Impaired motor cortical facilitatory-inhibitory circuit interaction in Parkinson's disease.

OBJECTIVE: Motor cortical (M1) inhibition and facilitation can be studied with short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). These circuits are altered in Parkinson's disease (PD). The sensorimotor measure short latency afferent inhibition (SAI) is possibly altered in PD. The aim was to determine if the manner in which these circuits interact with each other is abnormal in PD. METHODS: Fifteen PD patients were studied at rest in ON and OFF medication states, and were compared to 16 age-matched controls. A triple-stimulus transcranial magnetic stimulation paradigm was used to elicit a circuit of interest in the presence of another circuit. RESULTS: SICF was increased in PD OFF and PD ON conditions compared to controls. SICI facilitated SICF in controls and PD ON, but not in PD OFF. SICF in the presence of SICI negatively correlated with UPDRS-III scores in OFF and ON medication conditions. SAI showed similar inhibition of SICI in controls, PD OFF and PD ON conditions. CONCLUSIONS: The facilitatory effect of SICI on SICF is absent in PD OFF, but is restored with dopaminergic medication. SIGNIFICANCE: Impaired interaction between M1 circuits is a pathophysiological feature of PD.

Impaired theta-gamma coupling during working memory performance in schizophrenia.

BACKGROUND: Working memory deficits represent a core feature of schizophrenia. These deficits have been associated with dysfunctional dorsolateral prefrontal cortex (DLPFC) cortical oscillations. Theta-gamma coupling describes the modulation of gamma oscillations by theta phasic activity that has been directly associated with the ordering of information during working memory performance. Evaluating theta-gamma coupling may provide greater insight into the neural mechanisms mediating working memory deficits in this disorder. METHODS: Thirty-eight patients diagnosed with schizophrenia or schizoaffective disorder and 38 healthy controls performed the verbal N-Back task administered at 4 levels, while EEG was recorded. Theta (4-7Hz)-gamma (30-50Hz) coupling was calculated for target and non-target correct trials for each working memory load. The relationship between theta-gamma coupling and accuracy was determined. RESULTS: Theta-gamma coupling was significantly and selectively impaired during correct responses to target letters among schizophrenia patients compared to healthy controls. A significant and positive relationship was found between theta-gamma coupling and 3-Back accuracy in controls, while this relationship was not observed in patients. CONCLUSIONS: These findings suggest that impaired theta-gamma coupling contribute to working memory dysfunction in schizophrenia. Future work is needed to evaluate the predictive utility of theta-gamma coupling as a neurophysiological marker for functional outcomes in this disorder.

Investigating Cortical Inhibition in First-Degree Relatives and Probands in Schizophrenia.

Deficits in GABAergic inhibitory neurotransmission are a reliable finding in schizophrenia (SCZ) patients. Previous studies have reported that unaffected first-degree relatives of patients with SCZ demonstrate neurophysiological abnormalities that are intermediate between probands and healthy controls. In this study, first-degree relatives of patients with SCZ and their related probands were investigated to assess frontal cortical inhibition. Long-interval cortical inhibition (LICI) was measured from the dorsolateral prefrontal cortex (DLPFC) using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG). The study presents an extended sample of 129 subjects (66 subjects have been previously reported): 19 patients with SCZ or schizoaffective disorder, 30 unaffected first-degree relatives of these SCZ patients, 13 obsessive-compulsive disorder (OCD) patients, 18 unaffected first-degree relatives of these OCD patients and 49 healthy subjects. In the DLPFC, cortical inhibition was significantly decreased in patients with SCZ compared to healthy subjects. First-degree relatives of patients with SCZ showed significantly more cortical inhibition than their SCZ probands. No differences were demonstrated between first-degree relatives of SCZ patients and healthy subjects. Taken together, these findings show that more studies are needed to establish an objective biological marker for potential diagnostic usage in severe psychiatric disorders.

