF activity in the unstimulated

pre-motor cortex increased after 1-Hz rTMS. An ad hoc analysis of

effective connectivity confirmed that stimulated M1 became less

responsive to inputs from premotor and mesial motor areas. These

changes, that persisted for at least one hour after the stimulation,

suggest that M1 excitability can be modified, not only by peripheral and

exogenous inputs, but also by central inputs from other cortical areas

(see also [43]). A pre-treatment of M1 with rapid-rate rTMS (i.e. in line

with the experimental concept of ‘priming’) might temporally enhance

inhibitory effects of 1-Hz rTMS [44].

Figure I. (a) Sequential maps of the movement-related cerebral potential (MRCP) at a time close to the EMG onset (from 2200 to 200 ms) of the right thumb in basal

condition (upper line), and after 15 mins of 1-Hz rTMS of the left motor cortex (lower line of maps). The whole time course (from 23800 to 1000 ms) of MRCPs is

shown in the insert for both conditions: (b) where EMG and accelerometric patterns of thumb movements can also be appreciated (note the spatio/temporal similarity

of the movements). Scalp electrodes are placed as in (c), where gray areas represent the regions of interest. Note the amplitude reduction of the cerebral activity

preceding movements, both in the traces and in the maps (the blue-coded areas) and the trend for later SMA activation. Modified from [39], with permission.

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(a) Basal

Basal Real-rTMS

BP onset (C3) BP onset (C3)

EMG right ABP

Accelerometer

Time

–3800 ms 0 1000 ms

C3

C3Cz

CzC4 C4

+11 µV

–200 ms 200 ms

–11 µV

Real-rTMS

EMG onset

(b) (c)

4 µV

1 mV

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involuntary motor activities that are mainly due tosustained hyperexcitability of motor and related areas:for example, reducing dystonic symptoms in the ‘writer’scramp’ syndrome [45] or the cortical epileptic activity ofM1 that drives sub-continuous, contralateral muscletwitches [46], and improving tardive dyskinesia due toprolonged use of neuroleptics [47]. Of course, largercontrolled trials are needed to substantiate these findings.

TMS and emotionally-triggered movements

Another emerging field of research has investigated thestrong anatomico-functional connections of the supple-mentary motor area (SMA) with limbic structures, sug-gesting that the SMA might play a major role in triggeringmovements in response to an emotionally rich cue [48].This has been investigated recently by a paired-pulse TMSapproach (Box 1), in which a conditioning TMS stimulusover the SMA preceded a test stimulus over M1 in thecontext of visually guided motor acts triggered by emo-tional or neutral visual cues [49]. The impact of ‘emotional’or ‘neutral’ visual stimuli was monitored by recordingsympathetic skin responses from the palms. Skin responseswere present only with emotional stimuli. Conditioningof the SMA selectively enhanced M1 excitability in theemotional cues paradigm compared with TMS of M1without conditioning, or with SMA conditioning duringpresentation of neutral cues. The results support the

hypothesis that the SMA might act as a robust interfacebetween motor and limbic systems for processing ofemotionally rich cues for motor acts. Therefore, to raisemaximal facilitation, emotionally rich visual cues couldbe more effective than neutral ones for rehabilitativepurposes in corticospinal tract dysfunction [49].

Sensory functions and neglect

Following earlier studies [50,51], recent research hasfocused on TMS effects on somatosensory areas, to inves-tigate whether interfering with one hemisphere couldsignificantly affect ipsilateral and contralateral sensoryperception during a unimanual or a bimanual stimulationtask (Figure 1, square 2). Several recent observations arerelevant to the prospect of rehabilitation.

In healthy subjects, single-pulse TMS delivered to theright parietal cortex, 20–40 ms after bimanual stimu-lation, interfered with the detection of both contra- andipsilateral tactile stimuli to the fingers, whereas single-pulse TMS delivered to the right parietal cortex 50 msbefore the right tactile stimulus resulted in increasedsensitivity to ipsilateral stimuli. This suggests a TMS-induced disinhibition of the left parietal cortex by right-parietal stimulation [52].

Interestingly, rTMS of right posterior parietal or rightventral occipital lobe produced visual neglect with charac-teristics similar to those of patients with right-hemispheric

