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Background Objective Methods Results Conclusions Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high‐frequency repetitive somatosensory stimulation (RSS; HF‐RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low‐frequency RSS (LF‐RSS) increases them. However, direct testing on affected body parts was not conducted.This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms.We applied HF‐RSS and LF‐RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired‐pulse somatosensory evoked potentials, spatial lateral inhibition measured by double‐pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function.Both synchronous and asynchronous low‐frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired‐pulse somatosensory evoked potentials. Opposite effects were observed with high‐frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low‐frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high‐frequency stimulation operated in an opposite direction.Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low‐frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Noninvasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS), are emerging as promising tools for enhancing cognitive functions by modulating brain activity and enhancing cognitive functions. Despite their potential, the specific and combined effects of tDCS and tRNS on brain functions, especially regarding functional connectivity, cortical inhibition, and memory performance, are not well-understood. This study aims to explore the distinct and combined impacts of tDCS and tRNS on these neural and cognitive parameters. Using a within-subject design, ten participants underwent four stimulation conditions: sham, tDCS, tRNS, and combined tDCS + tRNS. We assessed the impact on resting-state functional connectivity, cortical inhibition via Cortical Silent Period (CSP), and visuospatial memory performance using the Corsi Block-tapping Test (CBT). Our results indicate that while tDCS appears to induce brain lateralization, tRNS has more generalized and dispersive effects. Interestingly, the combined application of tDCS and tRNS did not amplify these effects but rather suggested a non-synergistic interaction, possibly due to divergent mechanistic pathways, as observed across fMRI, CSP, and CBT measures. These findings illuminate the complex interplay between tDCS and tRNS, highlighting their non-additive effects when used concurrently and underscoring the necessity for further research to optimize their application for cognitive enhancement. [ABSTRACT FROM AUTHOR]

Schizophrenia has been associated with a reduced task-related modulation of cortical activity assessed through electroencephalography (EEG). However, to the best of our knowledge, no study so far has assessed the underpinnings of this decreased EEG modulation in schizophrenia. A possible substrate of these findings could be a decreased inhibitory function, a replicated finding in the field. In this pilot study, our aim was to explore the association between EEG modulation during a cognitive task and the inhibitory system function in vivo in a sample including healthy controls and patients with schizophrenia. We hypothesized that the replicated decreased task-related activity modulation during a cognitive task in schizophrenia would be related to a hypofunction of the inhibitory system. For this purpose, 27 healthy controls and 22 patients with schizophrenia (including 13 first episodes) performed a 3-condition auditory oddball task from which the spectral entropy modulation was calculated. In addition, cortical reactivity—as an index of the inhibitory function—was assessed by the administration of 75 monophasic transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex. Our results replicated the task-related cortical activity modulation deficit in schizophrenia patients. Moreover, schizophrenia patients showed higher cortical reactivity following transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex compared to healthy controls. Cortical reactivity was inversely associated with EEG modulation, supporting the idea that a hypofunction of the inhibitory system could hamper the task-related modulation of EEG activity. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS), via an electrical current being sent through the brains motor cortex, can elicit pain reduction and improved function in people with knee osteoarthritis (OA), compared to a sham. However, it is unknown whether tDCS-induced reductions in pain can be expected in hip OA given differences between hip and knee OA phenotypes. Methods: Two-armed (n ​= ​39 per arm), triple-blind, randomised controlled trial, with an 8-week intervention window and 8-week post-intervention follow-up assessing the efficacy of real anodal tDCS plus exercise versus sham tDCS plus exercise. Primary outcome measure is the International Hip Outcome Tool–33 (iHOT-33). Aims: The primary objective of this randomised controlled trial is to quantify the effect of tDCS and exercise on pain, disability and quality of life in people with hip OA. Our secondary objectives include: 1) quantifying the influence of motor cortex excitability and conditioned pain modulation on treatment effects, and 2) quantifying the economic cost/benefit of tDCS for improving health-related quality of life in people with hip OA. Analysis: Data distributions will be examined for each outcome and guide preliminary statistical between group test selections. Repeated mixed effects models will determine between-group differences for the primary outcome (iHOT-33), accounting for relevant confounders (i.e., age; sex; body mass index; radiographic severity) with relevant model assumptions examined. Secondary analysis will determine between-group differences for the other outcomes of interest (cortex excitability and conditioned pain modulation). Implications: This randomised controlled trial investigates a novel intervention to improve pain, function and quality of life in people with hip OA.

