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Theta burst stimulation (TBS), a specific form of repetitive transcranial magnetic stimulation (TMS), is a promising treatment for youth with Major Depressive Disorder (MDD) who do not respond to conventional therapies. However, given the variable response to TBS, a greater understanding of how baseline features relate to clinical response is needed to identify which patients are most likely to benefit from this treatment. In the current study, we sought to determine if baseline neurophysiology, specifically cortical excitation and/or inhibition, is associated with antidepressant response to TBS. In two independent open-label clinical trials, youth (aged 16–24 years old) with MDD underwent bilateral dorsolateral prefrontal cortex (DLPFC) TBS treatment. Clinical trial one and two consisted of 10 and 20 daily sessions of bilateral DLPFC TBS, respectively. At baseline, single-pulse TMS combined with electroencephalography was used to assess the neurophysiology of 4 cortical sites: bilateral DLPFC and inferior parietal lobule. Measures of cortical excitation and inhibition were indexed by TMS-evoked potentials (i.e., P30, N45, P60, N100, and P200). Depression severity was measured before, during and after treatment completion using the Hamilton Rating Scale for Depression—17. In both clinical trials, the baseline left DLPFC N45 and P60, which are believed to reflect inhibitory and excitatory mechanisms respectively, were predictors of clinical response. Specifically, greater (i.e., more negative) N45 and smaller P60 baseline values were associated with greater treatment response to TBS. Accordingly, cortical excitation and inhibition circuitry of the left DLPFC may have value as a TBS treatment response biomarker for youth with MDD. Clinical trial 1 registration number: NCT02472470 (June 15, 2015). Clinical trial 2 registration number: NCT03708172 (October 17, 2018). [ABSTRACT FROM AUTHOR]

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an effective way to evaluate neurophysiological processes at the level of the cortex. To further characterize the TMS-evoked potential (TEP) generated with TMS-EEG, beyond the motor cortex, we aimed to distinguish between cortical reactivity to TMS versus non-specific somatosensory and auditory co-activations using both single-pulse and paired-pulse protocols at suprathreshold stimulation intensities over the left dorsolateral prefrontal cortex (DLPFC). Fifteen right-handed healthy participants received six blocks of stimulation including single and paired TMS delivered as active-masked (i.e., TMS-EEG with auditory masking and foam spacing), active-unmasked (TMS-EEG without auditory masking and foam spacing) and sham (sham TMS coil). We evaluated cortical excitability following single-pulse TMS, and cortical inhibition following a paired-pulse paradigm (long-interval cortical inhibition (LICI)). Repeated measure ANOVAs revealed significant differences in mean cortical evoked activity (CEA) of active-masked, active-unmasked, and sham conditions for both the single-pulse (F(1.76, 24.63) = 21.88, p < 0.001, η2 = 0.61) and LICI (F(1.68, 23.49) = 10.09, p < 0.001, η2 = 0.42) protocols. Furthermore, global mean field amplitude (GMFA) differed significantly across the three conditions for both single-pulse (F(1.85, 25.89) = 24.68, p < 0.001, η2 = 0.64) and LICI (F(1.8, 25.16) = 14.29, p < 0.001, η2 = 0.5). Finally, only active LICI protocols but not sham stimulation ([active-masked (0.78 ± 0.16, P < 0.0001)], [active-unmasked (0.83 ± 0.25, P < 0.01)]) resulted in significant signal inhibition. While previous findings of a significant somatosensory and auditory contribution to the evoked EEG signal are replicated by our study, an artifact attenuated cortical reactivity can reliably be measured in the TMS-EEG signal with suprathreshold stimulation of DLPFC. Artifact attenuation can be accomplished using standard procedures, and even when masked, the level of cortical reactivity is still far above what is produced by sham stimulation. Our study illustrates that TMS-EEG of DLPFC remains a valid investigational tool. [ABSTRACT FROM AUTHOR]

