Symposia

TMS-Based Cortical Excitability Measurements

Leon-Sarmiento FE, Wayne State University, School of Medicine, Detroit, Michigan, USA

The understanding of brain circuits functioning has advanced enormously in recent years by using transcranial magnetic stimulation (TMS) cortical excitability assessment techniques. Single pulse TMS allows measurement of the motor evoked potential (MEP) thresholds obtained at rest or under muscle activation. These measures largely reflect the polarization state of neurons and the efficacy of synapses in the stimulation pathway from cortex to muscles. Stimulus-response curves also obtained at rest or muscle activation, reflect the ability to recruit output cells via intracortical connections and to produce repeated firing of corticospinal neurons. Cortical silent period (CSP), which is mediated by GABA_b, is a measure of cortico-cortical inhibition. Paired-pulse TMS, on the other hand, is useful to test intracortical inhibition (ICI) and facilitation (ICF) which reflect GABA_a and NMDA-dependent inhibitory and excitatory circuits in the cortex, respectively. All of the above neural measures are modulated after application of repetitive TMS (rTMS) either at low or high frequencies. While the mechanisms are not entirely clear, some of these changes may last from minutes to days. Data to date suggest that different neuronal populations are involved in each of the measurements and different intrinsic mechanisms may be participating in mediating these effects.

Electrophysiology of Cocaine-Induced Psychosis: Contribution of ERP and TMS

Boutros N N, Wayne State University, Detroit, Michigan, USA

Electrophysiological studies in cocaine-dependent individuals suggest a complex mechanism for the development of psychosis in these subjects. Inhibition of incoming irrelevant sensory input (i.e., sensory gating) has been repeatedly demonstrated in schizophrenia patients. A similar decrease in inhibitory capacity was demonstrated in abstinent cocaine users. This decreased inhibition was correlated with psychosis proneness in this population. On the other hand, initial and replication studies utilizing transcranial magnetic stimulation (TMS) to examine cortical excitability in this group provided evidence of increased cortical inhibition. This finding is interpreted as a compensatory protective mechanism against the epileptogenic properties of cocaine. The findings of increased inhibition demonstrated via TMS and decreased inhibition demonstrated via evoked responses presented a dilemma for interpretation. A most recent study utilizing additional TMS-based measures of cortical excitability, namely the paired-stimulus facilitation and inhibition, provided evidence consistent with increased excitability (or decreased inhibition). Given that the paired-stimulus TMS technique has been rather strongly linked with cortical inhibitory-excitatory mechanisms and that it is likely that sensory gating may be strongly influenced by subcortical mechanisms, we postulate that some form of a cortical subcortical imbalance in the excitatory-inhibitory balance may be important for the development of psychotic symptoms in cocaine users.

Cortical Inhibition and Facilitation in Psychiatric and Neurological Disorders

Chen R, Division of Neurology and Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada

Cortical activity depends on the balance between excitatory and inhibitory influences. Transcranial magnetic stimulation can be used to test different excitatory and inhibitory systems in the human motor cortex. Cortical inhibition that originates within the motor cortex includes short-interval intracortical inhibition (SICI), which is likely related to GABA-A transmission. SICI is a complex phenomenon and may represent the net effect of different inhibitory and excitatory circuits. The other forms cortico-cortical inhibitions are long-interval intracortical inhibition (LICI) and the silent period, which are likely related to GABA-B transmission. The motor cortex may also be inhibited by stimulation of other areas. Stimulation of the opposite motor cortex induces interhemispheric inhibition (IHI) that may be measured with the ipsilateral silent period or by a paired stimulation method. IHI at short (∼10 ms, IHI10) and long (∼40 ms, IHI40) interstimulus intervals are likely mediated by different mechanisms. Cerebellar stimulation also inhibits the motor cortex through transmission in the cerebellothalamocortical pathway. Stimulation of peripheral nerves inhibit the motor cortex and the effect of median nerve stimulation has been termed short and long latency afferent inhibition (SAI and LAI) depending on the time between nerve stimulation and TMS. These different cortical inhibitory circuits interact in a complex manner. For example, SICI is inhibited by LICI, IHI10 and cerebellar stimulation, but not by LAI. LAI inhibits IHI40 and motor cortical stimulation reduces the effect of cerebellar stimulation. Studies of individual cortical inhibitory circuits have provided useful information on the pathophysiology and effects of treatment in neurological and psychiatric disorders. Studies of how the interactions between inhibitory circuits are altered in different diseases may provide additional insights into the pathophysiology of these disorders. Studies on Parkinson's disease, the effects of deep brain stimulation and the pathophysiology of psychogenic dystonia will be used to illustrate how these measures can be used to examine the mechanisms of neurological and psychiatric disorders.