Introduction Around half of adults over the age of 60 experience sleep problems (Reid et al., 2006). The most common treatments for sleep disorders like insomnia are pharmacotherapy and cognitive behavioural therapy. Unfortunately, pharmacotherapy often leads to increased mortality and fall rates in older adults, whereas cognitive behavioural therapy is expensive and difficult to access (Patel et al., 2018). Hence, there is an urgent need for new effective and affordable treatments with reduced negative side effects. An important role for the initiation and maintenance of sleep is attributed to gamma-aminobutyric acid (GABA)-mediated inhibition (Saper et al., 2005). On one hand, it has been shown that GABA-mediated inhibition as well as GABA concentrations are lower in older compared to younger adults (Cuypers et al., 2018). On the other hand, balance training was shown to increase GABA-mediated inhibition in young (Taube et al., 2020) and older adults (Kuhn et al., 2023). Therefore, balance learning seems to be a promising treatment for older adults suffering from sleep problems. Furthermore, balance learning was shown to enhance functional connectivity (Ueta et al., 2022). In particular, functional connectivity in the sensorimotor cortex has been associated with better subjective sleep quality (Jiang et al., 2023). Therefore, we hypothesized that balance learning in older adults improves subjective sleep quality through an increase in GABA-mediated inhibition and sensorimotor network functional connectivity. Methods Forty healthy volunteers aged 64-81 years were randomly assigned to either follow a three-month balance learning intervention (minimum of 30 training sessions) or to continue with their daily routines. Thirty-six participants (18 in intervention group, 18 in control group) completed pre and post measurements and were included in the analysis. Before and after the three-month period, subjective sleep quality, balance performance, and neurophysiological and neuroimaging parameters were assessed. The Pittsburgh Sleep Quality Questionnaire (PSQI) was employed to evaluate subjective sleep quality in the preceding four weeks. Balance performance was assessed by determining the sway area in cm2 during a twenty second balance task on the most difficult wobble board level the participant still succeeded at. Short- interval intracortical inhibition (SICI), a measure of the activity of inhibitory interneurons in the motor cortex, was measured using transcranial magnetic stimulations while the participants were balancing on the same wobble board as during the balance performance assessment, and during an afternoon nap. Furthermore, resting-state functional connectivity was assessed with functional magnetic resonance imaging. The PSQI total scores were not normally distributed and therefore square root- transformed prior to the statistical analysis. Differences between post measurements were analysed using analysis of covariance (ANCOVA) with pre values as a covariate. Post-hoc t-tests were applied to determine the direction of change. Correlations between improvements in balance performance and sleep quality and neurochemical and neurophysiological measures were calculated using Spearman correlation analysis. Results ANCOVA revealed a significant effect of group on balance performance (p = 0.025). Post-hoc tests showed a significant improvement in performance after balance learning, indicated by a mean decrease of sway area by 33% (p = 0.002), while there was no significant change in the control group (p = 0.365). Furthermore, increases in balance performance were significantly associated with increases in SICI during execution of a balance task (r = -0.54, p = 0.02). ANCOVA