Figure 1. TMS and sensory neglect. (a) Theoretical framework of a possible pattern of left- and right-hemisphere contributions to the overall neural representation of ego-

centric space. (i) In normal individuals, the stream of transcallosal modulation is asymmetrically organized: inhibitory connections from the dominant to the non-dominant

hemisphere are stronger, thereby determining a slight hyperorientation of attention towards the right side. (ii) After a right-hemisphere lesion, such as caused by a stroke,

the imbalance between competing systems for lateral orientation results in excessive attention towards the right (ipsilesional) hemispace (dashed arrow), owing to the

unbalanced effect of the left hemisphere. (iii) In right brain-damaged patients, left frontal TMS would interfere with a hypothetical left frontal–right parietal inhibition vector,

with the net effect of a right parietal disinhibition and consequent partial restoration of left extinctions (black arrow). (Modified with permission from [56]). (b) Technical

equipment used for investigations of sensory neglect and extinction. A peripheral electrical stimulator delivering programmable low-voltage electric shocks to the fingers

triggered a transcranial magnetic stimulator (TMS) at appropriate inter-stimulus intervals (ISI) controlled by a timer. (Modified with permission from [52]). (c) Clock drawing

by a right-handed male patient suffering from left sensory neglect due to an ischaemic lesion of the right parietal region lasting some months. Drawings were made 15 days

before (i) and 15 days after (ii) a daily application of 1-Hz rTMS (15 min at 90% of the motor threshold) of the left posterior parietal cortex for two consecutive weeks. Note

the improvement in the detail in the left hemifield. (Modified with permission from [58].)

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– –

Lesi

on

–

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Left hemispatialattention

Right hemispatialattention

Left hemispatialattention

Right hemispatialattention

Left hemispatialattention

Left hemispace Right hemispace

Right hemispatialattention

(a) (b)

(c)

(i)

(i) (ii)

(ii)

(iii)TMS

TMS

Electricalstimulator

ISI timer

–

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lesions [53]. TMS of left-hemispheric frontal eye fieldsselectively facilitated responses to visual targets in theright hemifield, whereas bilateral effects were observedwhen TMS was delivered over the right hemisphere [54].Together, these findings suggest that the representationsof both the contra- and ipsilateral hemispaces are greaterin the right hemisphere [51,52] and that there is a ‘dorsal–near space/ ventral–far space’ segregation of processing inthe visual system that supports a dissociation betweenvisual neglect in near and far space seen in patients withdifferent types of right-hemispheric lesions.

The effects of paired-pulse TMS on contralateral tactileperception in normal subjects have been investigated via aprotocol in which the test stimulus was given after a single,fixed delay of 40 ms after the tactile stimulus [55]. Here,the conditioning TMS stimulus preceded the test stimulusat different inter-stimulus intervals (ISI) (ranging from1–15 ms) in different blocks of trials. Intensities werechosen according to the ICI/ICF curve originally describedfor M1 [10]. Results showed that paired-TMS stimuli overthe parietal cortex disrupted contralateral tactile detec-tion with a 1-ms ISI, and facilitated it with a 5-ms ISI. Thisproduces an ICI/ICF curve peaking differently from theone in the motor cortex, when intracortical facilitationoccurs at an ISI of about 10 ms [10].

Extinction, a clinical condition that can arise following aunilateral hemispheric lesion, causes a specific failure toperceive a contralesional sensory stimulus, only when thatstimulus is delivered simultaneously with another ipsi-lesional stimulus. Studies were carried out in patientswith right brain damage (RBD) due to stroke, to assess twomain questions: (1) are single- and paired-pulse TMS of theunaffected hemisphere able to modulate contralesionalextinction in patients with unilateral lesions?; and (2) doesleft-hemispheric paired-pulse TMS induce different effectson right tactile perception in RBD patients versus controls[56]? Briefly, the analysis focused on the effects of paired-pulse TMS at different ISIs over the left parietal andfrontal cortices, on ipsilesional (¼right) tactile detection,comparing the patients’ performance with that of a controlgroup, during unimanual (when no extinction was observed)and bimanual (when contralesional extinction emerged)tactile discrimination tasks. The transient disruption ofthe unaffected (left) hemisphere – during frontal-lobestimulation – restored the distribution of attention to thecontralesional side of space, thereby transiently improvingextinction phenomena. These findings support the modelof hemispheric imbalance, with disinhibition of the healthyhemisphere being the physiological basis of the ipsi-lesional (right hemispace) hyperattention in extinctionand neglect syndrome (Figure 1, square 1). At a mechan-istic level, TMS of the left frontal areas could transientlyblock ‘attentional’ neurones in the unaffected hemisphere,therefore transiently restoring a nearly normal trans-callosal modulation. As a general effect, this procedureis reorienting spatial attention toward the left hemi-space and might be proposed either as a test forprognosticating recovery or as a rehabilitation tool(Figure 1, square 3; [17,57,58]).

Within this research frame, the idea of testing thechronometry of spatial attention [59] by evaluating

whether the effects of left parietal and frontal TMSon contralesional extinction appear at different time-intervals in RBD patients was addressed. The meanpercentage of contralesional extinctions (TMS versusbaseline) for single or paired-pulse parietal TMS, witheither 1 ms or 10 ms ISI between conditioning and teststimuli, was measured in RBD patients. Left parietal andfrontal paired TMS had different effects on left extinction,depending on the ISI and on the time of application: with a1-ms ISI, the improvement in extinction was greater thanthat induced by single-pulse TMS, whereas with a 10-msISI, a complete reversal of the effects of single-pulse TMSoccurred. Thus, TMS effects on the parietal cortex beganearlier than those on the frontal cortex [59].

