Brain temporal complexity in explaining the therapeutic and cognitive effects of seizure therapy.

Over 350 million people worldwide suffer from depression, a third of whom are medication-resistant. Seizure therapy remains the most effective treatment in depression, even when many treatments fail. The utility of seizure therapy is limited due to its cognitive side effects and stigma. The biological targets of seizure therapy remain unknown, hindering design of new treatments with comparable efficacy. Seizures impact the brains temporal dynamicity observed through electroencephalography. This dynamicity reflects richness of information processing across distributed brain networks subserving affective and cognitive processes. We investigated the hypothesis that seizure therapy impacts mood (depressive symptoms) and cognition by modulating brain temporal dynamicity. We obtained resting-state electroencephalography from 34 patients (age = 46.0 ± 14.0, 21 females) receiving two types of seizure treatments-electroconvulsive therapy or magnetic seizure therapy. We used multi-scale entropy to quantify the complexity of the brain's temporal dynamics before and after seizure therapy. We discovered that reduction of complexity in fine timescales underlined successful therapeutic response to both seizure treatments. Greater reduction in complexity of fine timescales in parieto-occipital and central brain regions was significantly linked with greater improvement in depressive symptoms. Greater increase in complexity of coarse timescales was associated with greater decline in cognition including the autobiographical memory. These findings were region and timescale specific. That is, change in complexity in occipital regions (e.g. O2 electrode or right occipital pole) at fine timescales was only associated with change in depressive symptoms, and not change in cognition, and change in complexity in parieto-central regions (e.g. Pz electrode or intra and transparietal sulcus) at coarser timescale was only associated with change in cognition, and not depressive symptoms. Finally, region and timescale specific changes in complexity classified both antidepressant and cognitive response to seizure therapy with good (80%) and excellent (95%) accuracy, respectively. In this study, we discovered a novel biological target of seizure therapy: complexity of the brain resting state dynamics. Region and timescale dependent changes in complexity of the brain resting state dynamics is a novel mechanistic marker of response to seizure therapy that explains both the antidepressant response and cognitive changes associated with this treatment. This marker has tremendous potential to guide design of the new generation of antidepressant treatments.

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.

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.

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.

The Relationship Between Cortical Inhibition and Electroconvulsive Therapy in the Treatment of Major Depressive Disorder.

Dysfunctional cortical inhibition (CI) is postulated as a key neurophysiological mechanism in major depressive disorder. Electroconvulsive therapy (ECT) is the treatment of choice for resistant depression and ECT has been associated with enhanced CI. The objective of this study was to evaluate the relationship between CI and ECT response in resistant depression. Twenty-five patients with treatment resistant depression underwent an acute course of ECT. CI was indexed by the cortical silent period (CSP) and short-interval cortical inhibition (SICI), through TMS-EMG. CI and clinical response was measured prior to beginning an acute ECT course and within 48 hours of the last ECT treatment in the course. Clinical response to ECT was assessed by HDRS-17 before and after an acute course of ECT. We found that there was a significant difference in CSP at baseline between responder and non-responder groups (p = 0.044). Baseline CSP predicted therapeutic response to ECT with sensitivity of 80% and specificity of 60%. There were no changes in CSP or SICI after administration of the ECT course. Our findings suggest that duration of pre-treatment CSP may be a useful predictor of therapeutic response to ECT in patients with TRD.

The role of transcranial magnetic stimulation in treatment-resistant depression: a review.