revealed a significant effect of group on PSQI total score (p = 0.04). Post-hoc tests showed a significant decrease in the balance group by 23% (p = 0.015), indicating better subjective sleep quality after balance learning, while there was no significant change in the control group (p = 0.72). Improved subjective sleep quality in the balance group showed a trend towards an association with increased SICI while participants were falling asleep (r = -0.59, p = 0.07). Furthermore, there was a significant effect of group on functional connectivity (p = 0.005). In the balance group, functional connectivity increased by 40% (p = 0.003), while there were no significant changes in the control group (p = 0.32; p = 0.34). Correlation analysis at the population level revealed significant correlations between SICI during a balance task and balance performance (r = -0.4, p = 0.02), between SICI while balancing and functional connectivity (r = 0.38, p = 0.04), and between functional connectivity and balance performance (r = -0.5, p = 0.006). Discussion/Conclusion After three months of balance learning, older adults did not only show an improved balance performance but also significant improvements in their subjective sleep quality. Moreover, functional connectivity was significantly enhanced after balance learning and was positively associated with changes in SICI during execution of a balance task. These findings may be explained by the idea that functional connectivity plays a crucial role in the functional use of GABA, modulating inhibition across brain regions. Furthermore, the concept of task-specificity of intracortical inhibition is endorsed by the finding that specifically participants who showed an increase in GABAergic inhibition while falling asleep improved their subjective sleep quality. In conclusion, balance learning did improve subjective sleep quality and changes in functional connectivity and GABAergic inhibition might be (part of) the underlying mechanisms driving this change. References Cuypers, K., Maes, C., & Swinnen, S. P. (2018). Aging and GABA. Aging, 10(6), 1186-1187. https://doi.org/10.18632/aging.101480 Jiang, C., Cai, S., & Zhang, L. (2023). Functional connectivity of white matter and its association with sleep quality. Nature and Science of Sleep, 15, 287-300. https://doi.org/10.2147/NSS.S406120 Kuhn, Y.-A., Bugnon, M., Egger, S., Lehmann, N., Taubert, M., & Taube, W. (2023). Age-related decline in GABAergic intracortical inhibition can be counteracted by long-term learning of balance skills [Manuscript submitted for publication]. Neurosciences and Movement Science, University of Fribourg. Patel, D., Steinberg, J., & Patel, P. (2018). Insomnia in the elderly: A review. Journal of Clinical Sleep Medicine, 14(6), 1017-1024. https://doi.org/10.5664/jcsm.7172 Reid, K. J., Martinovich, Z., Finkel, S., Statsinger, J., Golden, R., Harter, K., & Zee, P. C. (2006). Sleep: A marker of physical and mental health in the elderly. The American Journal of Geriatric Psychiatry, 14(10), 860-866. https://doi.org/10.1097/01.JGP.0000206164.56404.ba Saper, C. B., Scammell, T. E., & Lu, J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437(7063), 1257-1263. https://doi.org/10.1038/nature04284 Taube, W., Gollhofer, A., & Lauber, B. (2020). Training-, muscle- and task-specific up- and downregulation of cortical inhibitory processes. European Journal of Neuroscience, 51(6), 1428-1440. https://doi.org/10.1111/ejn.14538 Ueta, K., Mizuguchi, N., Sugiyama, T., Isaka, T., & Otomo, S. (2022). The Motor Engram of Functional Connectivity Generated by Acute Whole-Body Dynamic Balance Training. Medicine and Science in Sports and Exercise, 54(4), 598-608. https://doi.org/10.1249/MSS.0000000000002829

BackgroundElectroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood.Methods/designThis neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity.DiscussionECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments.Trial registrationClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability. [ABSTRACT FROM AUTHOR]

Cortical GABAergic interneurons (INs) represent a diverse population of mainly locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP). However, a fourth group that includes neurogliaform cells (NGFCs) has been less well characterized due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 INs had more variable properties, with most cells corresponding to a diverse group of INs that strongly expresses the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several distinguishing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this underappreciated group of INs.

The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability.

Whether cortical excitation and inhibition functions differ between patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI) and healthy subjects and whether 0.5 mg/kg ketamine infusion can modulate cortical excitation and inhibition functions among patients with TRD–SI remain unclear. A total of 29 patients with TRD–SI and 35 age- and sex-matched healthy controls were assessed using paired-pulse transcranial magnetic stimulation. The patients were randomly assigned to receive either a single 0.5-mg/kg ketamine or 0.045-mg/kg midazolam infusion. Depressive and suicidal symptoms were assessed at baseline and 240 min after infusion. Intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI), all of which reflect cortical excitability and inhibition functions, were measured at the same time points. The patients with TRD–SI had lower ICF (p < 0.001) estimates (worse cortical excitatory function) and higher SICI (p = 0.032) and LICI (p < 0.001) estimates (worse cortical inhibitory function) compared with the control group. Higher SICI estimates at baseline were associated with greater baseline suicidal symptoms. No differences were found in the SICI, ICF, and LICI estimates at 240 min after the infusion between the two groups. Low-dose ketamine did not alter the cortical excitation and inhibition functions of the patients with TRD–SI. However, decreased SICI estimates (greater cortical inhibition function) were related to the reduction of suicidal symptoms. Dysfunction of cortical excitation and inhibition may play a crucial role in the pathomechanisms of TRD and suicidal symptoms. However, we found a lack of predictive ability of the baseline cortical excitation and inhibition parameters on the antidepressant and antisuicidal effect of low-dose ketamine infusion. [ABSTRACT FROM AUTHOR]

Functional paralysis (FP) or limb weakness is a common presentation of functional movement disorders (FMD), accounting for 18.1% of the clinical manifestations of FMD. The pathophysiology of FP is not known, but imaging studies have identified changes in structural and functional connectivity in multiple brain networks. It has been proposed that noninvasive brain stimulation techniques may be used to understand the pathophysiology of FP and may represent a possible therapeutic option. In this paper, we reviewed transcranial magnetic stimulation studies on functional paralysis, focusing on their pathophysiological and therapeutical implications. Overall, there is general agreement on the integrity of corticospinal pathways in FP, while conflicting results have been found about the net excitability of the primary motor cortex and its excitatory/inhibitory circuitry in resting conditions. The possible involvement of spinal cord circuits remains an under-investigated area. Repetitive transcranial magnetic stimulation appears to have a potential role as a safe and viable option for the treatment of functional paralysis, but more studies are needed to investigate optimal stimulation parameters and clarify its role in the context of other therapeutical options. [ABSTRACT FROM AUTHOR]

Background: The cortical silent period (CSP) and long-interval intracortical inhibition (LICI) are putative markers of γ-aminobutyric acid receptor type B (GABAB)-mediated inhibitory neurotransmission. We aimed to assess the association between LICI and CSP in youths. Methods: We analyzed data from three previous studies of youth who underwent CSP and LICI measurements with transcranial magnetic stimulation and electromyography. We assessed CSP and LICI association using Spearman rank correlation tests and multiple linear regression analyses adjusted for demographic and clinical covariates. Results: The sample included 16 healthy participants and 45 participants with depression. The general mean (SD) age was 15.5 (1.7), 14.3 (1.7) for healthy participants, and 15.9 (1.6) years for participants with depression. Measures were nonnormally distributed (Shapiro–Wilk, p < 0.001). CSP and LICI were not correlated at 100-millisecond (ρ = −0.2421, p = 0.06), 150-millisecond (ρ = −0.1612, p = 0.21), or 200-millisecond (ρ = −0.0507, p = 0.70) interstimulus intervals using Spearman rank correlation test. No correlations were found in the multiple regression analysis (p = 0.35). Conclusions: Although previous studies suggest that cortical silent period and long-interval intracortical inhibition measure GABAB receptor-mediated activity, these biomarkers were not associated in our sample of youths. Future studies should focus on the specific physiologic and pharmacodynamic properties assessed by CSP and LICI in younger populations. [ABSTRACT FROM AUTHOR]

The basal forebrain provides cholinergic inputs to primary visual cortex (V1) that play a key modulatory role on visual function. While basal forebrain afferents terminate in the infragranular layers of V1, acetylcholine is delivered to more superficial layers through volume transmission. Nevertheless, direct synaptic contact in deep layers 5 and 6 may provide a more immediate effect on V1 modulation. Using helper viruses with cell type specific promoters to target retrograde infection of pseudotyped and genetically modified rabies virus evidence was found for direct synaptic input onto V1 inhibitory neurons. These inputs were similar in number to geniculocortical inputs and, therefore, considered robust. In contrast, while clear evidence for dorsal lateral geniculate nucleus input to V1 excitatory neurons was found, there was no evidence of direct synaptic input from the basal forebrain. These results suggest a direct and more immediate influence of the basal forebrain on local V1 inhibition.

