The expression of GABA receptors in the human auditory cortex

Abstract : GABA, the primary inhibitory neurotransmitter, and its receptors play an important role in modulating neuronal activity in the central nervous system and are implicated in many neurological disorders. In this study, GABAA and GABAB receptor subunit expression was visualized by immunohistochemistry in human auditory areas TC (= primary auditory area), TB, and TA. Both hemispheres from nine neurologically normal subjects and from four patients with subacute or chronic stroke were included. In normal brains, GABAA receptor subunit (α1, α2, & β2/3) labeling produced neuropil staining throughout all cortical layers as well as labeling fibers and neurons in layer VI for all auditory areas. Densitometry profiles displayed differences in GABAA subunit expression between primary and non-primary areas. In contrast to the neuropil labeling of GABAA subunits, GABAB1 and GABAB2 subunit immunoreactivity was revealed on neuronal somata and proximal dendritic shafts of pyramidal and non-pyramidal neurons in layers II-III, more strongly on supra- than in infragranular layers. No differences were observed between auditory areas. In stroke cases, we observed a downregulation of the GABAA receptor α2 subunit in granular and infragranular layers, while the other GABAA and the two GABAB receptor subunits remained unchanged. Our results demonstrate a strong presence of GABAA and GABAB receptors in the human auditory cortex, suggesting a crucial role of GABA in shaping auditory responses in the primary and non-primary auditory areas. The differential laminar and area expression of GABAA subunits that we have found in the auditory areas and which is partially different from that in other cortical areas speaks in favor of a fine turning of GABA-ergic transmission in these different compartments. In contrast, GABAB expression displayed laminar, but not areal differences; its basic pattern was also very similar to that of other cortical areas, suggesting a more uniform role within the cerebral cortex. In subacute and chronic stroke, the selective GABAA α2 subunit downregulation is likely to influence postlesional plasticity and susceptibility to medication. The absence of changes in the GABAB receptors suggests different regulation than in other pathological conditions, such as epilepsy, schizophrenia or bipolar disorder, in which a downregulation has been reported. Résumé : GABA, le principal neurotransmetteur inhibiteur, et ses récepteurs jouent un rôle important en tant que modulateur de l'activité neuronale dans le système nerveux central et sont impliqués dans de nombreux désordres neurologiques. Dans cette étude, l'expression des sous-unités des récepteur GABAA et GABAB a été visualisée par immunohistochimie dans les aires auditives du cortex humains: le TC (= aire auditif primaire), le TB, et le TA. Les deux hémisphères de neuf sujets considérés normaux du point de vue neurologique et de quatre patients ayant subis un accident cérébro-vasculaire et se trouvant dans la phase subaiguë ou chronique étaient inclues. Dans les cerveaux normaux, les immunohistochimies contre les sous-unités α1, α2, & β2/3 du récepteur GABAA ont marqué le neuropil dans toutes les couches corticales ainsi que les fibres et les neurones de la couche VI dans toutes les aires auditives. Le profile densitométrique montre des différences dans l'expression des sous-unités du récepteur GABAA entre les aires primaires et non-primaires. Contrairement au marquage de neuropil par les sous-unités du recepteur GABAA, 1'immunoréactivité des sous-unités GABAB1 et GABAB2 a été révélée sur les corps cellulaires neuronaux et les dendrites proximaux des neurones pyramidaux et non-pyramidaux dans les couches II-III et est plus dense dans les couches supragranulaires que dans les couches infragranulaires. Aucune différence n'a été observée entre les aires auditives. Dans des cas lésionnels, nous avons observé une diminution de la sous-unité α2 du récepteur GABAA dans les couches granulaires et infragranulaires, alors que le marquage des autres sous-unités du récepteur GABAA et des deux sous-unités de récepteur GABAB reste inchangé. Nos résultats démontrent une présence forte des récepteurs GABAA et GABAB dans le cortex auditif humain, suggérant un rôle crucial du neurotransmetteur GABA dans la formation de la réponse auditive dans les aires auditives primaires et non-primaires. L'expression différentielle des sous-unités de GABAA entre les couches corticales et entre les aires auditives et qui est partiellement différente de celle observée dans d'autres aires corticales préconise une modulation fine de la transmission GABA-ergic en ces différents compartiments. En revanche, l'expression de GABAB a montré des différences laminaires, mais non régionales ; son motif d'expression de base est également très semblable à celui d'autres aires corticales, suggérant un rôle plus uniforme dans le cortex cérébral. Dans les phases subaiguë et chronique des accidents cérébro-vasculaires, la diminution sélective de la sous-unité α2 du recepteur GABAA est susceptible d'influencer la plasticité et la susceptibilité postlésionnelle au médicament. L'absence de changement pour les récepteurs GABAB suggère que le récepteur est régulé différemment après un accident cerebro-vasculaire par rapport à d'autres conditions pathologiques, telles que l'épilepsie, la schizophrénie ou le désordre bipolaire, dans lesquels une diminution de ces sous-unités a été rapportée.

