Mera S. Barr

Long-Interval Cortical Inhibition from the Dorsolateral Prefrontal Cortex : a TMS-EEG Study

Several studies have demonstrated that cortical inhibition (CI) can be recorded by paired transcranial magnetic stimulation (TMS) of the motor cortex and recorded by surface electromyography (EMG). However, recording CI from other cortical regions that are more closely associated with the pathophysiology of some neurological and psychiatric disorders (eg, dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously unattainable. This study, therefore, was designed to investigate whether CI could be measured directly from the motor cortex and DLPFC by combining TMS with electroencephalography (EEG). Long-interval CI (LICI) is a TMS paradigm that was used to index CI in the motor cortex and DLPFC in healthy subjects. In the motor cortex, LICI resulted in significant suppression (32.8±30.5%) of mean cortical evoked activity on EEG, which was strongly correlated with LICI recorded by EMG. In the DLPFC, LICI resulted in significant suppression (30.1±26.9%) of mean cortical evoked activity and also correlated with LICI in the motor cortex. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurological and psychiatric disorders.

Evidence for gamma inhibition deficits in the dorsolateral prefrontal cortex of patients with schizophrenia

Previous studies have shown that patients with schizophrenia and bipolar disorder have deficits in cortical inhibition. Through the combination of interleaved transcranial magnetic stimulation and electroencephalography, we have recently reported on methods in which cortical inhibition can be measured from the dorsolateral prefrontal cortex, a cortical region that is more closely associated with the pathophysiology of schizophrenia. Furthermore, it is possible to index cortical inhibition of specific oscillatory frequencies including the gamma band (30-50 Hz) whose modulation has been related to higher order cortical processing. In this study, we show that patients with schizophrenia have significant deficits of cortical inhibition of gamma oscillations in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder, while no deficits are demonstrated in the motor cortex. These results suggest that the lack of inhibition of gamma oscillations in the dorsolateral prefrontal cortex may represent an important frontal neurophysiological deficit, which may be responsible for the spectrum of deficits commonly found in schizophrenia.

Optimal Transcranial Magnetic Stimulation Coil Placement for Targeting the Dorsolateral Prefrontal Cortex Using Novel Magnetic Resonance Image-Guided Neuronavigation

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including major depressive disorder and schizophrenia. In this regard, the DLPFC has been targeted in repetitive transcranial magnetic stimulation (rTMS) studies as a form of treatment to those patients who are resistant to medications. The ‘5‐cm method’ and the ‘10‐20 method’ for positioning the transcranial magnetic stimulation (TMS) coil over DLPFC have been scrutinised due to poor targeting accuracies attributed to inter‐subject variability. We evaluated the accuracy of such methods to localise the DLPFC on the scalp in 15 healthy subjects and compared them with our novel neuronavigational method, which first estimates the DLPFC position in the cortex based on a standard template and then determines the most appropriate position on the scalp in which to place the TMS coil. Our neuronavigational method yielded a scalp position for the left DLPFC between electrodes F3 and F5 in standard space and was closest to electrode F5 in individual space. Further, we found that there was significantly less inter‐subject variability using our neuronavigational method for localising the DLPFC on the scalp compared with the ‘5‐cm method’ and the ‘10‐20 method’. Our findings also suggest that the ‘10‐20 method’ is superior to the ‘5‐cm method’ in reducing inter‐subject variability and that electrode F5 should be the stimulation location of choice when MRI co‐registration is not available. Hum Brain Mapp, 2010.

Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory

Gamma (gamma) oscillations (30-50 Hz) elicited during working memory (WM) are altered in schizophrenia (SCZ). However, the nature of the relationship between evoked frontal oscillatory activity, WM performance and symptom severity has yet to be ascertained. This study had two objectives. First, to extend previous studies by examining delta, theta, alpha, beta, and gamma (delta, theta, alpha, beta, and gamma) oscillatory activities during the N-back task in SCZ patients compared to healthy subjects; second, to evaluate the relationship between oscillatory activities elicited during the N-back, performance, and clinical symptoms in SCZ patients. Patients with SCZ elicited excessive frontal gamma oscillatory activity that was most pronounced in the 3-back condition compared to healthy subjects. Reduced frontal beta activity at all WM loads was also observed in patients with SCZ compared to healthy subjects. Task performance was inversely correlated with negative symptoms but not with positive symptoms. Our findings suggest that evoked frontal oscillatory activities during WM are selectively altered in the gamma and beta frequency bands that may contribute to WM impairment in SCZ patients. These findings may provide important insights into the pathophysiology underlying WM deficits, its relationship to negative symptoms and may represent a potential neurobiological marker for cognitive enhancing strategies in SCZ.

Potentiation of gamma oscillatory activity through repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

Neuronal oscillations in the gamma (γ) frequency range (30–50 Hz) have been associated with cognition. Working memory (WM), a cognitive task involving the on-line maintenance and manipulation of information, elicits increases in γ oscillations with greater cognitive demand, particularly in the dorsolateral prefrontal cortex (DLPFC). The generation and modulation of γ oscillations have been attributed to inhibitory interneuron networks that use γ -aminobutyric acid (GABA) as their principal neurotransmitter. Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to modify cognition and GABA inhibitory mechanisms, particularly with higher frequencies (ie, 10–20 Hz). We measured the effect of high-frequency rTMS applied to the DLPFC on γ-oscillations elicited during the N-back WM task in healthy individuals. Active rTMS significantly increased γ-oscillations generated during the N-back conditions with the greatest cognitive demand. Further, no significant changes were found in other frequency ranges, suggesting that rTMS selectively modulates γ-oscillations in the frontal brain regions. These findings provide important insights into the neurophysiological mechanisms that underlie higher-order cognitive processes, and suggest that rTMS may be used as a cognitive enhancing strategy in neuropsychiatric disorders that suffer from cognitive deficits.

The role of the corpus callosum in transcranial magnetic stimulation induced interhemispheric signal propagation.

BACKGROUND The corpus callosum, the main interhemispheric connection in the brain, may serve to preserve functional asymmetry between homologous cortical regions. METHODS To test this hypothesis, 30 healthy adult subjects underwent combined transcranial magnetic stimulation (TMS)-electroencephalography procedures. Nineteen of these subjects also completed diffusion tensor imaging and tractography procedures. We examined the relationship between microstructural integrity of subdivisions of the corpus callosum with TMS-induced interhemispheric signal propagation. RESULTS We found a significant inverse relationship between microstructural integrity of callosal motor fibers with TMS-induced interhemispheric signal propagation from left to right motor cortex. We also found a significant inverse relationship between microstructural integrity of genu fibers of the corpus callosum and TMS-induced interhemispheric signal propagation from left to right dorsolateral prefrontal cortex (DLPFC). We then demonstrated neuroanatomic specificity of these relationships. CONCLUSIONS Taken together, our findings suggest that TMS-induced interhemispheric signal propagation is transcallosally mediated and neuroanatomically specific and support a role for the corpus callosum in preservation of functional asymmetry between homologous cortical regions. Delineation of the relationship between corpus callosum microstructure and interhemispheric signal propagation in neuropsychiatric disorders, such as schizophrenia, may reveal novel mechanisms of pathophysiology.

Can Repetitive Magnetic Stimulation Improve Cognition in Schizophrenia? Pilot Data from a Randomized Controlled Trial

BACKGROUND Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels. METHODS In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course. RESULTS The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohens d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects. CONCLUSIONS These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia.

