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Year: 2009

Cross-modal plasticity in the human thalamus: evidence fromintraoperative macrostimulations

Jetzer, AK; Morel, A; Magnin, M; Jeanmonod, D

Jetzer, AK; Morel, A; Magnin, M; Jeanmonod, D (2009). Cross-modal plasticity in the human thalamus: evidencefrom intraoperative macrostimulations. Neuroscience, 164:1867-1875.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Neuroscience 2009, 164:1867-1875.

Jetzer, AK; Morel, A; Magnin, M; Jeanmonod, D (2009). Cross-modal plasticity in the human thalamus: evidencefrom intraoperative macrostimulations. Neuroscience, 164:1867-1875.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Neuroscience 2009, 164:1867-1875.

26.11.2009

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CROSS-MODAL PLASTICITY IN THE HUMAN THALAMUS: EVIDENCE

FROM INTRAOPERATIVE MACROSTIMULATIONS

A.K. Jetzer 1, A. Morel 2, M. Magnin 3 and D. Jeanmonod 1

1Department of Functional Neurosurgery, Neurosurgery Clinic, University Hospital Zürich,

Sternwartstrasse 6, 8091 Zürich, Switzerland.

2Center for Clinical Research, University Hospital Zürich, Sternwartstrasse 6, 8091 Zürich,

Switzerland.

3INSERM, U879, Bron, F-69677 France.

Corresponding author:

Dr. Anne Morel

Center for Clinical Research

University Hospital Zürich

Sternwartstrasse 6

CH-8091 Zürich

Tel: ++41-44-255-4036

Fax: ++41-44-255-8946

e-mail: anne.morel@usz.ch

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Running title: cross-modal plasticity in the human thalamus

To the Section Editor: Dr. Miles Herkenham, Bethesda, MD, USA

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LIST OF ABBREVIATIONS

Cing Cingulate cortex

CL Central lateral nucleus

CLp Posterior part of CL

CLT CL-Thalamotomy

EEG Electroencephalography

ft Fasciculus thalamicus

fl Fasciculus lenticularis

HFS High frequency stimulation

Ins Insula

LTS Low-threshold calcium spikes

MD Mediodorsal nucleus

MEG Magnetoencephlography

MR Magnetic resonance

NP Neurogenic pain

Npsy Neuropsychatric

OCD Obsessive-compulsive disorder

PD Pakinson’s disease

PF Prefrontal cortex

PM Premotor cortex

POC Posterior complex

PTT Pallidothalamic tractotomy

PuM Medial pulvinar nucleus

SMA Supplementary motor cortex

TCD Thalamocortical dysrhythmia

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TP Temporal pole

VA Ventral anterior nucleus

VLa Ventral lateral anterior nucleus

VLpv Ventral devision of the ventral lateral posterior nucleus

VM Ventral medial nucleus

VPI Ventral posterior inferior nucleus

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ABSTRACT

During stereotactic functional neurosurgery, stimulation procedure to control for proper target

localization provides a unique opportunity to investigate pathophysiological phenomena that

cannot be addressed in experimental setups. Here we report on the distribution of response

modalities to 487 intraoperative thalamic stimulations performed in 24 neurogenic pain (NP),

17 parkinsonian (PD) and 10 neuropsychiatric (Npsy) patients. Threshold responses were

subdivided into somatosensory, motor and affective, and compared between medial (central

lateral nucleus) and lateral (ventral anterior, ventral lateral and ventral medial) thalamic nuclei

and between patients groups. Major findings were as follows: in the medial thalamus, evoked

responses were for a large majority (95%) somatosensory in NP patients, 47% were motor in

PD patients, and 54% affective in Npsy patients. In the lateral thalamus, a much higher

proportion of somatosensory (83%) than motor responses (5%) was evoked in NP patients,

while the proportion was reversed in PD patients (69% motor versus 21% somatosensory).

These results provide the first evidence for functional cross-modal changes in lateral and

medial thalamic nuclei in response to intraoperative stimulations in different functional

disorders. This extensive functional reorganization sheds new light on wide-range plasticity in

the adult human thalamocortical system.

Keywords: neurogenic pain, neuropsychiatry, Parkinson’s disease, plasticity, stereotactic

surgery, thalamocortical dysrhythmia

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INTRODUCTION

Physiological exploration of the human thalamus during stereotactic functional neurosurgery

represents a standard procedure for assessing proper target localization. The selection of

targets is based on anatomical and physiological knowledge of the brain circuits involved in

the different pathologies and their position determined on a stereotactic anatomical atlas.