Paired-TMS has also been used to unmask the inhi-bitory and/or excitatory mechanisms of spatial attention[60]. Again, the performance of RBD patients and controls(i.e. a right tactile perception task during unimanualand bimanual stimulation) was compared: here, pairs ofconditioning–test TMS stimuli with a 1-ms ISI precededthe sensory discrimination task by 30 ms. In controls, thisdisrupted right tactile perception more than single-pulseTMS; in the patients, left paired-pulse TMS simplyaffected right tactile perception as much as single-pulseTMS. During unimanual right stimulation, both singleand paired-pulse TMS had the same effect in patients andcontrols. It was concluded that the basic mechanism ofpaired-pulse TMS is probably intact in patients, but itsperception is altered by concurrent left-sided stimulation.

Taken together, such experimental frameworks seem ofinterest in developing innovative rehabilitation strategiesfor extinction and neglect symptoms, and could theoretic-ally be extended to other rehabilitative procedures dealingwith space and body perception.

Reasoning, memory and other cognitive activities

It is known that rTMS of the dorsolateral prefrontal cortextransiently impairs encoding and retrieval mechanisms inhuman memory when TMS is coincident with either visuo-spatial [61] or verbal stimuli [62,63], suggesting a causalrole for this region in the long-term memory process.Interference with rTMS is therefore complementary tomore traditional neuroimaging studies based on haemo-dynamic (fMRI) or metabolic (PET) approaches to cogni-tive challenges. However, it should be kept in mind thatthe same kind of rTMS (usually a high-frequency train)delivered on the same region (left prefrontal cortex) onhealthy subjects, can also enhance, rather than disrupt,cognitive performance. These effects include selectiveshortening of picture naming [64] and action namingwithout changing verbal reaction times for naming objects[65], improving subjects’ speed at finding the solution to areasoning puzzle [66], and improving performance on achoice reaction task [67]. Developing theories that try toexplain these apparent discrepancies have given relevanceto the behavioral context in which TMS over a given regionis applied [20,54,68–70]. It can be hypothesized for examplethat rTMS – by shifting the level of cortical excitability –might allow either more or less access (by interfering, forexample, with the functioning of local inhibitory circuits)to brain networks relevant for the experimented task.

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These effects might vary depending on the timing of theTMS stimulation and on the hierarchical role of the brainarea stimulated within the whole functional networkunderpinning the function under investigation. Thismechanism would also partly explain why a specific levelof (pre-)activation of a given brain region would be neededto obtain the maximal behavioral benefit from TMS [21].

Another reasonably promising field for TMS in cogni-tive rehabilitation is the use of EEG individual a frequency(IAF) as a ‘physiological template’ to set the best tuning ofrTMS for inducing transient improvements of cognitiveperformance [71]. When rTMS was delivered over the rightparietal cortex at IAF (usually 10–12 Hz) þ 1 Hz, thecombined increase of the a power (which is generallyrelated to good cognitive performance) was paralleled by ashortening of the time required to successfully complete apsychophysical task of mental rotation. Synchronicitybetween rTMS and EEG rhythms seems, therefore, anattractive technique, but further studies are needed toinvestigate whether and how this approach could haverehabilitative effects on patients with cognitive impairment(and concomitant changes in their resting brain activity).

Recent efforts in many laboratories are now directed atunderstanding the potential of daily applications of rTMSin treating drug-resistant depression and other psychi-atric diseases [72], acute or chronic pain [73,74], tinnitus[75] and epilepsy [12]. These and other applications(see [14]) point to rTMS as a true therapeutic tool asopposed to a merely rehabilitative one. Much remains to belearned in this burgeoning field.

Conclusions

There are exciting prospects for the use of TMS as a tool topromote changes of brain activity paralleled by behavioralimprovements, although, at present, these are generallyshort-lived. However, a growing body of evidence is con-verging on the possibility that TMS induces an exogenousplastic rearrangement of synaptic efficacy in the stimu-lated network. Most evidence comes from studies onsensorimotor areas, but the principles are probablyequally applicable to networks subserving cognition,emotion and mood regulation. Future work on TMS as arehabilitative tool in cases of cognitive impairmentrepresents a challenge that might be as consequential asit is exciting (see also Box 3).

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Box 3. Questions for future research

† What are the fundamental mechanisms (and precise safety limits)

by which rTMS modifies brain activity and induces behavioral

improvements, both in the short and the long term? An under-

standing of these issues requires further parallel experiments in

animals and humans.

†Modifying brain–behavior relationships might lead to maladaptive

rather than beneficial effects in the long term. Future studies should

address these possibilities, which on the basis of current knowledge

of TMS/brain mechanisms of action, cannot be excluded a priori.

What are the ethical questions raised by long-term effects?

†What can we explain of the psychological mechanisms of plasticity

and recovery?

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