Recording Inhibition Directly from the Cortex Through Transcranial Magnetic Stimulation

Daskalakis Z J, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

Several studies have demonstrated that cortical inhibition (CI) can be recorded through paired transcranial magnetic stimulation (TMS) of the motor cortex and recorded peripherally through electromyography (EMG). Measuring CI has been invaluable in the understanding of both the physiology of the cortex as well as the pathophysiology of several neurological and psychiatric disorders. However, in these studies evaluation of CI was limited to the motor cortex and recorded in the periphery through EMG. Recording CI by combining TMS with surface electroencephalography (EEG) was previously limited by the fact that the TMS stimulus artifact obscured recordings within a meaningful time window necessary to record CI (i.e., first 200 msec). Recent advances in EEG technology have allowed for EEG waveforms to be recorded following TMS by limiting the effect of the stimulus artifact. Recordings to date through have been limited to single pulse TMS and not to paired-pulse TMS necessary to index CI. The purpose of this study, therefore, was to evaluate the relationship between EEG and EMG measures of CI in motor cortex through paired TMS.

To evaluate CI we used the TMS inhibitory paradigm, long interval cortical inhibition (LICI) with an interstimulus interval of 100 msec in 13 healthy subjects.

Our results demonstrate a significant correlation (r=0.86, p=0.0001) between EMG and EEG measures of CI.

These data provide compelling evidence that LICI, as indexed through EEG, is strongly related to LICI as indexed through EMG, and therefore mediated by the same cortical GABAergic inhibitory processes. These data also suggest that cortical areas previously inaccessible to recording CI through TMS can now be indexed.

Cognitive Deficits in Parkinson's Disease: Functional Neuroimaging & Computational Modeling Studies

Monchi O, Institut Universitaire de Gériatire de Montréal, University of Montreal, Canada

Executive dysfunction is a well identified problem in patients with Parkinson's disease (PD). To tackle this problem, previously, we have developed computational neuroscience model of fronto-striatal activity during the performance of the Wisconsin Card Sorting Task (WCST), a well characterized set-shifting task (Monchi & Taylor, 1999; Monchi et al., 2000). Based on the predictions of the computational model, we have used an event-related fMRI paradigm to test both healthy young adults and PD patients to investigate the role of prefrontal cortex (PFC) and basal ganglia during different stages of the sorting task. In PD patients, decreased activation in PFC regions was observed only during those stages of sorting task engaging the striatum while increased activation was found in those prefrontal areas not engaging the striatum. It appeared that frontal activity during executive processes in PD is dependent on striatal involvement, and that deficits in both nigrostriatal and meso-cortical dopamine may play a role in the executive deficits observed in those patients (Monchi et al., 2004, 2007).

Cerebral Plasticity Associated With Motor Learning

Doyon J, University of Montreal, Canada

Motor skill learning refers to the process by which movements either produced alone or in a sequence, come to be performed effortlessly through repeated practice. From a functional neuroanatomy viewpoint, Doyon and colleagues (2002, 2003) have recently proposed that interactions between the cortico-striatal (CS) and cortico-cerebellar (CC) systems are critical for establishing the motor routines used to acquire motor skilled behaviors. When consolidation has occurred and the subject's performance on the task has become automatic, however, the neural representation associated with this new skill is then believed to be distributed in a network of structures that depends on the type of motor skill acquired with practice: Activity within the cortico-striatal and cortico-cerebellar systems is thought to be sufficient, respectively, for maintaining the acquisition of a sequence of movements (i.e., motor sequence learning) and for acquiring the internal model necessary to adapt to sensorimotor changes in the environment (i.e., motor adaptation). In this presentation, the results of a large body of studies in healthy human subjects that examined the functional anatomy and the cerebral plasticity associated with these two forms of memory will be discussed using brain imaging technology. Studies in clinical populations (e.g., Parkinson's disease) demonstrating the functional interplay between these two neural networks will also be presented.

Cortico-Basal Ganglia Functional Interactions in Parkinson's Disease

Strafella A, Toronto Western Hospital and Research Institute, Movement Disorders Center, PET Imaging-Center of Addiction and Mental Health, University of Toronto, Canada

Several animal studies have shown that striatal dopamine can be released under direct control of glutamatergic cortico-striatal efferents. In Parkinson's disease (PD), abnormalities in cortico-striatal interactions are believed to play an important role in the pathophysiology of the disease. Previously, we have reported that, in healthy subjects, repetitive transcranial magnetic stimulation (rTMS) of motor cortex (MC) induces focal dopamine release in the ipsilateral putamen. In this presentation, we will present recent PET imaging studies demonstrating abnormalities in fronto-striatal modulation of dopamine release in PD which are believed to represent a possible in-vivo expression of a loss of functional segregation of cortical information to the striatum and an indirect evidence of abnormal cortico-striatal transmission in early PD. These observations will introduce and provide the rationale for our recent [150] H20 PET studies involving PD patients with extradural electrodes implanted over the motor cortex for the treatment of their movement disorders.