Characterization of Glutamatergic and GABAA-Mediated Neurotransmission in Motor and Dorsolateral Prefrontal Cortex Using Paired-Pulse TMS-EEG.

Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABAA receptor-mediated inhibition and glutamatergic excitatory transmission, respectively. Conventionally these measures have been restricted to the motor cortex. We investigated whether SICI and ICF could be recorded from the dorsolateral prefrontal cortex (DLPFC) using combined TMS and electroencephalography (TMS-EEG). We first characterized the neural signature of SICI and ICF in M1 in terms of TMS-evoked potentials (TEPs) and spectral power modulation. Subsequently, these paradigms were applied in the DLPFC to determine whether similar neural signatures were evident. With TMS at M1, SICI and ICF led to bidirectional modulation (inhibition and facilitation, respectively) of P30 and P60 TEP amplitude, which correlated with MEP amplitude changes. With DLPFC stimulation, P60 was bidirectionally modulated by SICI and ICF in the same manner as for M1 stimulation, whereas P30 was absent. The sole modulation of early TEP components is in contradistinction to other measures such as long-interval intracortical inhibition and may reflect modulation of short latency excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Overall, the data suggest that SICI and ICF can be recorded using TMS-EEG in DLPFC providing noninvasive measures of glutamatergic and GABAA receptor-mediated neurotransmission. This may facilitate future research attempting to ascertain the role of these neurotransmitters in the pathophysiology and treatment of neurological and psychiatric disorders.

Age and gender interactions in white matter of schizophrenia and obsessive compulsive disorder compared to non-psychiatric controls: commonalities across disorders.

Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) are psychiatric disorders with abnormalities in white matter structure. These disorders share high comorbidity and family history of OCD is a risk factor for SCZ which suggests some shared neurobiology. White matter was examined using diffusion tensor imaging in relativity large samples of SCZ (N = 48), OCD (N = 38) and non-psychiatric controls (N = 45). Fractional anisotropy (FA) was calculated and tract based spatial statistics were used to compare groups. In a whole brain analysis, SCZ and OCD both showed small FA reductions relative to controls in the corpus callosum. Both SCZ and OCD showed accelerated reductions in FA with age; specifically in the left superior longitudinal fasciculus in OCD, while the SCZ group demonstrated a more widespread pattern of FA reduction. Patient groups did not differ from each other in total FA or age effects in any regions. A general linear model using 13 a-priori regions of interest showed marginal group, group*gender, and group*age interactions. When OCD and SCZ groups were analyzed together, these marginal effects became significant (p < 0.05), suggesting commonalities exist between these patient groups. Overall, our results demonstrate a similar pattern of accelerated white matter decline with age and greater white matter deficit in females in OCD and SCZ, with overlap in the spatial pattern of deficits. There was no evidence for statistical differences in overall white matter between OCD and SCZ. Taken together, the results support the notion of shared neurobiology in SCZ and OCD.

A meta-analysis of the effects of aging on motor cortex neurophysiology assessed by transcranial magnetic stimulation.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a non-invasive tool used for studying cortical excitability and plasticity in the human brain. This review aims to quantitatively synthesize the literature on age-related differences in cortical excitability and plasticity, examined by TMS. METHODS: A literature search was conducted using MEDLINE, Embase, and PsycINFO from 1980 to December 2015. We extracted studies with healthy old (50-89years) versus young (16-49years) individuals that utilized the following TMS measures: resting motor threshold (RMT), short-interval cortical inhibition (SICI), short-latency afferent inhibition (SAI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS). RESULTS: We found a significant increase in RMT (g=0.414, 95% confidence interval (CI) [0.284, 0.544], p<0.001), a significant decrease in SAI (g=0.778, 95% CI [0.478, 1.078], p<0.001), and a trending decrease in LTP-like plasticity (g=-0.528, 95% CI [-1.157, 0.100] p<0.1) with age. CONCLUSIONS: Our findings suggest an age-dependent reduction in cortical excitability and sensorimotor integration within the human motor cortex. SIGNIFICANCE: Alterations in the ability to regulate cortical excitability, sensorimotor integration and plasticity may underlie several age-related motor deficits.