Brain aging in the oldest-old.

Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD) decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA) fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions were also significantly lower than those reported in younger AD cases. Overall, there is evidence that pathological substrates of cognitive deterioration in the oldest-old are different from those observed in the younger-old. Microvascular parameters such as mean capillary diameters may be key factors to consider for the prediction of cognitive decline in the oldest-old. Neuropathological particularities of the oldest-old may be related to "longevity-enabling" genes although little or nothing is known in this promising field of future research.

Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro.

Linking the structural connectivity of brain circuits to their cooperative dynamics and emergent functions is a central aim of neuroscience research. Graph theory has recently been applied to study the structure-function relationship of networks, where dynamical similarity of different nodes has been turned into a "static" functional connection. However, the capability of the brain to adapt, learn and process external stimuli requires a constant dynamical functional rewiring between circuitries and cell assemblies. Hence, we must capture the changes of network functional connectivity over time. Multi-electrode array data present a unique challenge within this framework. We study the dynamics of gamma oscillations in acute slices of the somatosensory cortex from juvenile mice recorded by planar multi-electrode arrays. Bursts of gamma oscillatory activity lasting a few hundred milliseconds could be initiated only by brief trains of electrical stimulations applied at the deepest cortical layers and simultaneously delivered at multiple locations. Local field potentials were used to study the spatio-temporal properties and the instantaneous synchronization profile of the gamma oscillatory activity, combined with current source density (CSD) analysis. Pair-wise differences in the oscillation phase were used to determine the presence of instantaneous synchronization between the different sites of the circuitry during the oscillatory period. Despite variation in the duration of the oscillatory response over successive trials, they showed a constant average power, suggesting that the rate of expenditure of energy during the gamma bursts is consistent across repeated stimulations. Within each gamma burst, the functional connectivity map reflected the columnar organization of the neocortex. Over successive trials, an apparently random rearrangement of the functional connectivity was observed, with a more stable columnar than horizontal organization. This work reveals new features of evoked gamma oscillations in developing cortex.

Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925).

INTRODUCTION: The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment. PATIENTS AND METHODS: At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by chi(2) tests and logistic regression models in all the 3,866 of 4,004 patients eligible to the trial who received the allocated treatment. RESULTS: Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities. CONCLUSIONS: IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia.

The neurochemical profile of the cortex develops in a region and time specific manner, which can be distorted by psychiatric and other neurological pathologies. Pre-clinical studies often involve experimental mouse models. In this study, we determined the neurochemical profile of C57BL/6 mice in a longitudinal study design to provide a reference frame for the normal developing mouse cortex. Using in vivo proton NMR spectroscopy at 14 T, we measured the concentrations of 18 metabolites in the anterior and posterior cortex on postnatal days (P) 10, 20, 30, 60 and 90. Cortical development was marked by alterations of highly concentrated metabolites, such as N-acetylaspartate, glutamate, taurine and creatine. Regional specificity was represented by early variations in the concentration of glutamine, aspartate and choline. In adult animals, regional concentration differences were found for N-acetylaspartate, creatine and myo-inositol. In this study, animals were exposed to recurrent isoflurane anaesthesia. Additional experiments showed that the latter was devoid of major effects on behaviour or cortical neurochemical profile. In conclusion, the high sensitivity and reproducibility of the measurements achieved at 14 T allowed us to identify developmental variations of cortical areas within the mouse cortex.

Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex.

We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutations in some clock genes modify the markers of sleep homeostasis and an increase in homeostatic sleep drive alters clock gene expression in the forebrain. Here, we investigate a possible mechanism by which sleep deprivation (SD) could alter clock gene expression by quantifying DNA-binding of the core-clock transcription factors CLOCK, NPAS2, and BMAL1 to the cis-regulatory sequences of target clock genes in mice. Using chromatin immunoprecipitation (ChIP), we first showed that, as reported for the liver, DNA-binding of CLOCK and BMAL1 to target clock genes changes in function of time-of-day in the cerebral cortex. Tissue extracts were collected at ZT0 (light onset), -6, -12, and -18, and DNA enrichment of E-box or E'-box containing sequences was measured by qPCR. CLOCK and BMAL1 binding to Cry1, Dbp, Per1, and Per2 depended on time-of-day, with maximum values reached at around ZT6. We then observed that SD, performed between ZT0 and -6, significantly decreased DNA-binding of CLOCK and BMAL1 to Dbp, consistent with the observed decrease in Dbp mRNA levels after SD. The DNA-binding of NPAS2 and BMAL1 to Per2 was also decreased by SD, although SD is known to increase Per2 expression in the cortex. DNA-binding to Per1 and Cry1 was not affected by SD. Our results show that the sleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA-binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadian changes in DNA-binding of core clock components in tissues peripheral to the suprachiasmatic nuclei could, in fact, be sleep-wake driven.

Demyelination in mild cognitive impairment suggests progression path to Alzheimer's disease.

The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.

Connectome alterations in schizophrenia

Introduction : DTI has proven to be an exquisite biomarker of tissue microstructure integrity. This technique has been successfully applied to schizophrenia in showing that fractional anisotropy (FA, a marker of white matter integrity) is diminished in several areas of the brain (Kyriakopoulos M et al (2008)). New ways of representing diffusion data emerged recently and achieved to create structural connectivity maps in healthy brains (Hagmann P et al. (2008)). These maps have the capacity to study alterations over the entire brain at the connection and network level. This is of high interest in complex disconnection diseases like schizophrenia. We report on the specific network alterations of schizophrenic patients. Methods : 13 patients with chronic schizophrenia were recruited from in-patient, day treatment, out-patient clinics. Comparison subjects were recruited and group-matched to patients on age, sex, handedness, and parental social economic-status. This study was approved by the local IRB and subjects had to give informed written consent. They were scanned with a 3T clinical MRI scanner. DTI and high-resolution anatomical T1w imaging were performed during the same session. The path from diffusion MRI to a multi-resolution structural connection matrices of the entire brain is a five steps process that was performed in a similar way as described in Hagmann P et al. (2008). (1) DTI and T1w MRI of the brain, (2) segmentation of white and gray matter, (3) white matter tractography, (4) segmentation of the cortex into 242 ROIs of equal surface area covering the entire cortex (Fig 1), (5) the connection network was constructed by measuring for each ROI to ROI connection the related average FA along the corresponding tract. Results : For every connection between 2 ROIs of the network we tested the hypothesis H0: "average FA along fiber pathway is larger or equal in patients than in controls". H0 was rejected for connections where average FA in a connection was significantly lower in patients than in controls. Threshold p-value was 0.01 corrected for multiple comparisons with false discovery rate. We identified consistently that temporal, occipito-temporal, precuneo-temporal as well as frontal inferior and precuneo-cingulate connections were altered (Fig 2: significant connections in yellow). This is in agreement with the known literature, which showed across several studies that FA is diminished in several areas of the brain. More precisely, abnormalities were reported in the prefrontal and temporal white matter and to some extent also in the parietal and occipital regions. The alterations reported in the literature specifically included the corpus callosum, the arcuate fasciculus and the cingulum bundle, which was the case here as well. In addition small world indexes are significantly reduced in patients (p<0.01) (Fig. 3). Conclusions : Using connectome mapping to characterize differences in structural connectivity between healthy and diseased subjects we were able to show widespread connectional alterations in schizophrenia patients and systematic small worldness decrease, which is a marker of network desorganization. More generally, we described a method that has the capacity to sensitively identify structure alterations in complex disconnection syndromes where lesions are widespread throughout the connectional network.