Renaissance of Surgery for Movement Disorders

Moro E Toronto Western Hospital, Movement Disorders Center, University of Toronto, Canada

The recent advances of stereotactic neurosurgery, neurophysiology and neuroimaging have rejuvenated the surgical treatment of many movement disorders. New surgical techniques, particularly deep brain stimulation (DBS), have been successfully applied in Parkinson's disease (PD), essential tremor (ET), dystonia and tics. The subthalamic nucleus, the globus pallidus pars interna and the thalamus (especially the Vim nucleus) have been targeted in DBS. However, since when DBS was started for tremor in the 80′s, several steps have been done towards understanding the mechanism of action, finding new targets, optimizing patient selection criteria and outcome. In this process, the stimulation of the motor cortex for PD and ET has also been explored. More recently, pedunculopontine nucleus DBS has been applied in PD patients with encouraging results. The objective of this lecture is to provide an overview of literature, mechanisms of action, patient selection criteria and outcome of DBS for movement disorders obtained in our center.

Laterality in Psychosis With and Without Depression

Prichep L S, John E R, Kosta A, Brain Research Laboratories, NYU School of Medicine, NY, NY, USA

Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA

The clinical heterogeneity of psychosis and the role of laterality in psychiatric disorders is well recognized. We have recently published results which show significant electrophysiological heterogeneity in these patients as well, (John, et al., 2007). This study focuses on evidence of laterality in a group of inpatients with severe depression and negative symptoms, and another, with hallucinations and positive symptoms and a control group of outpatients with a diagnosis of depression, but no psychotic features. Eyes Closed Resting EEGs were obtained and subjected to neurometric QEEG analysis. In addition, source localization of the scalp recorded EEGs was studied and compared between groups, using VARETA (Variable Resolution Electromagnetic Tomography, Bosch-Bayard, et al., 2001). Clear differences in the topographic Z-maps and the VARETA images at the maxima and minima of the very narrow band frequency distributions were found. Abnormal sources in patients with depressive symptoms were more lateralized (right-sided). Outpatient depressive patients also showed more right sided sources. Psychotics with positive symptoms showed more bilateral abnormalities. Differences in the underlying sources of the groups were seen and will be discussed.

EEG Tomography on the Right-Hemispheric Vigilance System in Narcolepsy Patients

Saletu B, Anderer P, Saletu M, Saletu-Zyhlarz GM, Medical University of Vienna, Austria

By means of low-resolution brain electromagnetic tomography (LORETA) asymmetries in brain function as well as drug-induced changes were studied in narcolepsy patients.

The aim of the study was to identify brain regions associated with vigilance in untreated and modafinil-treated narcoleptics by means of LORETA. Sixteen drug-free narcoleptics and 16 normal controls were included in the baseline investigation. Subsequently patients participated in a double blind, placebo-controlled crossover study receiving a 3-week fixed titration of modafinil (200, 300, 400 mg) and placebo. Measurements comprised LORETA, the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) obtained before and after 3-week therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant inter-group differences in the resting EEG (R-EEG), but not in the vigilance-controlled recordings (V-EEG). Subsequent univariate analysis revealed a decrease in alpha-2 and beta 1–3 power in prefrontal, temporal and parietal cortices, with the right hemisphere slightly more involved in this vigilance decrement. Modafinil 400mg/d as compared with placebo-induced changes opposite to the aforementioned baseline differences (key-lock principle) with a preponderance of the left hemisphere. This increase in vigilance resulted in the MSLT and the ESS improvement. LORETA objectified a functional deterioration of the fronto-temporo-parietal network of the right-hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil on the left hemisphere, which is less affected by the disease.