Microelectrode recordings and stimulations in patients with different functional disorders

have already provided evidence for abnormal activities in both lateral and medial thalamus

(Lenz et al. 1989; Jeanmonod et al. 1994, 1996; Magnin et al. 2000), as well as alterations in

receptive field representations and somatotopic organization in the lateral thalamus after nerve

injury such as limb amputation (Lenz et al. 1994, 1998; Hua et al. 2000; Ohara and Lenz

2001; see also Anderson et al. 2006). These plastic changes resemble those observed in the

human somatosensory cortex (Flor et al. 1998; Elbert and Rockstroh 2004), as well as those

well recognized at cortical and subcortical levels in non-human primates and present also in

other cortical sensory and motor areas (Garraghty and Kaas 1991; Kaas 1991; Buonomano

and Merzenich 1998; Florence et al. 2000; Merzenich 2002). Until now, intraoperative

stimulations in the human thalamus were mostly applied to specific nuclei and most reports

concern unimodal plasticity, although divergent thalamo-cortico-thalamic and thalamo-

reticulo-thalamic pathways provide anatomical support for cross-modality interactions

(Crabtree and Isaac 2002). Indeed, evocation of a strong affective component by stimulation

in the ventroposterior complex was reported in a patient with both motor and panic disorder

(Lenz et al. 1995). In the present study, we addressed the question of how plasticity may be

expressed in different parts of the thalamus and in different functional disorders by

comparing responses to high frequency stimulation (HFS) in two regions of the thalamus

(medial versus lateral nuclei) in neurogenic pain, parkinsonian and neuropsychiatric patients

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undergoing stereotactic neurosurgery. The results show important reorganization of response

modalities in the course of the three diseases, which we propose to be due to a common

thalamocortical dysrhythmic (TCD) process (Llinas et al., 1999; 2005).

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MATERIAL AND METHODS

Patients

Three groups of patients were examined during surgery (Table 1): The first group consisted of

24 patients with NP (11 males and 13 females, aged between 26 and 79 years at the time of

operation). The causal lesion was central in one, peripheral in 20 and mixed in three patients.

Pain duration at the time of the operation varied from one to 29 years. The second group

included 17 patients with PD (12 males and five females, aged between 41 and 73 years at the

time of operation). Two patients had tremor only, 12 tremor and akinesia and three akinesia

alone. At the time of the operation, the duration of the condition varied between four and 21

years. In the third group, 10 patients (six males and four females, aged between 21 and 67

years at the time of the operation) suffered from neuropsychiatric disorders (five patients with

obsessive-compulsive disorder (OCD), two with a combination of OCD and depression, one

with OCD coupled with depression and anxiety, one with psychosis and one with a

combination of OCD, depression, psychosis and anxiety). At the time of operation, disease

duration ranged from seven to 57 years with an average of 20.6 years (Table 1).

Operations

In all patients, chronicity, resistance to drug-therapy and a significant reduction of their

quality of life had been documented before the operation was proposed. Informed consent was

obtained from all patients and procedures were approved by the University Hospital ethics

committee. All operations were conducted under local anesthesia and with magnetic

resonance (MR) and electrophysiological guidance. The electrode reached the computer-

calculated target through a prefrontal approach. Target coordinates were defined on a

stereotactic atlas of the human thalamus (Morel et al. 1997) and were directed at 1) the

posterior central lateral nucleus (CLp), and 2) the pallido-thalamic tract (fasciculi lenticularis,

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fl, and thalamicus, ft) in the fields of Forel. The first operation (CLT, for CL-thalamotomy;

Fig. 1a) was performed in the three groups of patients based on the recruiting properties of CL

neurons through "diffuse" projections to the cortex (Morison and Dempsey 1942; Jones and

Leavitt 1974; Macchi and Bentivoglio 1986) and on the presence of abnormal low threshold

calcium spikes (LTS) bursting activities in these patients (Jeanmonod et al. 1996). The second

operation (PTT, for pallidothalamic tractotomy, Fig. 1b) was performed in PD patients in

whom the overactive pallidothalamic afferents induce excess inhibition in thalamic related

nuclei (Magnin et al. 2000; Aufenberg et al. 2005; Gallay et al. 2008), as well as in a group of

NP patients to decrease thalamic inhibition (Jeanmonod et al. 2001b). Penetrations aiming at

CLp crossed a large extent of the posterior part of the CL nucleus and those aiming at pallido-

thalamic tract reached the target through the ventral anterior (VA), ventral medial (VM)

nuclei (shown in Fig. 1) and ventral lateral anterior (VLa). For every target, one penetration

only was performed.