Unbiased cluster estimation of electrophysiological brain response.

BACKGROUND: Recent increase in the size and complexity of electrophysiological data from multidimensional electroencephalography (EEG) and magnetoencephalography (MEG) studies has prompted the development of sophisticated statistical frameworks for data analysis. One of the main challenges for such frameworks is the multiple comparisons problem, where the large number of statistical tests performed within a high-dimensional dataset lead to an increased risk of Type I errors (false positives). A solution to this problem, cluster analysis, applies the biologically-motivated knowledge of correlation between adjacent voxels in one or more dimensions of the dataset to correct for the multiple comparisons problem and detect true neurophysiological effects. Cluster-based methods provide increased sensitivity towards detecting neurophysiological events compared to conservative methods such as Bonferroni correction, but are limited by their dependency on an initial cluster-forming statistical threshold (e.g. t-score, alpha) obstructing precise comparisons of results across studies. NEW METHOD: Rather than selecting a single threshold value, unbiased cluster estimation (UCE) computes a significance distribution across all possible threshold values to provide an unbiased overall significance value. COMPARISON TO EXISTING METHODS: UCE functions as a novel extension to existing cluster analysis methods. RESULTS: Using data from EEG combined with brain stimulation study, we showed the impact of statistical threshold on outcome measures and introduction of bias. We showed the application of UCE for different study designs (e.g., within-group, between-group comparisons). CONCLUSION: We propose that researchers consider employing UCE for multidimensional EEG/MEG datasets toward an unbiased comparison of results between subjects, groups, and studies.

Prefrontal White Matter Structure Mediates the Influence of GAD1 on Working Memory.

The glutamic acid decarboxylase 1 (GAD1) gene is a major determinant of γ-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter modulating local neuronal circuitry. GABAergic dysfunction and expression of GAD1 have been implicated in the pathophysiology of schizophrenia, and in working memory impairment. We examined the influence of the functional GAD1 rs3749034 variant on white matter fractional anisotropy (FA), cortical thickness, and working memory performance in schizophrenia patients and healthy controls (N=197). Using transcranial magnetic stimulation with electroencephalography (TMS-EEG), we subsequently examined the effect of rs3749034 on long-interval cortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients and healthy controls (N=66). We found that the rs3749034 T-allele carrier risk group had lower voxel-wise FA in the prefrontal cortex region (PFWE-corrected<0.05) but not cortical thickness. Mixed-model regression revealed a significant effect on attentional processing and working memory across four performance measures (F1,182=11.5, P=8 × 10(-4)). FA in the prefrontal cortex was associated with digit-span performance. Voxel-wise mediation analysis revealed that the effect GAD1 on poorer digit-span performance statistically predicted the lower white matter FA (PFWE-corrected<0.05). In exploratory analysis, we found a prominent GAD1 genotype-by-diagnosis interaction on DLPFC LICI (F1,56=14.3, P=4.1 × 10(-4)). Our findings converge on variation in GAD1 gene predicting a susceptibility mechanism that affects white matter FA, GABAergic inhibitory neurotransmission in the DLPFC, and working memory performance. Furthermore, via voxel mediation of FA and TMS-EEG intervention, we provide evidence for a potentially causal mechanism through which aberrant DLPFC GABA signaling may contribute to working memory dysfunction.

Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia.

BACKGROUND: Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI in patients treated with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or are related to clozapine treatment. METHODS: TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine. RESULTS: CSP was significantly longer after 6 weeks of treatment with clozapine (p=0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p>0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p>0.05). CONCLUSIONS: This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABAB mediated inhibitory neurotransmission. Potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia.

Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia.