The investigational potential of TMS in psychiatry is largely underutilized. In the current article, we present the results of five studies with similar TMS protocols that looked at the investigative applications of TMS via measuring cortical reactivity as potential biomarkers in mood disorders. The first two studies, evaluate potential of TMS parameters and Motor neuron system (MNS) as state or trait markers of BD. Third and fourth studies evaluate these as endophenotypic markers of BD. The fifth study which is an RCT evaluating add-on yoga in UD, evaluates if markers of CI can index the therapeutic response of yoga. In study one MT1 was significantly greater in the SM (symptomatic-mania) group compared to HC (healthy-control) (P=0.032). The cortical inhibition measures SICI was reduced in SM(P=0.021) and BD (remitted Bipolar) (P=0.023) groups compared to HC. LICI was increased in the SM(0.021) and BD(P=0.06) groups compared to HC. In study two, a significant group x time interaction effect was observed indicating higher putative MNS-activity mediation in patients compared to HC on SlCl(P=0.024), LlCl(P=0.033). There were no significant group differences noted in the endophenotype studies. The fifth study showed a significant time X group interaction for CSP, favoring improvement in YG (yoga-group) (p<0.01).No significant change was observed for LICI(p=0.2), SICI(p=0.5). Limitations of these studies notwithstanding, we conclude that cortical reactivity measured using TMS is a potential biomarker across the course of mood disorders, starting from state and trait markers to understanding the therapeutic mechanism of a particular treatment modality in these disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood. Methods/design This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity. Discussion ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments. Trial registration ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI. [ABSTRACT FROM AUTHOR]

Biochemical processes underpin the structure and function of the visual cortex, yet our understanding of the fundamental neurochemistry of the visual brain is incomplete. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive brain imaging tool that allows chemical quantification of living tissue by detecting minute differences in the resonant frequency of molecules. Application of MRS in the human brain in vivo has advanced our understanding of how the visual brain consumes energy to support neural function, how its neural substrates change as a result of disease or dysfunction, and how neural populations signal during perception and plasticity. The aim of this review is to provide an entry point to researchers interested in investigating the neurochemistry of the visual system using in vivo measurements. We provide a basic overview of MRS principles, and then discuss recent findings in four topics of vision science: (i) visual perception, plasticity in the (ii) healthy and (iii) dysfunctional visual system, and (iv) during visual stimulation. Taken together, evidence suggests that the neurochemistry of the visual system provides important novel insights into how we perceive the world. [ABSTRACT FROM AUTHOR]

Background: Although numerous studies reported some changes of cortical silent period (CSP), an indicator of gamma-aminobutyric acid (GABA) function in central nervous system, in schizophrenia patients, it has been unknown how the disease stage and antipsychotic medication affect CSP values. Methods: The present study conducted a systematic review of previous literature comparing CSP between schizophrenia patients and healthy subjects, and then performed meta-analysis on the effects of (1) the disease stage and (2) antipsychotics on CSP. Results: (1) In the comparison of the disease stage comprising a total of 17 reports, there was no significant difference in CSP between patients under drug-naïve first-episode psychoses and healthy controls, or between patients with antipsychotic medication and healthy controls. (2) In the comparison of the antipsychotic class, patients treated with clozapine were longer in CSP compared to healthy controls. Patients treated with olanzapine/quetiapine or with other type of antipsychotics were not different from healthy controls. Regarding other type of antipsychotics, the iteration analysis after leaving out one literature showed that patients were shorter in CSP than healthy controls. Conclusion: The results showed that clozapine seems to surely prolong CSP, indicating the enhancement of GABA transmission via GABAB receptors, suggesting the possible relationship between the CSP prolongation by clozapine and its high efficacy in psychopathology. The finding of shorter CSP in patients with other type of antipsychotics was distinct from clozapine/olanzapine/quetiapine, but was difficult to interpret since this group included a variety of transcranial magnetic stimulation (TMS) methodologies and patients' background. [ABSTRACT FROM AUTHOR]