The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation. The neural substrates of depression may differ by sex. Here the authors show that depression is associated with distinct brain connectivity changes in men and in women that are explained by sex-specific transcriptomic signatures involving genes previously implicated in synapse function, immune signalling, and depression risk. [ABSTRACT FROM AUTHOR]

Investigating effects of aging on neurophysiological mechanisms underlying working memory provides a better understanding of potential targets for brain intervention to prevent cognitive decline. Theta-gamma coupling (TGC) indexes the ability to order information processed during working memory tasks. Frontal theta event-related synchronization (ERS) and parietal alpha event-related desynchronization (ERD) index cognitive control and interference inhibition, respectively. Relative contributions of TGC, theta ERS, and alpha ERD in relation to stimulus presentation are not characterized. Further, differential effect of normal aging on pre- or post-stimulus processes is unknown. Electroencephalography was recorded in 66 younger and 41 older healthy participants while performing 3-back working memory task. We assessed relationships between 3-back task performance and each of post-stimulus TGC, pre-stimulus parietal alpha ERD, and pre-stimulus frontal theta ERS in each age group. While older adults performed worse on 3-back task than younger adults, TGC, alpha ERD, or theta ERS did not differ between the two groups. TGC was positively associated with 3-back performance in both age groups; pre-stimulus alpha ERD was associated with performance among younger adults; and pre-stimulus theta ERS was not associated with performance in either group. Our findings suggest that both pre-stimulus interference inhibition and post-stimulus ordering of information are important for working memory in younger adults. In contrast, performance in older adults appears to depend only on post-stimulus ordering of information. These specific contributions of neurophysiological resources may explain the poorer performance of older adults and suggest different targets to enhance working memory in age groups. [ABSTRACT FROM AUTHOR]

Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal of this study was to bilaterally target the insular region using the H-coil with repetitive Transcranial Magnetic Stimulation (rTMS) and subsequently measure changes in dopamine levels using Positron Emission Tomography (PET) with [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO). This was a within-subject, crossover, blinded and sham-controlled pilot study. Eight healthy, right-handed subjects, aged 19-45, participated in the investigation. All subjects underwent 3 PHNO-PET scans preceded by rTMS (sham, 1 Hz or 10 Hz), on 3 separate days. Low frequency rTMS (1 Hz), targeting the insular cortex, significantly decreased dopamine levels in the substantia nigra, sensorimotor striatum and associative striatum. Replicating this study in tobacco smokers or alcoholics would be a logical follow-up to assess whether H-coil stimulation of the bilateral insula can be employed as a treatment option for addiction. Trial registration: NCT02212405. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Substance-related and addictive disorders, in particular gambling disorder, are known to be associated with risky decision-making behavior. Several neuroimaging studies have identified the involvement of the insular cortex in decision-making under risk. However, the extent of this involvement remains unclear and the specific contributions of two distinct insular subregions, the rostral agranular (RAIC) and the caudal granular (CGIC), have yet to be examined. Animals were trained to perform a rat gambling task (rGT), in which subjects chose between four options that differed in the magnitude and probability of rewards and penalties. In order to address the roles of the RAIC and CGIC in established choice behavior, pharmacological inactivations of these two subregions via local infusions of GABA receptor agonists were performed following 30 rGT training sessions. The contribution made by the RAIC or CGIC to the acquisition of choice behavior was also determined by lesioning these areas before behavioral training. Inactivation of the RAIC, but not of the CGIC, shifted rats' preference toward options with greater reward frequency and lower punishment. Before rGT acquisition, lesions of the RAIC, but not the CGIC, likewise resulted in a higher preference for options with greater reward frequency and lower punishment, and this persisted throughout the 30 training sessions. Our results provide confirmation of the involvement of the RAIC in rGT choice behavior and suggest that the RAIC may mediate detrimental risky decision-making behavior, such as that associated with addiction and gambling disorder. [ABSTRACT FROM AUTHOR]