Stimulation Procedure

During the course of the operation, monopolar macrostimulations (1 ms square pulses at 100

Hz during 30s, Radionics radiofrequency generator, model RFG-3C) were applied every two

millimetres along the penetration. The voltage was slowly increased until the patient reported

a response to the stimulation or a motor response was observed by the three observers present

during the operation. For ethical reasons and to preserve spatial specificity, stimulations did

not exceed three volts. For this study we analysed the stimulation effect which was observed

at the lowest voltage (threshold voltage) in every stimulation point. The number of

stimulation points per penetration were in average 6 in medial thalamus and 4 in lateral

thalamus. At the end of the operation, a radiofrequency thermolesion with a 3-4 mm diameter

and length of 7 mm (for PTT) or 13-14 mm (for CLT) was placed. Two to three days after the

operation, patients underwent a T1 weighed MRI control to visualize the lesion and to

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reconstruct the electrode trajectory by projection onto the atlas (see Fig. 1). The position of

reconstructed penetrations was found within +/- 1.5 mm in lateromedial and anteroposterior

axes from the planned trajectory in agreement with a previous evaluation of our stereotactic

technique (Bourgeois et al. 1999). The precision of the reconstruction was limited by the

definition of the center of the lesion in MRI, the resolution of postoperative MRI for

mediolateral distances, as well as the interindividual anatomical variability (Morel, 2007).

The position of stimulation points in a sample of our NP, PD and Npsy patients is illustrated

in Figure 2.

Table 1 indicates, for each group of patients, the number of targets and stimulation

points in medial and lateral thalamic nuclei. A total of 224 stimulations were analyzed in 24

NP patients, 169 in 17 PD patients, and 94 in 10 Npsy patients. There are more penetrations

than patients because some patients had more than one target (bilateral CLT or PTT, or CLT

plus PTT). Stimulation sites were in the medial (CLp) and lateral (VA, VLa, and VM)

thalamic nuclei, the latter nuclei being explored along the penetration dorsal to the PTT

target. The projection of stimulation points from our reconstructed penetrations is presented

on sagittal atlas plane 7.2 mm lateral to thalamo-ventricular border in Figure 2 (a-c). At this

level, the stimulation sites are shown mainly in the VA and VM nuclei, but few sites were

also obtained at the antero-medial border of the ventral division of the ventral lateral posterior

nucleus (VLpv) (Fig. 2a) and along penetrations through VLa which appears in sagittal plane

L8.1 (see Morel et al., 1997; Morel, 2007). At that level also, the border of CLp with the

mediodorsal nucleus (MD) is displaced more anteriorly and probably includes the points

shown in MD at sagittal level 7.2.

Responses were divided into somatosensory, motor and affective. Threshold

somatosensory responses were reported as a superficial, mainly tingling and sometimes

thermic sensation, or as a deep pressure sensation, rarely as pain. Suprathreshold intensities

produced mostly unchanged sensations, however becoming unpleasant because of their

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intensity. They were thus only applied in the beginning of our experience and were not

considered in this study. For comparison between pain localization and response to

stimulation in NP patients, the whole body was divided into eight regions, namely “face”,

“head and neck”, “superior trunk”, “inferior trunk”, “proximal upper limb”, “distal upper

limb”, “proximal lower limb” and “distal lower limb”. The patient’s pain and reported

sensations during stimulation were projected onto the same eight body regions and compared.

They were rated as either “centered” if they coincided with the pain localization or “surround”

if they projected outside the pain area. Stimulations which evoked a sensation in the pain area

as well as in other body parts were rated as “centered and surround”.

Motor effects were observed on upper and lower extremities and consisted of clonic

or tonic movements in NP and Npsy patients, and of a decrease, suppression or increase of

tremor and/or of distal hypo- or bradykinesia in PD patients. Affective reactions to

stimulation were grouped into “depression/sadness” or “anxiety/fear”. Bimodal responses

(e.g. somatosensory and motor) were counted separately. Comparisons of response modalities

were made 1) between medial and lateral thalamic nuclei, and 2) between patient groups.