Abnormal gamma-aminobutyric acid inhibitory neurotransmission is a key pathophysiological mechanism underlying schizophrenia. Transcranial magnetic stimulation can be combined with electroencephalography to index long-interval cortical inhibition, a measure of GABAergic receptor-mediated inhibitory neurotransmission from the frontal and motor cortex. In previous studies we have reported that schizophrenia is associated with inhibitory deficits in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder. The main objective of the current study was to replicate and extend these initial findings by evaluating long-interval cortical inhibition from the dorsolateral prefrontal cortex in patients with schizophrenia compared to patients with obsessive-compulsive disorder. A total of 111 participants were assessed: 38 patients with schizophrenia (average age: 35.71 years, 25 males, 13 females), 27 patients with obsessive-compulsive disorder (average age: 36.15 years, 11 males, 16 females) and 46 healthy subjects (average age: 33.63 years, 23 females, 23 males). Long-interval cortical inhibition was measured from the dorsolateral prefrontal cortex and motor cortex through combined transcranial magnetic stimulation and electroencephalography. In the dorsolateral prefrontal cortex, long-interval cortical inhibition was significantly reduced in patients with schizophrenia compared to healthy subjects (P = 0.004) and not significantly different between patients with obsessive-compulsive disorder and healthy subjects (P = 0.5445). Long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex were also significantly greater in patients with schizophrenia compared to patients with obsessive-compulsive disorder (P = 0.0465). There were no significant differences in long-interval cortical inhibition across all three groups in the motor cortex. These results demonstrate that long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex are specific to patients with schizophrenia and are not a generalized deficit that is shared by disorders of severe psychopathology.

Age-related differences in working memory evoked gamma oscillations.

OBJECTIVE: Working memory is associated with gamma oscillations (30-50 Hz). Previous studies have demonstrated altered gamma oscillations in the elderly population that may be related to general cognitive decline. However, it is unknown how gamma oscillations change with age or if there is an age when gamma oscillations optimally mediate working memory performance. That is, gamma oscillations may be maximal in middle-aged adults compared to younger and elderly adults. The objective of this study was to evaluate working memory evoked gamma oscillations in adults aged 19-29 years (mean 23.32 ± 2.85 1 SD) compared to adults aged 30-60 years (mean 39.10 ± 8.11 1 SD). METHODS: Subjects completed the verbal N-back task administered at four working loads (0, 1, 2, 3), while electroencephalography (EEG) was collected. Gamma power was measured during correct responses. RESULTS: Reduced gamma oscillations were observed in the adults aged 19-29 compared to those aged 30-60 years. Age was found to be positively related to the power of gamma oscillations. No differences were found on N-Back accuracy. CONCLUSIONS: Increased working memory evoked gamma oscillatory activity may provide a neurophysiological marker in the healthy aging brain.

Characterizing long interval cortical inhibition over the time-frequency domain.

OBJECTIVE: Long-interval cortical inhibition (LICI) can be recorded from motor and non-motor regions of the cortex through combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). This study aimed to evaluate additional dimensions of LICI characteristics over an extended time-frequency and spatial domain. This was done by introducing two alternative measures of LICI signal amplitude: the Discrete Fourier Transform (DFT) and the Hilbert transform (HT). Both approaches estimate signal amplitude not taking into account the phase. In both cases LICI was measured as the difference between the unconditioned and conditioned activity evoked by the test pulse. Finally, we evaluated whether the topographical patterns of single and paired responses differed beyond the expected variations in amplitude. MATERIALS AND METHODS: LICI was delivered as single and paired pulses to the motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) in 33 healthy subjects with TMS-EEG. RESULTS: Significant differences (p<0.0001) between the unconditioned and conditioned evoked activity were found for both the DLPFC and MC using both methods (i.e., DFT and HT) after correcting for multiple comparisons in the time-frequency domain. The influence of inhibition was found to be significantly larger in space and time than previously considered. Single and paired conditions differ in intensity, but also in their topographic pattern (i.e., the specific spatiotemporal configuration of active sources). CONCLUSION: Similar results were found by both DFT and HT. The effect of inhibition across the cortex was also found to be complex and extended. In particular, it was found that LICI may be measured with high sensitivity in areas that were relatively distant from the stimulation site, which may have important practical applications. The analysis presented in this study overcomes some limitations of previous studies and could serve as a key reference for future studies examining TMS-indices of inhibition/excitation in healthy and diseased states.