Major depressive disorder (MDD) is a prevalent mental illness associated with significant impairment in quality of life and treatment resistance in as many as 50% of patients. Few alternatives to psychopharmacological and electroconvulsive therapy (ECT) exist. Transcranial magnetic stimulation (TMS) is one such alternative with demonstrated efficacy in the treatment of both MDD and treatment- resistant depression (TRD). Accrued evidence from meta-analyses suggests that rTMS has moderate effect sizes in both MDD and TRD, comparable, though less robust, to those seen in ECT treated patients, and similar to those seen with antidepressant treatment in TRD. To date, rTMS has been used in adult, pediatric, and geriatric populations with success. Predictors of response include lower age, lower degrees of treatment resistance, and the absence of comorbid anxiety or psychotic symptoms. rTMS is cost-effective when compared to existing treatments for TRD including psychopharmacological interventions and ECT. More research, however, is needed to determine the most optimal stimulation parameters. Accelerated treatment over a short duration of time, sequential bilateral stimulation, extended number of pulses per session are potential methods of optimizing efficacy over current unilateral stimulation protocols. The extent to which rTMS can be pushed to engender the greatest possible clinical effects while avoiding seizure induction remains unknown.

A randomized double-blind sham-controlled comparison of unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant major depression.

OBJECTIVES: High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). There are few published reports on the efficacy of sequential bilateral rTMS compared to HFL and sham rTMS. Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD. METHODS: Subjects between the ages of 18 and 85 were recruited from a tertiary care university hospital. Seventy-four subjects with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. The rates of remission were compared among the three treatment groups. RESULTS: The remission rates differed significantly among the three treatment groups using a modified intention to treat analysis that excluded subjects who did not respond to electroconvulsive therapy (ECT) during the current episode. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the unilateral group did not differ from either group. CONCLUSION: These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

Evidence for GABAergic inhibitory deficits in major depressive disorder.

Converging evidence suggests that deficits in gamma-aminobutyric acid (GABA) functioning are implicated in the pathophysiology of major depressive disorder (MDD). This is highlighted by research investigating cortical inhibition (CI), a process whereby GABAergic interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) paradigms evaluate this marker of neuronal inhibitory activity in the cortex. This review will examine the neuroanatomic and neurophysiological evidence from neuroimaging, molecular, treatment, and TMS studies linking dysfunctional GABAergic neurotransmission to MDD.

Evidence of cortical inhibitory deficits in major depressive disorder.

BACKGROUND: Several lines of evidence suggest that major depressive disorder is associated with deficits in gamma-aminobutyric acid (GABA) inhibitory neurotransmission. Transcranial magnetic stimulation represents a noninvasive technique to measure cortical inhibition. In this study, we endeavored to measure cortical inhibition in medicated patients with treatment resistant major depressive disorder (TRD), unmedicated patients with major depressive disorder, and medicated euthymic patients with a history of major depressive disorder and compare them with healthy subjects. METHODS: Twenty-five patients with TRD, 16 unmedicated patients with major depressive disorder, 19 medicated euthymic patients with previous major depressive disorder (i.e., 17-item Hamilton Rating Scale for Depression < 8), and 25 healthy subjects were enrolled. Cortical inhibition was measured with transcranial magnetic stimulation paradigms known as short-interval cortical inhibition and the cortical silent period, which index GABA(A) and GABA(B) receptor-mediated inhibitory neurotransmission, respectively. RESULTS: All major depressive disorder patient groups demonstrated significant cortical silent period deficits compared with healthy subjects. By contrast, only TRD patients demonstrated significant deficits in short-interval cortical inhibition compared with healthy subjects, medicated euthymic major depressive disorder patients, and unmedicated major depressive disorder patients. The TRD patients also demonstrated a significantly greater resting motor threshold compared with all other clinical subgroups and healthy subjects, suggesting that TRD was also associated with hypoexcitability of the frontal cortex. CONCLUSIONS: Our findings suggest that GABA(B) neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABA(A) receptor-mediated inhibitory deficits.

Repetitive transcranial magnetic stimulation for major depressive disorder: a review.