Suppression of γ -Oscillations in the Dorsolateral Prefrontal Cortex following Long Interval Cortical Inhibition: A TMS–EEG Study

Gamma (γ)-oscillations (30–50 Hz) represent important electrophysiological measures, which are generated through the execution of higher order cognitive tasks (eg, working memory) in the dorsolateral prefrontal cortex (DLPFC). By contrast, cortical inhibition (CI) refers to a neurophysiological process in which GABAergic inhibitory interneurons selectively suppress the activation of other neurons in the cortex. Recently, abnormalities in both CI and γ-oscillations have been associated with various neuropsychiatric disorders including schizophrenia. Animal research suggests that suppression of γ-oscillations is, in part, mediated through GABAergic inhibitory neurotransmission. However, no such evidence has been demonstrated in human, largely because of technological limitations. Recently, we reported on novel methods permitting the recording of CI from the DLPFC through transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). The aim of this study was to examine the effects of GABAergic inhibitory neurotransmission on γ-oscillations by combining TMS with EEG. Long interval cortical inhibition (LICI), a paired TMS paradigm, was used to index GABAB receptor mediated inhibitory neurotransmission in the motor cortex and DLPFC of healthy individuals. γ-Oscillations were significantly inhibited by LICI (38.1±26.5%; p⩽0.013) in the DLPFC but not in the motor cortex. These results provide neurophysiological evidence to demonstrate γ-oscillations are inhibited by LICI in the DLPFC but not in the motor cortex. Such specificity suggests that the modulation of γ-oscillations may represent an important neurophysiological process that may, in part, be responsible for optimal DLPFC functioning in healthy human subjects.

Reliability of Long-Interval Cortical Inhibition in Healthy Human Subjects: A TMS–EEG Study

Cortical inhibition (CI) is measured by transcranial magnetic stimulation (TMS) combined with electromyography (EMG) through long-interval CI (LICI) and cortical silent period (CSP) paradigms. Recently, we illustrated that LICI can be measured from the dorsolateral prefrontal cortex (DLPFC) through combined TMS with electroencephalography (EEG). We further demonstrated that LICI had different effects on cortical oscillations in the DLPFC compared with motor cortex. The purpose of this study was to establish the validity and reliability of TMS-EEG indices of CI and to replicate our previous findings in an extended sample. The validity of TMS-EEG was examined by evaluating its relationship to standard EMG measures of LICI and the CSP in the left motor cortex in 36 and 16 subjects, respectively. Test-retest reliability was examined in 14 subjects who returned for a repeat session within 7 days of the first session. LICI was applied to the left DLPFC in 30 subjects to compare LICI in the DLPFC with that in the motor cortex. In the motor cortex, EEG measures of LICI correlated with EMG measures of LICI and CSP. All indices of LICI showed high test-retest reliability in motor cortex and DLPFC. Gamma and beta oscillations were significantly inhibited in the DLPFC but not in the motor cortex, confirming previous findings in an extended sample. These findings demonstrate that indexing LICI through TMS combined with EEG is a valid and reliable method to evaluate inhibition from motor and prefrontal regions.

Gamma oscillations in schizophrenia: Mechanisms and clinical significance

Brain oscillations are increasingly used for understanding complex psychiatric disorders. Gamma (30-50Hz) oscillations have warranted special attention due to their omnipresence in cognitive tasks. For patients with schizophrenia (SCZ), a disease associated with poor cognition, abnormal gamma oscillations have been reported in many experimental paradigms. The goal of this paper is to review the literature on gamma oscillations in SCZ. The review is structured into four sections. First, the functional role, neurobiology, and analysis of brain oscillations, especially gamma oscillations will be outlined. Second, the neurobiological abnormalities of SCZ in relation to gamma oscillations will be reviewed. Third, selected paradigms for investigating irregular gamma oscillations in SCZ will be discussed in detail. Finally, a discussion on the limitations of current findings and potential future research directions will be provided. The reviewed evidence suggests that gamma oscillations are disrupted in SCZ and could account for cognitive disturbances in this disorder. With additional analysis and experimentation, these indices may ultimately serve as endophenotypes that facilitate the development of etiologically based diagnostic methods, foster early identification and treatment, and advance our understanding of the complex genetic mechanisms involved in this disorder.