The statistical significance of comparisons was evaluated with Wilcoxon rank sum tests for

unpaired data and p< 0.05 was considered as significant.

This test was chosen because of a non-normal distribution of the data. The significance of the

test was calculated on the absolute values, but to ease comparisons, percentages were also

calculated, and their values are given in the text and in Figure 3.

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RESULTS

The results revealed major differences in the distributions of response modalities between

thalamic nuclei and between patient groups (Figs. 2 and 3). In NP patients, the large majority

of all stimulations in medial and lateral nuclei (95% and 83%, respectively) evoked a

somatosensory sensation, while only 7% and 5% (respectively in medial and lateral nuclei)

produced a motor effect. There were no affective responses. In terms of body representation,

31% of somatosensory responses in CLp were “centered”, 22% were “centered and surround”

and 42% were “surround”. In VA, VLa and VM, 47% were “centered”, 6% were “centered

and surround” and 30% were “surround”. The difference was significant (p=0.01) in the

proportion of responses “centered and surround” between lateral and medial nuclei.

In PD patients, 68% of stimulations in CLp and 21% in VA, VLa and VM induced a

somatosensory sensation, with a significant difference (p=0.0004) between the two thalamic

groups. A motor response was observed significantly more often in VA, VLa and VM (69%

of responses) than in CLp (47%) (p=0.032). Neither in CLp nor in VA, VLa and VM did an

affective response occur.

The most significant finding is the much higher proportion of somatosensory (83%)

than motor responses (5%) (p=0.001) evoked in NP patients in the motor VA, VLa and VM

nuclei. Furthermore, in the same nuclei, the proportion was reversed in PD patients with

motor responses more commonly evoked than somatosensory responses (69% versus 21%, p=

0.077). In the CLp, the proportion of somatosensory (95%) versus motor responses (7%)

(p=0.001) found in NP patients was replaced by a smaller ratio in PD patients (68% versus

47%, p=0.270) (Fig. 3).

Affective responses were evoked only in Npsy patients (Figs. 2 and 3) where they

represented 54% of all stimulations in CLp, with 50% resulting in a feeling of fear or anxiety

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and 4% in a feeling of sadness or depression. Other responses in this patient group were

somatosensory (50%) and motor (13 %).

DISCUSSION

Choice of Targets and Anatomical Networks

Early experiences in functional stereotactic neurosurgery, though with limited anatomo-

functional basis and technical support, already provided significant results in different

functional disorders. The thalamus has been from the beginning an important target for

neurogenic pain and motor disorders, and both medial and lateral nuclei were explored (Sano

et al., 1966; Cooper et al. 1969; Goldmann et al. 1992; Gybels et al. 1993; Yamashiro and

Tasker 1994; Burchiel 1995; Velasco et al. 1995; Benabid et al. 1996; Abosch and Lozano

2003). In the medial thalamus, the intralaminar nuclei, including the central lateral and centre

médian nuclei, were chosen in neurogenic pain for their connections with the medial

spinothalamic tract, and more generally for their recruiting properties through "diffuse"

projections to the cortex (Morison and Dempsey 1942; Mehler 1966, 1974; Sano et al. 1966;

Jones and Leavitt 1974; Macchi and Bentivoglio 1986; Jeanmonod et al. 1996, 2001a). With

recent reappraisal of the anatomical boundaries of the CL, particularly its posterior extension

(Hirai and Jones 1989; Morel et al. 1997, Morel 2007) and on the basis of its extensive

projections to the cortex and thalamic reticular nucleus, this nucleus has been re-updated as a

neurosurgical target, alone or in combination with others, for surgical interventions in several

functional disorders (Jeanmonod et al. 1996, 2001a,b, 2003).

The pre-thalamic, pallidothalamic tractotomy (PTT) approach is aimed at interrupting

an increased inhibitory influence onto the thalamus from sensorimotor and associative pallidal

territories, and this with only a small lesion (Fig. 1b and d) (Magnin et al. 2001, Aufenberg et

al. 2005, Gallay et al, 2008). Primarily indicated against Parkinson’s disease, the PTT has also

been performed in a small group of neurogenic pain patients presenting a continuous pain

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component, often of compressive quality, which tends to resist available procedures including

CLT (Jeanmonod et al. 2001b).

These two targets, CLp and the pallidothalamic tract, allowed to explore two largely

distinct anatomical groups of thalamic nuclei, and compare their functional organisation in

different pathological conditions using responses to intraoperative macrostimulations.