Generally, rewards that are received sooner are often preferred over future rewards, and the time between the choice and the reception of the reward is an important factor that influences our decisions, a phenomenon called delay discounting (DD). In DD, the medial prefrontal cortex (MePFC) and striatal dopamine neurotransmission both play an important role. We used repetitive transcranial magnetic stimulation (rTMS) to transiently activate the MePFC to evaluate its behavioral effect on the DD paradigm, and subsequently to measure its effect on striatal dopamine. Twenty-four right-handed young healthy subjects (11 females; age: 22.1±2.9 years) underwent DD following 10 Hz-rTMS of the MePFC and vertex stimulation (control condition). Thereafter, 11 subjects (5 females; age: 22.2±2.87 years) completed the PET study at rest using [11C]-(+)-PHNO following 10 Hz-rTMS of the MePFC and vertex. Modulation of the MePFC excitability influenced the subjective level of DD for delayed rewards and interfered with synaptic dopamine level in the striatum. The present study yielded findings that might reconcile the role of these areas in inter-temporal decision making and dopamine modulation, suggesting that the subjective sense of time and value of reward are critically controlled by these important regions. [ABSTRACT FROM AUTHOR]

Recently, deep brain stimulation (DBS) has been evaluated as an experimental therapy for treatment-resistant depression. Although there have been encouraging results in open-label trials, about half of the patients fail to achieve meaningful benefit. Although progress has been made in understanding the neurobiology of MDD, the ability to characterize differences in brain dynamics between those who do and do not benefit from DBS is lacking. In this study, we investigated EEG resting-state data recorded from 12 patients that have undergone DBS surgery. Of those, six patients were classified as responders to DBS, defined as an improvement of 50% or more on the 17-item Hamilton Rating Scale for Depression (HAMD-17). We compared hemispheric frontal theta and parietal alpha power asymmetry and synchronization asymmetry between responders and non-responders. Hemispheric power asymmetry showed statistically significant differences between responders and non-responders with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry was characterized by an increase in frontal theta in the right hemisphere relative to the left combined with an increase in parietal alpha in the left hemisphere relative to the right in non-responders compared with responders. Hemispheric mean synchronization asymmetry showed a statistically significant difference between responders and non-responders in the theta band, with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry resulted from an increase in frontal synchronization in the right hemisphere relative to the left combined with an increase in parietal synchronization in the left hemisphere relative to the right in non-responders compared with responders. Connectivity diagrams revealed long-range differences in frontal/central-parietal connectivity between the two groups in the theta band. This pattern was observed irrespective of whether EEG data were collected with active DBS or with the DBS stimulation turned off, suggesting stable functional and possibly structural modifications that may be attributed to plasticity. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder characterised by a complex phenotype including positive, negative, affective and cognitive symptoms. Various theories have been developed to integrate the clinical phenotype into a strong neurobiological framework. One theory describes schizophrenia as a disorder of impaired neural plasticity. Recently, non-invasive brain stimulation techniques have garnered much attention to their ability to modulate plasticity and treat schizophrenia. The aim of this review is to introduce the basic physiological principles of conventional non-invasive brain stimulation techniques and to review the available evidence for schizophrenia. Despite promising evidence for efficacy in a large number of clinical trials, we continue to have a rudimentary understanding of the underlying neurobiology. Additional investigation is required to improve the response rates to non-invasive brain stimulation, to reduce the interindividual variability and to improve the understanding of non-invasive brain stimulation in schizophrenia. [ABSTRACT FROM AUTHOR]