Functional paralysis (FP) or limb weakness is a common presentation of functional movement disorders (FMD), accounting for 18.1% of the clinical manifestations of FMD. The pathophysiology of FP is not known, but imaging studies have identified changes in structural and functional connectivity in multiple brain networks. It has been proposed that noninvasive brain stimulation techniques may be used to understand the pathophysiology of FP and may represent a possible therapeutic option. In this paper, we reviewed transcranial magnetic stimulation studies on functional paralysis, focusing on their pathophysiological and therapeutical implications. Overall, there is general agreement on the integrity of corticospinal pathways in FP, while conflicting results have been found about the net excitability of the primary motor cortex and its excitatory/inhibitory circuitry in resting conditions. The possible involvement of spinal cord circuits remains an under-investigated area. Repetitive transcranial magnetic stimulation appears to have a potential role as a safe and viable option for the treatment of functional paralysis, but more studies are needed to investigate optimal stimulation parameters and clarify its role in the context of other therapeutical options.

Background: The cortical silent period (CSP) and long-interval intracortical inhibition (LICI) are putative markers of γ-aminobutyric acid receptor type B (GABAB)-mediated inhibitory neurotransmission. We aimed to assess the association between LICI and CSP in youths. Methods: We analyzed data from three previous studies of youth who underwent CSP and LICI measurements with transcranial magnetic stimulation and electromyography. We assessed CSP and LICI association using Spearman rank correlation tests and multiple linear regression analyses adjusted for demographic and clinical covariates. Results: The sample included 16 healthy participants and 45 participants with depression. The general mean (SD) age was 15.5 (1.7), 14.3 (1.7) for healthy participants, and 15.9 (1.6) years for participants with depression. Measures were nonnormally distributed (Shapiro–Wilk, p < 0.001). CSP and LICI were not correlated at 100-millisecond (ρ = −0.2421, p = 0.06), 150-millisecond (ρ = −0.1612, p = 0.21), or 200-millisecond (ρ = −0.0507, p = 0.70) interstimulus intervals using Spearman rank correlation test. No correlations were found in the multiple regression analysis (p = 0.35). Conclusions: Although previous studies suggest that cortical silent period and long-interval intracortical inhibition measure GABAB receptor-mediated activity, these biomarkers were not associated in our sample of youths. Future studies should focus on the specific physiologic and pharmacodynamic properties assessed by CSP and LICI in younger populations.

LIS1 (PAFAH1B1) plays a major role in the developing cerebral cortex, and haploinsufficient mutations cause human lissencephaly type 1. We have studied morphological and functional properties of the cerebral cortex of mutant mice harboring a deletion in the first exon of the mouse Lis1 (Pafah1b1) gene, which encodes for the LisH domain. The Lis1/sLis1 animals had an overall unaltered cortical structure but showed an abnormal distribution of cortical GABAergic interneurons (those expressing calbindin, calretinin, or parvalbumin), which mainly accumulated in the deep neocortical layers. Interestingly, the study of the oscillatory activity revealed an apparent inability of the cortical circuits to produce correct activity patterns. Moreover, the fast spiking (FS) inhibitory GABAergic interneurons exhibited several abnormalities regarding the size of the action potentials, the threshold for spike firing, the time course of the action potential after-hyperpolarization (AHP), the firing frequency, and the frequency and peak amplitude of spontaneous excitatory postsynaptic currents (sEPSC’s). These morphological and functional alterations in the cortical inhibitory system characterize the Lis1/sLis1 mouse as a model of mild lissencephaly, showing a phenotype less drastic than the typical phenotype attributed to classical lissencephaly. Therefore, the results described in the present manuscript corroborate the idea that mutations in some regions of the Lis1 gene can produce phenotypes more similar to those typically described in schizophrenic and autistic patients and animal models.

BackgroundMajor depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls.MethodsWe measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls.ResultsThe overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group (t(17) = −2.8, p = 0.01), whereas no potentiation was observed in patients.ConclusionsPotentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size.SignificanceThese findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients.