Proposed Mechanisms Underlying Thalamocortical Plasticity

The switch of modality according to the symptoms, particularly pronounced in the lateral

thalamic group, implies functional reorganisation of the thalamus due to disease processes. A

thalamocortical dysrhythmic process (TCD) has been proposed (Llinas et al., 1999) for a

whole range of neurological disorders including those described above, and is viewed as

primarily relevant to the observations described in this study. It consists in the protracted

neuronal hyperpolarisation due to disfascilitation or overinhibition of thalamic neurons from

an alteration of cortical, basal ganglia or peripheral inputs, as well as by thalamic lesions. In

this state of hyperpolarisation, thalamic cells produce LTS bursts discharging in the delta-

theta (2.5-5.6Hz) frequency range (Jeanmonod et al., 1996). This thalamic low frequency

rhythmicity recruits, via resonant oscillatory thalamocortical interactions, the related cortical

structures which show increased low frequency theta production as observed with MEG

(Llinàs et al., 1999) and EEG (Sarnthein et al., 2006, 2007). Divergent cortico-thalamic

efferents, particularly to so called “matrix” neurons which project back widely to the cortex

(Jones, 2001), as well as cortico-reticulo-thalamic projections provide the necessary coherent

diffusion of these frequencies to extended thalamic and cortical areas. In the cortex, as a

consequence of the juxtaposition of high and low frequency domains, the next step has been

proposed to be an asymmetrical collateral corticocortical GABAergic inhibition resulting in a

disinhibitory fringe of high frequency excitation, the so-called “edge effect” (Llinàs et al.,

1999, 2005). Low frequency generation is not by itself pathological since it underlies normal

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physiological states such as slow wave sleep (Curro Dossi et al., 1992; Steriade et al., 1993)

and normal cognition (Sarnthein et al., 1998; Klimesch, 1999; Jensen and Tesche, 2002). It is

only the excess and persistent, i.e. unmodulated, production of theta activity that is the basis

of the undesirable (or diseased) TCD state. On one hand, increased theta production correlates

with reduced cortical activation and thus with the appearance of negative symptoms like

akinesia or hypoaesthesia. The consequent increased “edge effect”, on the other hand,

correlates with the appearance of the positive symptomatology (e.g. tremor, neurogenic pain,

hallucinations). It manifests as an increased production of MEG and EEG high frequencies,

and its interfrequency generation is supported by high MEG and EEG coherences between

theta and beta domains (Llinàs et al., 1999; 2005; Sarnthein et al., 2006).

We propose to explain the observed symptom-related plastic modality representation

in the medial (CLp) and lateral (VA/VLa/VM) thalamus on the basis of dynamic changes, for

example long term potentiation (Cooke and Bliss, 2006), imposed by the TCD on the related

thalamocortical networks. One key element for the TCD-related cross-modal effects is the

anatomical divergence of corticothalamic, corticoreticular, reticulothalamic and

thalamocortical connections. This divergence allows to progressively recruit neighbouring

thalamocortical loops into an altered, wide-ranging interplay. That such an interplay indeed

exists has been recently indicated by other studies (Ploner et al. 2006; Jech et al. 2006).

The major thalamocortical networks proposed to be involved in the plastic changes

revealed by thalamic stimulations in the three groups of patients are schematically illustrated

in Figure 4. They are based on connections described mainly in the primate literature. The

presentation of structures as functional units in frames does not imply that every area or

nucleus in a frame receives and sends connections to all partners in the other frame. In

neurogenic pain (NP) (Fig. 4A), two major thalamocortical domains are involved, one linking

cortical pain areas (SII, insula [Ins] and cingulate [Cing] cortex) with the thalamic ventral

posterior inferior (VPI), posterior complex (POC), central lateral (CL) and medial pulvinar

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(PuM) nuclei, the other linking premotor (PM), supplementary (SMA) and prefrontal cortex

(PF) with thalamic VA, VLa and VM nuclei where stimulations are performed. By divergent

thalamocortical (pathway 1), corticothalamic (pathway 2), reticulothalamic (pathway 3) and

corticocortical (pathway 4) connections, the stimulation in the motor thalamus can induce

effects in the modality of the system primarily affected, i.e. the somatosensory system in NP.