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ- and γ-activity and θ-phase-γ-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that obsessive-compulsive disorder (OCD) is associated with an inability to inhibit unwanted intrusive thoughts. The neurophysiological mechanisms mediating such inhibitory deficits include abnormalities in cortical γ-aminobutyric acid (GABA) inhibitory as well as N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms. Molecular evidence suggests that both these neurotransmitter systems are involved in OCD. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to ascertain neurophysiological indices of inhibitory GABA and facilitatory NMDA receptor-mediated mechanisms. In this study, both mechanisms were indexed in 34 patients with OCD (23 unmedicated and 11 medicated) and compared with 34 healthy subjects. Cortical inhibitory and facilitatory neurotransmission was measured using TMS paradigms known as short-interval cortical inhibition (SICI), cortical silent period (CSP), and intracortical facilitation (ICF). Patients with OCD demonstrated significantly shortened CSP (p<0.001, Cohen's d=0.91) and increased ICF (p<0.009, Cohen's d=0.71) compared with healthy subjects. By contrast, there were no significant deficits in SICI. After excluding patients with OCD and comorbid major depressive disorder (MDD) from the analysis, these differences remained significant. Our findings suggest that OCD is associated with dysregulation in cortical inhibitory and facilitatory neurotransmission. Specifically, these findings suggest impairments in GABAB receptor-mediated and NMDA receptor-mediated neurotransmission. These findings are consistent with previously published genetic studies implicating GABAB, and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form the basis for this disorder. [ABSTRACT FROM AUTHOR]

Active compounds in cannabis such as tetrahydrocannabinol (THC) interact with the inhibitory neurotransmitter δ-aminobutyric acid (GABA) but little is known about the functional effects of cannabis on human cortical brain processes. Therefore, the aim of the study was to investigate whether patients with chronic cannabis use demonstrate abnormalities in cortical inhibition or excitability. In all, 42 chronic cannabis using subjects (divided into heavy and light using subjects) and 19 controls were included in the study. Single and paired pulse transcranial magnetic stimulation were used to assess a number of parameters of cortical inhibition and cortical excitability. In addition, psychomotor function and THC plasma levels were measured. Both cannabis using groups (heavy and light use) demonstrated a reduction in short interval cortical inhibition compared with healthy controls, but there was no difference in other measures of cortical inhibition or cortical excitability. There was also no difference between the two groups on measures of psychomotor performance. Chronic cannabis use is associated with a reduction in cortical inhibition potentially related to activity at the GABAA receptors. Further research is required to explore whether this results from chronic cannabis use or reflects an underlying predisposition to developing chronic substance use problems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.Neuropsychopharmacology (2009) 34, 1543–1551; doi:10.1038/npp.2008.211; published online 26 November 2008 [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery–Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.Neuropsychopharmacology (2009) 34, 1255–1262; doi:10.1038/npp.2008.233; published online 14 January 2009 [ABSTRACT FROM AUTHOR]

Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery–Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.Neuropsychopharmacology (2009) 34, 522–534; doi:10.1038/npp.2008.118; published online 13 August 2008 [ABSTRACT FROM AUTHOR]

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.Neuropsychopharmacology (2008) 33, 2860–2869; doi:10.1038/npp.2008.22; published online 5 March 2008 [ABSTRACT FROM AUTHOR]

It has been suggested that the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are mediated through changes in cortical inhibition (CI). However, in healthy human subjects the effects of rTMS on CI have been inconsistent. Therefore, this study sought to improve on the methodological limitations of previous studies by exploring several different rTMS-stimulus conditions on inhibition in the human motor cortex. In the first experiment, 12 healthy control subjects were randomly assigned to receive regular 1, 10 or 20 Hz rTMS in a counterbalanced order with sessions separated by at least 1 week. In the second experiment, 10 of these 12 subjects received priming rTMS (600 stimuli at 6 Hz followed by 600 stimuli at 1 Hz). Cortical inhibition was indexed using short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Corticospinal excitability was indexed using motor threshold and MEP amplitude. We found no significant overall change in SICI, although there was a significant correlation between changes in SICI with baseline SICI. Subjects with greater SICI at baseline tended to have reduction in SICI post-rTMS, whereas subjects with less SICI tended to have increase in SICI post-rTMS. There was also a significant lengthening of the CSP with higher stimulation frequencies compared to lower stimulation frequencies. These findings suggest that rTMS increases CI, particularly in subjects with reduced baseline inhibition, a finding consistent with the concept of homeostatic plasticity. Baseline physiological characteristics may be further explored as a method to select patients who may benefit from rTMS treatment. [ABSTRACT FROM AUTHOR]