Comparative evaluation of an ambulatory EEG platform vs. clinical gold standard.

Electroencephalography (EEG) testing in clinical labs makes use of large amplifiers and complex software for data acquisition. While there are new ambulatory electroencephalogram (EEG) systems, few have been directly compared to a gold standard system. Here, an ultra-low power wireless EEG system designed by Imec is tested against the gold standard Neuroscan SynAmps2 EEG system, recording simultaneously from the same laboratory cap prepared with electrode gel. The data was analyzed using correlation analysis for both time domain and frequency domain data. The analysis indicated a high Pearson's correlation coefficient (mean=0.957, median=0.985) with high confidence (mean P=0.002) for 10-second sets of data transformed to the frequency domain. The time domain results had acceptable Pearson's coefficient (mean=0.580, median =0.706) with high confidence (mean P=0.008).

Perfectionism, anxiety, and depressive distress: evidence for the mediating role of negative automatic thoughts and anxiety sensitivity.

OBJECTIVE: This study assessed a mediational model in which negative automatic thoughts and anxiety sensitivity were hypothesized to mediate the relationship between perfectionism cognitions and depressive and anxiety symptoms. PARTICIPANTS: Participants were undergraduate students from an urban Canadian university. The data were collected from July 2009 to August 2010. METHODS: In a cross-sectional evaluation, 992 undergraduate participants completed questionnaires that assessed perfectionism cognitions, negative automatic thinking, anxiety sensitivity, and anxiety and depressive symptoms. RESULTS: Mediational analysis confirmed the role of anxiety sensitivity and negative automatic thoughts in mediating the association between perfectionistic cognitions, anxiety symptoms, and depressive distress. Furthermore, in line with previous studies, nearly a third of students displayed an elevated prevalence of anxiety and depressive symptoms. CONCLUSIONS: This study further clarified the associations and mediating relationships among mood states associated with perfectionism.

A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders.

OBJECTIVE: To evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ). METHODS: Paradigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012. RESULTS: A significant Hedge's g was found for decreased SICI (g=0.572, 95% confidence interval [0.179, 0.966], p=0.004), enhanced intracortical facilitation (g=0.446, 95% confidence interval [0.042, 0.849], p=0.030) and decreased CSP (g=-0.466, 95% confidence interval [-0.881, -0.052], p=0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g=0.641, 95% confidence interval [0.384, 0.898], p=0.000) and shortened CSP (g=-1.232, 95% confidence interval [-1.530, -0.933], p=0.000). In SCZ, a significant Hedge's g was shown for decreased SICI (g=0.476, 95% confidence interval [0.331, 0.620], p=0.000). CONCLUSION: Inhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD. SIGNIFICANCE: Provides a clear platform from which diagnostic procedures can be developed.

Meditation-related increases in GABAB modulated cortical inhibition.