The existence of the divergent pathways 1, 2 and 3 has been only partially demonstrated by

anatomical methods. They are included in our scheme because they obey the general

organisation pattern of thalamocortical and corticothalamic divergent projections, allowing,

together with corticocortical interactions, to explain the observed cross-modal effects.

Stimulations in CLp in parkinsonian (PD) patients (Fig. 4B) can have motor effects directly

through its connections with PM, SMA and PF cortex (pathway 1) as well as through

reticulothalamic connections (pathway 3). In similar manner, stimulations in CLp in

neuropsychiatric (Npsy) patients (Fig. 4C) can evoke affective responses through its

connections with associative and paralimbic cortical areas (temporal pole TP, PF, Cing, Ins)

(pathway 1) as well as through reticulothalamic connections (pathway 3). It is important to

note that the posterior part of the CL nucleus (CLp) includes part of the densocellular MD

nucleus defined by others (see Morel et al. 1997).

Mechanisms of Action of HFS

From the stimulations performed during stereotactic surgery to guide electrode placement,

most of the effects were studied in terms of symptom modulation to assess optimal target

position (Takahashi et al. 1998). Fewer studies addressed other aspects, like plasticity, and

these were focused on lateral, somatosensory nuclei (Lenz et al. 1995, 1998; Lenz and Byl

1999). In the present study, the large number of stimulations performed during stereotactic

operations in patients with different syndromes provides a unique opportunity to examine the

distribution of response modalities in the human thalamus and their relation to different

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pathologies. Our stimulation frequency was 100 Hz, in the range of the usual frequencies used

for therapeutic stimulation protocols. Experimental data (Urbano et al. 2002) provide

evidence for a fast (milliseconds) thalamocortical synaptic transmission failure during

stimulations of thalamic nuclei at such frequencies. We propose that the stimulation responses

in this study reflect changes of the low and high frequency interplay in the cortex, altering the

established frequency distribution due to the TCD and thus arousing the observed clinical

manifestations through new cortical frequency distributions. For example, a given low

frequency domain may be joined by an area of stimulation-related synaptic transmission

failure, thus altering the form, extent and localization of the surrounding high frequency

“edge effect”, and leading to the observed stimulation responses. Indeed, a zone of low

frequency and an area of synaptic transmission failure may both reduce the corticocortical

inhibition on their neighbours and thus contribute to the development of a new surrounding

“edge effect” area.

Interpretation of the Results

In the medial thalamus, the dominance of somatosensory responses in all patient groups may

be related at least in part to the anatomical organisation of the CL nucleus, in particular to its

afferents from the medial spinothalamic tract (Mehler 1966, 1974; Hodge and Apkarian1990;

Apkarian and Hodge 1989; Willis and Westlund 1997; Craig et al. 2002; Jones 2002;

Graziano and Jones 2004). This is strengthened by almost pure somatosensory representation

in the postero-inferior part of CLp where spinothalamic afferents enter the nucleus. It can thus

be proposed that CLp is locked in a somatosensory modality on one hand but shows an

impressive plasticity according to TCD on the other. First, the quality and localization of the

evoked somatosensory responses coincide often with that of the pain in NP patients. Second,

motor responses are more often encountered in PD than in the other two groups of patients

(Fig. 3). Third, there is a specific appearance of affective responses observed only in

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neuropsychiatric patients (Figs. 2C and 3). These plastic changes may be explained by the

largely divergent projections of CLp onto parietal, motor and limbic cortices (Fig. 4) (Jones

1985).

In the lateral thalamus (VA, VLa and VM), the dominance of somatosensory

responses in NP patients and of motor responses in PD patients (Fig. 2a and b) suggests no

prevailing fixed modality but a dominant TCD-related plastic phenomenon in the two patient

groups examined. The presence of dominant somatosensory responses in NP patients is

particularly striking because these nuclei receive little, if any, peripheral input (Stepniewska

et al. 2003; Craig 2008) and project dominantly to premotor and supplementary motor cortex

(Matelli and Lupino 1996; Rouiller et al. 1999; Morel et al. 2005). Some factors could lead to

a “misplacement” of the electrode more posteriorly and laterally into VLp or VPL, which

receive somatosensory inputs. The first two factors to mention are the precision of the

reconstruction method, estimated to +/-1.5 mm (see Methods), and the interindividual

anatomical variability: if we cannot exclude some involvement of the VLp, it may not be the

case for VPL, which is too distant posteriorly and laterally (Morel, 2007). A third factor may

be thalamic atrophy, which has been reported in neurogenic pain patients (Apkarian et al.