MOLECULAR REORGANIZATION FOLLOWING SENSORY STIMULATION IN THE ADULT MOUSE BARREL CORTEX

Sensory information is an important factor in shaping neuronal circuits during development and adulthood. In the barrel cortex of adult rodents, cells from layer IV are able to adapt their functional state to an increased flow of sensory information from the mystacial whisker follicles. Previous studies in our group have shown that whisker stimulation induces the formation of inhibitory synapses in the corresponding barrel (Knott et al., 2002) and decreases neuronal responses toward the deflection of the stimulated whisker (Quairiaux et al., 2007). Together these observations have turned the barrel cortex into a model to study homeostatic plasticity. At the cellular level, neuronal activity triggers intracellular signaling cascades leading to a transcriptional response. To further characterize the molecular pathways involved in the synaptic changes after whisker stimulation in the adult mouse, a previous doctoral student in our group performed a microarray analysis on laser-dissected barrels in sections through layer IV. This study identified the regulation (up and down) of a series of genes in the stimulated barrels (thesis of Johnston-Wenger, 2010). We here focused on ten genes that presented the highest fold change according to the microarray analysis. Out of these genes, 7 are known as neuronal activity-dependent genes (Tnncl, Nptx2, Sorcs3, Ptgs2, Nr4a2, Npas4 and Adcyapl) whereas three have so far not been related to neuronal plasticity (Scn7a, Pcdhl5 and Cede3). The study aimed at confirming the results of the microarray analysis and localizing molecular modifications in the stimulated barrel column at the cellular level. In situ hybridization for Pcdhl5 after different periods of whisker stimulation (3, 6, 9, 15, 24 hrs) allowed us to confirm that the 1.25 fold change used for the microarray analysis is an appropriate threshold for considering a regulation significant after sensory-stimulation. Moreover, we confirmed with in situ hybridization a significant upregulation of the genes of interest in the stimulated barrels. In situ hybridization and immunohistochemistry allowed us to observe the distribution of the genes of interest and the corresponding protein products at the cellular level. Three observations were made: 1) alterations of the expression was restricted to the stimulated barrels for all genes tested; 2) within a barrel column not all cells responded to whisker stimulation with an altered gene expression; 3) in the stimulated barrels, two different patterns of mRNA and protein expression can be distinguished. We hypothesize that this segregation of the activity-induced gene expression reflects the segregation of the two principal thalamocortical pathways conveying the sensory information to the barrel cortex. Moreover, only neurons reaching the critical threshold will modify their gene expression program resulting in structural as well as physiological modifications that prevent the subsequent propagation of the excess of excitation to the postsynaptic targets. The activity-induced gene expression is therefore adapted in a cell-type-specific manner to induce a homeostatic response to the entire neuronal network involved in the integration of the sensory information. This to our knowledge the first study showing the distinct, but complementary contribution of the two thalamocortical pathways in experience-dependent plasticity in the adult mouse barrel cortex. -- L'information sensorielle nous permet de continuellement façonner nos circuits neuronaux autant durant le développement qu'à l'âge adulte. Chez le rongeur l'information sensorielle perçue par les vibrisses est intégrée au niveau du cortex somatosensoriel primaire (appelé en anglais « barrel cortex ») dont les cellules de la couche IV sont capables d'adapter leur état fonctionnel en réponse à une augmentation d'activité neuronale. Ce modèle expérimental a permis à notre groupe de recherche d'observer des changements rapides du circuit neuronal en fonction de l'activité sensorielle. En effet, la stimulation continue d'une vibrisse d'une souris adulte pendant 24 heures induit non seulement un remaniement synaptique (Knott et al., 2002), mais également des changements physiologiques au niveau des neurones du tonneau correspondant (Quairiaux et al., 2007). Ces observations nous permettent d'affirmer que le « barrel cortex » est un modèle approprié pour y étudier la plasticité synaptique. Au niveau cellulaire, l'activité neuronale déclenche des cascades de signalisation intracellulaire résultant en une réponse transcriptionnelle. Afin de caractériser les voies moléculaires impliquées dans la plasticité synaptique, une puce à ARN nous a permis de comparer l'expression de gènes entre un tonneau correspondant à une vibrisse stimulée et un tonneau d'une vibrisse non-stimulée (Nathalie). Cette analyse a révélé un certain nombre de gènes régulés de manière positive ou négative par l'augmentation de l'activité neuronale. Nous nous sommes concentrés sur 10 gènes dont l'expression est fortement régulée. L'expression de sept d'entre eux a déjà été démontrée comme dépendante de l'activité neuronale (Tnncl, Nptx2, Sorcs3, Ptgs2, Nr4a2, Npas4 otAdcyapl) alors que l'expression des trois autres (Scn7a, Pcdhl5 et Cedei) n'a pour le moment pas encore été liée à la plasticité neuronale. Le but de cette thèse est de confirmer les résultats de la puce à ARN et de déterminer dans quel type cellulaire ces gènes sont exprimés. L'hybridation in situ pour le gène Pcdhl5, après différentes périodes de stimulation des vibrisses (3, 6, 9, 15 et 24 heures), nous a permis de confirmer que le seuil de 1.25x utilisé dans l'analyse de la puce à ARN est approprié pour considérer qu'un gène est régulé de manière significative par la stimulation sensorielle. Nous avons également pu confirmer à l'aide de cette technique que la stimulation sensorielle augmente significativement l'expression de ces dix gènes. L'expression de ces gènes au niveau cellulaire a été observée à l'aide des techniques d'hybridation in situ et d'immunohistochimie. Trois observations ont été faites : 1) la régulation de ces gènes est restreinte aux tonneaux correspondants aux vibrisses stimulées ; 2) au niveau d'une colonne corticale correspondant aux vibrisses stimulées, seules certaines cellules présentent une altération de leur expression génique ; 3) au niveau des tonneaux stimulés, deux profils d'expression d'ARNm et de protéines sont observés. Notre hypothèse est que cette distribution pourrait correspondre à la terminaison ségrégée des deux voies thalamocortical qui amènent l'information sensorielle dans le cortex cérébral. De plus, seul les neurones atteignant le seuil critique d'activation modifient leur expression génique en réponse à la stimulation sensorielle. Ces changements d'expression géniques vont permettre à la cellule de modifier ses propriétés structurales et physiologiques de manière a prevenir la propagation d'un excès d'activité neuronale au niveau de ses cibles postsynaptics. L'activité neuronale agit donc spécifiquement sur certains types cellulaires de maniere a induire une réponse homéostatique au niveau du réseau neuronal impliqué dans l'integration de l'information sensorielle. Nos travaux démontrent pour une première fois que les deux voies sensorielles contribuent d'une manière distincte et complémentaire à la plasticité corticale induite par un changement de l'activité sensorielle chez la souris adulte.

The perception of touch and the ventral somatosensory pathway.

In humans, touching the skin is known to activate, among others, the contralateral primary somatosensory cortex on the postcentral gyrus together with the bilateral parietal operculum (i.e. the anatomical site of the secondary somatosensory cortex). But which brain regions beyond the postcentral gyrus specifically contribute to the perception of touch remains speculative. In this study we collected structural magnetic resonance imaging scans and neurological examination reports of patients with brain injuries or stroke in the left or right hemisphere, but not in the postcentral gyrus as the entry site of cortical somatosensory processing. Using voxel-based lesion-symptom mapping, we compared patients with impaired touch perception (i.e. hypoaesthesia) to patients without such touch impairments. Patients with hypoaesthesia as compared to control patients differed in one single brain cluster comprising the contralateral parietal operculum together with the anterior and posterior insular cortex, the putamen, as well as subcortical white matter connections reaching ventrally towards prefrontal structures. This finding confirms previous speculations on the 'ventral pathway of somatosensory perception' and causally links these brain structures to the perception of touch.