Several studies demonstrated that repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for treatment-resistant major depressive disorder (TRD). Recent metaanalyses and more recent large multicentre studies provided evidence suggesting that rTMS is indeed a promising treatment; however, its efficacy has often been shown to be modest, compared with sham stimulation. We review these lines of evidence and discuss several reasons that may explain the modest therapeutic efficacy in most of these studies, including: most involved left-sided treatment alone to the dorsolateral prefrontal cortex (DLPFC) only, which may be less optimal than applying bilateral stimulation; suboptimal methods were used to target the DLPFC (that is, the 5-cm anterior method), limiting the treatment potential of inherently a targeted form of treatment; some treatment durations were short (that is, 2 to 4 weeks); and stimulation intensity might have been insufficient by not considering coil-to-cortex distance, which has been linked to rTMS-induced antidepressant response. Future studies attempting to address the above-mentioned limitations are necessary to potentially optimize the efficacy of this already promising treatment option in TRD. Finally, it is also essential that research investigate the mechanisms of therapeutic efficacy, thus increases in understanding can be translated into enhanced treatment. For several reasons that will be reviewed, cortical excitability may represent an important mechanism, linked to the therapeutic efficacy of this disorder.

Evaluating the relationship between long interval cortical inhibition, working memory and gamma band activity in the dorsolateral prefrontal cortex.

Recent reports have demonstrated that long interval cortical inhibition (LICI) can be indexed in the dorsolateral prefrontal cortex (DLPFC) in healthy controls. LICI is a neurophysiologic process indexed using transcranial magnetic stimulation and is closely associated with cortical GABA(B) receptor mediated inhibitory neurotransmission. Several previous studies have also reported that gamma band activity represents a neurophysiological process that is mediated, in part, through GABAergic inhibitory neurotransmission and may subserve several cognitive operations including working memory (WM) in the DLPFC. The intension of the current study, therefore, was to directly evaluate the relationship between these neurophysiological processes in healthy subjects. Eleven right-handed healthy subjects participated in this experiment in which gamma band activity was measured through simultaneous recording of electroencephalography (EEG) during the N-back task, a cognitive task designed to index WM. LICI was recorded through EEG from the left DLFPC, left motor cortex and through EMG of peripheral hand muscles in a separate session according to previously published methods. There was no evidence for a relationship in the DLPFC between LICI and gamma band activity elicited during the N-back task, though there was a significant relationship between LICI and performance on the 3-back condition, the N-back condition of greatest difficulty. In conclusion these data provide evidence to suggest that in the DLPFC, there is no direct relationship between GABA(B) receptor mediated inhibitory neurotransmission and gamma band activity. However, our data does suggest that LICI was related to 3-back performance providing evidence implicating DLPFC GABAergic inhibitory neurotransmission in WM performance.

Cortical inhibitory dysfunction in bipolar disorder: a study using transcranial magnetic stimulation.

OBJECTIVE: Neuroanatomic evidence suggests that patients with bipolar disorder (BD) have impaired cortical inhibition (CI). However, there is little in vivo neurophysiological evidence supporting the occurrence of such impairments in this disorder. Using 3 transcranial magnetic stimulation paradigms, known as short-interval CI (SICI), cortical silent period (SP), and interhemispheric inhibition (IHI), the authors measured inhibition in the motor cortex. METHOD: Fifteen patients with BD and 15 healthy subjects were enrolled. Short-interval CI involves stimulating with a subthreshold pulse a few milliseconds before a suprathreshold pulse, thereby inhibiting the size of the motor-evoked potential (MEP) produced by the suprathreshold pulse. In the SP paradigm, inhibition is reflected by the SP duration (ie, the duration of electromyographic activity cessation following a transcranial magnetic stimulation-induced MEP). Interhemispheric inhibition involves a subthreshold conditioning stimulus applied to the right motor cortex several milliseconds before a suprathreshold test stimulus is applied to the left motor cortex which inhibits the size of the MEP produced by the test stimulus by 50% to 75%. RESULTS: Patients with BD demonstrated deficits in all 3 paradigms: SICI (F1,28 = 5.55, P = 0.03; Cohen d = 0.86), SP (F1,28 = 5.24, P = 0.03; Cohen d = 0.84), and IHI (F1,28 = 3.41, P = 0.02; Cohen d = 0.77) compared with healthy volunteers with a large effect size. CONCLUSIONS: Our study supports the hypothesis that CI is decreased in BD. Further understanding of the neurophysiology of such deficiencies may help to elucidate future treatment options.