2004). However, the decrease of gray matter density was significant only in the right thalamus

and our stimulations were distributed in left and right thalami. Finally, taking into

consideration all three factors, a somatosensory dominance should have been also observed in

PD patients, which is not the case (see Fig. 2). Another interpretation for the somatosensory

dominance in the lateral thalamus of NP patients is that the VA, VLa and VM nuclei receive

major inputs from output nuclei of the basal ganglia, i.e. the internal pallidum (to the

parvocellular division of VA and VLa) and the substantia nigra (to VM and the magnocellular

division of VA) (Ilinsky et al. 1985; Parent and Hazrati 1995; Percheron 1996; Sidibé et al.

1997). Since however most if not all of the cortical mantle projects to the basal ganglia,

including somatosensory cortex (Parent and Hazrati 1995), a role of these thalamic nuclei in

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somatosensory and pain processing may be envisaged, supported by involvement of PM and

SMA in brain responses to pain (e.g. Peyron et al. 2000; Bingel et al. 2004). In addition,

nociceptive responses have been reported in the striatum (Chudler and Dong, 1995).This

represents a favourable context for the development of the observed TCD-related plastic

changes.

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CONCLUSION

Comparative study of responses to intraoperative HFS stimulations between two regions of

the thalamus (medial and lateral) and three groups of patients (NP, PD and Npsy) reveals

important cross-modal thalamic reorganizations in the course of the diseases. This plastic

process, extending in broad areas of the hemisphere, can be explained by the divergent

organization of the thalamocortical system and its dysrhythmic state in functional brain

disorders.

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ACKNOWLEGMENTS

We thank V. Streit for her skilful histological work and Th. Dorizzi for help in statistical

analysis.

Funding: Swiss National Science Foundation (31-54179.98, 31-68248.02).

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FIGURE LEGENDS

Figure 1: Sagittal atlas projections of CLT and PTT lesions (gray areas in a and b) as

reconstructed from two-day postoperative sagittal T1-weighted MRI (c and d). Oedema

visible in MRI is not included in the outlined lesions in panels a and b. The pallidothalamic

tract through fasciculi thalamicus (ft) and lenticularis (fl) is represented in blue (panel b).

Horizontal dotted lines (in a and b) represent the stereotactic intercommissural plane.

Abbreviations: AV, anteroventral; CL, central lateral; CLp, posterior part of the CL; CM,

centre médian; LD, lateral dorsal; Li, limitans; MD, mediodorsal; MDpc, parvocellular part of

MD; Pf, parafascicular; PuM, medial pulvinar; R, reticular nucleus; RN, red nucleus; STh,

subthalamic nucleus; VA(pc,mc), ventral anterior (parvo- and magnocellular divisions); VLp

(v,d), ventral lateral posterior (ventral and dorsal divisions); VM, ventral medial; VPMpc,

ventral posterior medial, parvocellular division; ZI, zona incerta. Scale bars: 2 mm (a), 10 mm

(c).

Figure 2: Sagittal atlas projections of response modalities to intraoperative thalamic

stimulations in 4 neurogenic pain (NP), 5 parkinsonian (PD) and 4 neuropsychiatric (Npsy)

patients obtained between sagittal levels L7 and L8. Symbols correspond to different patients

and colour indicates somatosensory (red), motor (green), affective (blue) or bimodal (e.g.

red/green or red/blue) responses. Scale bar (a): 2 mm. Same conventions as in Figure 1.

Figure 3: Distribution of response modalities to stimulation in the medial (CLp) and lateral

(VA, VLa, VM) thalamus. In each group of patients (NP, PD and Npsy) data are expressed in

percentages of the total of stimulations performed in the medial or the lateral. Note that for a

given pathology the sum of the three percentages is not equal to 100% due either to

stimulations without any response or to stimulations evoking more than one response

modality.

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Fig. 4: Schematic representation of the major thalamocortical, corticocortical and

corticothalamic networks involved in the plastic process evoked by thalamic stimulations in

neurogenic pain (A), Parkinson’s disease (B) and neuropsychiatric disorders (C). Color codes

are the same as in Figures 2 and 3, i.e. red for somatosensory/nociceptive, green for motor,

and blue for limbic/paralimbic pathways. Colored arrows designate the connections presumed

to be responsible for the cross-modal responses obtained with thalamic stimulations in the

three chronic pathological situations. See text for more details.

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