Anatomical correlates for category-specific naming of objects and actions: A brain stimulation mapping study.

The production of object and action words can be dissociated in aphasics, yet their anatomical correlates have been difficult to distinguish in functional imaging studies. To investigate the extent to which the cortical neural networks underlying object- and action-naming processing overlap, we performed electrostimulation mapping (ESM), which is a neurosurgical mapping technique routinely used to examine language function during brain-tumor resections. Forty-one right-handed patients who had surgery for a brain tumor were asked to perform overt naming of object and action pictures under stimulation. Overall, 73 out of the 633 stimulated cortical sites (11.5%) were associated with stimulation-induced language interferences. These interference sites were very much localized (<1 cm(2) ), and showed substantial variability across individuals in their exact localization. Stimulation interfered with both object and action naming over 44 sites, whereas it specifically interfered with object naming over 19 sites and with action naming over 10 sites. Specific object-naming sites were mainly identified in Broca's area (Brodmann area 44/45) and the temporal cortex, whereas action-naming specific sites were mainly identified in the posterior midfrontal gyrus (Brodmann area 6/9) and Broca's area (P = 0.003 by the Fisher's exact test). The anatomical loci we emphasized are in line with a cortical distinction between objects and actions based on conceptual/semantic features, so the prefrontal/premotor cortex would preferentially support sensorimotor contingencies associated with actions, whereas the temporal cortex would preferentially underpin (functional) properties of objects. Hum Brain Mapp 35:429-443, 2014. © 2012 Wiley Periodicals, Inc.

Primary motor cortex inhibition in spinal cord injuries.

OBJECTIVES AND METHODS: Excitability changes in the primary motor cortex in 17 spinal-cord injured (SCI) patients and 10 controls were studied with paired-pulse transcranial magnetic stimulation. The paired pulses were applied at inter-stimulus intervals (ISI) of 2 ms and 15 ms while motor evoked potentials (MEP) were recorded in the biceps brachii (Bic), the abductor pollicis brevis (APB) and the tibialis anterior (TA) muscles. RESULTS: The study revealed a significant decrease in cortical motor excitability in the first weeks after SCI concerning the representation of both the affected muscles innervated from spinal segments below the lesion, and the spared muscles rostral to the lesion. In the patients with motor-incomplete injury, but not in those with motor-complete injury, the initial cortical inhibition of affected muscles was temporarily reduced 2-3 months following injury. The degree of inhibition in cortical areas representing the spared muscles was observed to be smaller in patients with no voluntary TA activity compared to patients with some activity remaining in the TA. Surprisingly, motor-cortical inhibition was observed not only at ISI 2 ms but also at ISI 15 ms. The inhibition persisted in patients who returned for a follow-up measurement 2-3 years later. CONCLUSION: The present data showed different evaluation of cortical excitability between patients with complete and incomplete spinal cord lesion. Our results provide more insight into the pathophysiology of SCI and contribute to the ongoing discussion about the recovery process and therapy of SCI patients.