BACKGROUND: Recent reports suggest meditation practice improves attentional performance and emotional regulation. The process of meditation apparently increases activation in the prefrontal cortex (PFC) and stimulates the reticular nucleus of the thalamus, implicating the production and delivery of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABAergic inhibitory interneurons have a central role in cortical inhibition (CI), modulating cortical excitability and neural plasticity. OBJECTIVE/HYPOTHESIS: Changes in CI, after completion of a single meditation session, were investigated and compared to a non-meditating control activity. METHODS: Transcranial magnetic stimulation (TMS), a non-invasive method of examining CI, was used to evaluate changes before and after a 60 min meditation session. Seventy right-handed healthy subjects (n = 35 meditators, n = 35 non-meditators) were assessed using TMS related measures of cortical silent period (CSP) and short intra cortical inhibition (SICI), with stimulation of the motor cortex coordinated with EMG recording of peripheral hand muscles. RESULTS: For the meditators, CSP and SICI were measured before and after meditation sessions while age-sex matched healthy control subjects were identically assessed after a non-meditating activity (television watching). The meditators showed a statistically significant increase in CSP after meditation compared to non-meditators after an equivalent period of television watching (P = 0.02) while no significant between-group differences were observed in the SICI. CONCLUSION: These findings indicate meditation processes are linked to GABAergic cortical inhibition, a mechanism previously implicated in improved cognitive performance and enhanced emotional regulation.

Impact of participant incentives and direct and snowball sampling on survey response rate in an ethnically diverse community: results from a pilot study of physical activity and the built environment.

Community-wide efforts to encourage healthy behaviours must respond to the needs of existing neighbourhoods, especially those where low physical activity (PA) is associated with social, economic, and cultural challenges. This study reports on the effect of direct and snowball sampling strategies and financial incentive levels on the response rates of a built environment and PA survey in a predominately urban, low-SES new-immigrant community. Women residing in the Jane-Finch neighbourhood of Toronto, Ontario were selected to participate by quasi-random sampling, yielding a response rate of 41.5%. The survey completion rate per contact attempt increased 2-fold when incentives were increased from $10 to $20 and a further threefold following the increase from $20 to $30. Snowball sampled respondents were older, less likely to have full-time employment, and had lower educational attainment than directly sampled participants. With appropriate incentives, face-to-face contact, and snowball sampling, survey-based research is feasible within a low-SES, high minority population.

Evaluating a Web-based cognitive-behavioral therapy for maladaptive perfectionism in university students.

OBJECTIVE: This study assessed a Web-based cognitive-behavioral therapy (CBT) for maladaptive perfectionism, investigating perfectionism, anxiety, depression, negative automatic thoughts, and perceived stress. PARTICIPANTS: Participants were undergraduate students defined as maladaptive perfectionists through a screening questionnaire at an urban university. The data were collected from July 2009 to August 2010. METHODS: Forty-seven maladaptive perfectionists were randomly assigned to a 12-week CBT or a wait-list control group and assessed via questionnaires at pre- and postintervention. Statistical procedures included t tests, Pearson correlations, and analysis of covariance. RESULTS: At the postintervention measure, the CBT group demonstrated significant decreases in anxiety sensitivity and negative automatic thoughts compared to the control group. Within the CBT group, changes in perfectionism scores were significantly correlated with positive changes in depression, anxiety, stress, and automatic thoughts. CONCLUSIONS: The treatment group improved on psychological outcomes, demonstrating the effectiveness of a Web-based CBT for perfectionism in a university setting.

Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions.

Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive-compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electro encephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders.

Combined transcranial magnetic stimulation and electroencephalography: its past, present and future.

Transcranial magnetic stimulation (TMS) is used to index several neurophysiological processes including excitability, inhibition and plasticity. However, these measures are conventionally limited to the motor cortex and recorded from peripheral muscles. This represents a significant limitation when non-motor neurophysiological processes are of primary interest. In the last several years, TMS has been combined with electroencephalography (EEG) to derive such measures directly from the cortex. Initial studies demonstrated that meaningful recordings could be derived without being substantially affected by TMS stimulus artifact due to advancements in EEG amplifier technology. Subsequently, TMS measures of cortical excitability were reliably recorded and found to be related with more conventional TMS electromyography recordings of excitability in the cortex. More recently, other key neurophysiological indices including cortical inhibition and interhemispheric connectivity have also been reported. In this article, such findings will be reviewed and their importance discussed vis à vis healthy and disease states. We will conclude by highlighting the limitations of this work and discuss their potential future applications as a biomarker of disease states.