Reduced Event-Related Brain Potentials to Novelty in Clinical Depression

Bruder GE, Tenke CE, Kayser J, Kroppmann CJ, Gates NA, Schaller J, Stewart JW, New York State Psychiatric Institute and College of Physicians & Surgeons, Columbia University, New York, USA

Novel distracter stimuli in an oddball target detection task elicit a short latency “novelty P3” potential with a frontocentral scalp distribution. In an initial study using a 31 channel EEG montage, we found that unmedicated depressed patients had reduced amplitude of an early, frontocentral P3 to novel stimuli when compared to healthy controls, but they did not differ in a later P3 with a parietal maximum topography. In an independent replication, event-related potentials (ERPs) of larger samples were measured using a higher density of scalp electrodes. ERPs of 49 depressed patients and 51 healthy controls were measured from 67 channels during a novelty oddball task (Friedman et al., 1993). Novel sounds (e.g., dog bark, human cough: 100–400 ms duration, p=.12) were intermixed with infrequent target tones (500Hz, p=.12) and frequent non-target tones (350Hz, p=.76) in a pseudorandom order (1000ms ISI) for eight 50 trial blocks. Subjects responded as quickly as possible to target tones only. The early P3 to novel stimuli was significantly reduced in depressed patients compared to controls. Combined use of current source density (CSD) and principal components analysis (PCA) techniques (see Kayser, Tenke, 2006) confirmed the specificity of an early midcentral source for novel stimuli. The results of these two studies are consistent with reduced frontocentral activity to novel stimuli in clinically depressed patients. This is indicative of dysfunction of the distributed neural network, involving frontal, anterior cingulate, and hippocampal regions, which is thought to mediate orienting of attention to novel sounds.

Neurophysiological Characteristics in Mania in Males and Females (LORETA Source Analysis)

Flor-Henry P, Lind J, Koles Z Clinical Diagnostics and Research Centre, Alberta Hospital Edmonton, Edmonton, Alberta, Canada University of Alberta, Alberta, Canada

Nineteen unmedicated dextral female manics and 15 unmedicated dextral male manics were studied and compared to 77 female and 62 male dextral controls, respectively. LORETA sources were determined in the Eyes Open and Eyes Closed conditions derived from 43 channels after factorization of the power matrices. In general, male manics had increased sources in the right hemisphere and female manics increased sources in the left hemisphere. When male manics, however, are compared to male depressives (n=50) they show increased sources in the left as do female manics when compared to female depressives (n=76). Male depressives have increased right hemispheric sources whereas female depressives have increased sources bilaterally when compared to mania. There is independent evidence which suggests the following neurophysiological model for the manic depressive syndrome ¹ : the fundamental disturbance originates in the right hemisphere. With increasing disorganization contralateral disinhibition leads to dysfunctional left hemisphere overactivation (mania) or through transcallosal inhibition (psychotic depression).

Interictal Discharges in Borderline and Antisocial Personality Disorders and in Panic Attacks Patients

Boutros N N, Peters D, Wayne State University, School of Medicine, Detroit, Michigan, USA

While personality disorders remain to be mainly viewed within a dynamic or cognitive psychology models, evidence for these disorders being of a neuropsychiatric nature is accumulating. Evidence for an increased prevalence of EEG abnormalities in these populations will be reviewed with suggestions on how these findings should be incorporated in the case formulation and management of an individual patient. Similarly, the data regarding the prevalence of epileptic activity in Panic Disorder and the implications for treatment will be presented.

Interictal Non-Epileptic Discharges - Their Meaning in the Context of Non-Epileptic Seizures

Trimble M, Institute of Neurology, University College of London, Queen Square, London, United Kingdom

Non-epileptic seizures (pseudoseizures) are a considerable clinical problem and in spite of much education with regards to seizure detection and diagnosis the number of patients who are mistakenly diagnosed as having epilepsy seems to remain fairly constant at around 20% of those attending seizure clinics with intractable attacks.

One of the main problems is the EEG in such patients often contains abnormalities which, while being reported as non-specific, become interpreted as diagnostic of epilepsy. This literature will be reviewed and put in the context of the other papers discussed in this symposium, with a view to looking at ways such misidentification can be prevented and the possibilities of future research in the interface area between the EEG and psychopathology.

Interictal Epileptic Spikes Studied With Combined EEG and fMRI

Gotman J, Montreal Neurological Institute McGill University, Montréal, Québec, Canada

The possibility to combine EEG recording with fMRI opens the opportunity to uncover the regions of the brain showing changes in metabolism and blood flow in response to epileptic spikes seen in the scalp EEG. These regions are presumably involved in the abnormal neuronal activity at the origin of epileptic discharges. We will review briefly the methodology involved in performing such studies, including the special techniques required for recording the EEG inside the scanner. We then discuss the results obtained in patients with different types of focal epileptic disorders and in patients with primary generalized epilepsy. The results indicate that interictal epileptic discharges may affect brain areas beyond the presumed region in which they are generated, including subcortical structures.