L'hémisphérotomie péri-insulaire: technique chirurgicale, monitoring EEG intraopératoire et résultats sur le contrôle de l'épilepsie [Periinsular hemispherotomy: surgical technique, intraoperative EEG monitoring and results on seizure outcome]

Peri-insular hemispherotomy is a surgical technique used in the treatment of drug-resistant epilepsy of hemispheric origin. It is based on the exposure of insula and semi-circular sulci, providing access to the lateral ventricle through a supra- and infra-insular window. From inside the ventricle, a parasagittal callosotomy is performed. The basal and medial portion of the frontal lobe is isolated. Projections to the anterior commissure are interrupted at the time of amygdala resection. The hippocampal tail and fimbria-fornix are disrupted posteriorly. We report our experience of 18 cases treated with this approach. More than half of them presented with congenital epilepsy. Neuronavigation was useful in precisely determining the center and extent of the craniotomy, as well as the direction of tractotomies and callosotomy, allowing minimal exposure and blood loss. Intra-operative monitoring by scalp EEG on the contralateral hemisphere was used to follow the progression of the number of interictal spikes during the disconnection procedure. Approximately 90% of patients were in Engel's Class I. We observed one case who presented with transient postoperative neurological deterioration probably due to CSF overdrainage and documented one case of incomplete disconnection in a patient presenting with hemimegalencephaly who needed a second operation. We observed a good correlation between a significant decrease in the number of spikes at the end of the procedure and seizure outcome. Peri-insular hemispherotomy provides a functional disconnection of the hemisphere with minimal resection of cerebral tissue. It is an efficient technique with a low complication rate. Intra-operative EEG monitoring might be used as a predictive factor of completeness of the disconnection and consequently, seizure outcome.

Multispectral brain morphometry in Tourette syndrome persisting into adulthood.

Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1- and diffusion-weighted structural magnetic resonance images, we examined 40 adults with Tourette syndrome in comparison with 40 age- and gender-matched healthy controls. Patients with Tourette syndrome showed relative grey matter volume reduction in orbitofrontal, anterior cingulate and ventrolateral prefrontal cortices bilaterally. Cortical thinning extended into the limbic mesial temporal lobe. The grey matter changes were modulated additionally by the presence of co-morbidities and symptom severity. Prefrontal cortical thickness reduction correlated negatively with tic severity, while volume increase in primary somatosensory cortex depended on the intensity of premonitory sensations. Orbitofrontal cortex volume changes were further associated with abnormal water diffusivity within grey matter. White matter analysis revealed changes in fibre coherence in patients with Tourette syndrome within anterior parts of the corpus callosum. The severity of motor tics and premonitory urges had an impact on the integrity of tracts corresponding to cortico-cortical and cortico-subcortical connections. Our results provide empirical support for a patho-aetiological model of Tourette syndrome based on developmental abnormalities, with perturbation of compensatory systems marking persistence of symptoms into adulthood. We interpret the symptom severity related grey matter volume increase in distinct functional brain areas as evidence of ongoing structural plasticity. The convergence of evidence from volume and water diffusivity imaging strengthens the validity of our findings and attests to the value of a novel multimodal combination of volume and cortical thickness estimations that provides unique and complementary information by exploiting their differential sensitivity to structural change.

Neurofilament triplet proteins are restricted to a subset of neurons in the rat neocortex.

The cellular localisation of neurofilament triplet subunits was investigated in the rat neocortex. A subset of mainly pyramidal neurons showed colocalisation of subunit immunolabelling throughout the neocortex, including labelling with the antibody SMI32, which has been used extensively in other studies of the primate cortex as a selective cellular marker. Neurofilament-labelled neurons were principally localised to two or three cell layers in most cortical regions, but dramatically reduced labelling was present in areas such as the perirhinal cortex, anterior cingulate and a strip of cortex extending from caudal motor regions through the medial parietal region to secondary visual areas. However, quantitative analysis demonstrated a similar proportion (10-20%) of cells with neurofilament triplet labelling in regions of high or low labelling. Combining retrograde tracing with immunolabelling showed that cellular content of the neurofilament proteins was not correlated with the length of projection. Double labelling immunohistochemistry demonstrated that neurofilament content in axons was closely associated with myelination. Analysis of SMI32 labelling in development indicated that content of this epitope within cell bodies was associated with relatively late maturation, between postnatal days 14 and 21. This study is further evidence of a cell type-specific regulation of neurofilament proteins within neocortical neurons. Neurofilament triplet content may be more closely related to the degree of myelination, rather than the absolute length, of the projecting axon.