Previous studies suggest that antipsychotic medications may alter cortical inhibition (CI). The current study was designed to determine if typical or atypical antipsychotics indeed alter CI in healthy subjects using three CI paradigms as measured with transcranial magnetic stimulation (TMS): short interval intracortical inhibition (SICI), cortical silent period (CSP) and transcallosal inhibition (TCI). CI was measured before, 6 and 24 h after being randomly assigned to receive a single dose of 2 mg haloperidol (n=8), 10 mg olanzapine (n=10) or placebo (n=9). There was no significant effect on any measure of CI at 6 and 24 h after receiving olanzapine, haloperidol or placebo. Moreover, no significant change in the motor threshold was observed across the three medication groups. Therefore, single administration of an antipsychotic has no effect on CI or resting motor threshold. Whether chronic, repeated administration of antipsychotics has effects on CI requires further investigation. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is a highly effective neuromodulatory intervention for treatment-resistant major depressive disorder (MDD). Presently, however, understanding of its neurophysiological effects remains incomplete. In the present study, we utilised resting-state electroencephalography (RS-EEG) to explore changes in functional connectivity, network topology, and spectral power elicited by an acute open-label course of ECT in a cohort of 23 patients with treatment-resistant MDD. RS-EEG was recorded prior to commencement of ECT and again within 48 h following each patient's final treatment session. Our results show that ECT was able to enhance connectivity within lower (delta and theta) frequency bands across subnetworks largely confined to fronto-central channels, while, conversely, more widespread subnetworks of reduced connectivity emerged within faster (alpha and beta) bands following treatment. Graph-based topological analyses revealed changes in measures of functional segregation (clustering coefficient), integration (characteristic path length), and small-world architecture following ECT. Finally, post-treatment enhancement of delta and theta spectral power was observed, which showed a positive association with the number of ECT sessions received. Overall, our findings indicate that RS-EEG can provide a sensitive measure of dynamic neural activity following ECT and highlight network-based analyses as a promising avenue for furthering mechanistic understanding of the effects of convulsive therapies. [ABSTRACT FROM AUTHOR]

Purpose: Review recent meta-analyses and clinical trials investigating the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) for concurrent pain and depressive symptoms.Recent Findings: Recent meta-analyses have included both pain and depression outcomes in fibromyalgia and chronic pain. Randomized controlled trials have also been conducted in post-herpetic neuralgia, trauma-related headache, and neuropathic pain with attention to both pain and depressive symptoms. In general, studies have demonstrated reduction in pain in patients with fibromyalgia as an add-on treatment, post-herpetic neuralgia, trauma-related headache, and neuropathic pain. There are variable findings for reduction in depressive symptoms in patients with co-morbid pain disorders. Theta burst stimulation (TBS) is a novel rTMS protocol that has recently been investigated in patients with depression and some smaller trials in patients with co-morbid pain disorders. These emerging treatment options may have similar or greater therapeutic potency and may be delivered with greater efficiency. There is evidence to support the use of rTMS for its analgesic effects in various pain syndromes. The variable results between trials for treatment of concurrent depressive symptoms may be due to heterogeneity in treatment protocols including parameters such as site of stimulation (primary motor cortex versus dorsolateral prefrontal cortex) and restrictions in the patient population which usually exclude primary psychiatric diagnoses. Future trials should work to standardize these protocols, investigate novel protocols like TBS, and continue to include standardized assessment of concurrent psychiatric outcomes such as depression and anxiety. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]