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking. Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects. Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined. Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration. Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD. [ABSTRACT FROM AUTHOR]

• Results provide further evidence of distinct motor cortex (M1) interneurons. • AP corticospinal excitability increased after acute exercise. • AP intracortical inhibition decreased after acute exercise. • Acute exercise had no significant effect on measures of PA TMS. • M1 interneurons may be important in exercise-induced excitability modulations. Acute exercise can modulate the excitability of the non-exercised upper-limb representation in the primary motor cortex (M1). Accumulating evidence demonstrates acute exercise affects measures of M1 intracortical excitability, with some studies also showing altered corticospinal excitability. However, the influence of distinct M1 interneuron populations on the modulation of intracortical and corticospinal excitability following acute exercise is currently unknown. We assessed the impact of an acute bout of leg cycling exercise on unique M1 interneuron excitability of a non-exercised intrinsic hand muscle using transcranial magnetic stimulation (TMS) in young adults. Specifically, posterior-to-anterior (PA) and anterior-to-posterior (AP) TMS current directions were used to measure the excitability of distinct populations of interneurons before and after an acute bout of exercise or rest. Motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) were measured in the PA and AP current directions in M1 at two time points separated by 25 min of rest, as well as immediately and 30 min after a 25-minute bout of moderate-intensity cycling exercise. Thirty minutes after exercise, MEP amplitudes were significantly larger than other timepoints when measured with AP current, whereas MEP amplitudes derived from PA current did not show this effect. Similarly, SICI was significantly decreased immediately following acute exercise measured with AP but not PA current. Our findings suggest that the excitability of unique M1 interneurons are differentially modulated by acute exercise. These results indicate that M1 interneurons preferentially activated by AP current may play an important role in the exercise-induced modulation of intracortical and corticospinal excitability. [ABSTRACT FROM AUTHOR]

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking.Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects.Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined.Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration.Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD.

Noninvasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS), are emerging as promising tools for enhancing cognitive functions by modulating brain activity and enhancing cognitive functions. Despite their potential, the specific and combined effects of tDCS and tRNS on brain functions, especially regarding functional connectivity, cortical inhibition, and memory performance, are not well-understood. This study aims to explore the distinct and combined impacts of tDCS and tRNS on these neural and cognitive parameters. Using a within-subject design, ten participants underwent four stimulation conditions: sham, tDCS, tRNS, and combined tDCS + tRNS. We assessed the impact on resting-state functional connectivity, cortical inhibition via Cortical Silent Period (CSP), and visuospatial memory performance using the Corsi Block-tapping Test (CBT). Our results indicate that while tDCS appears to induce brain lateralization, tRNS has more generalized and dispersive effects. Interestingly, the combined application of tDCS and tRNS did not amplify these effects but rather suggested a non-synergistic interaction, possibly due to divergent mechanistic pathways, as observed across fMRI, CSP, and CBT measures. These findings illuminate the complex interplay between tDCS and tRNS, highlighting their non-additive effects when used concurrently and underscoring the necessity for further research to optimize their application for cognitive enhancement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Huang, Lee, Chang, Wang and Lin.)

Long-interval intracortical inhibition (LICI) is a paired-pulse transcranial magnetic stimulation (TMS) paradigm mediated in part by gamma-aminobutyric acid receptor B (GABAB) inhibition. Prior work has examined LICI as a putative biomarker in an array of neuropsychiatric disorders. This review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sought to examine existing literature focused on LICI as a biomarker in neuropsychiatric disorders. There were 113 articles that met the inclusion criteria. Existing literature suggests that LICI may have utility as a biomarker of GABAB functioning but more research with increased methodologic rigor is needed. The extant LICI literature has heterogenous methodology and inconsistencies in findings. Existing findings to date are also non-specific to disease. Future research should carefully consider existing methodological weaknesses and implement high-quality test-retest reliability studies.

When observers view a perceptually bistable stimulus, their perception changes stochastically. Various studies have shown across-observer correlations in the percept durations for different bistable stimuli including binocular rivalry stimuli and bistable moving plaids. Previous work on binocular rivalry posits that neural inhibition in the visual hierarchy is a factor involved in the perceptual fluctuations in that paradigm. Here, in order to investigate whether between-observer variability in cortical inhibition underlies correlated percept durations between binocular rivalry and bistable moving plaid perception, we used center-surround suppression as a behavioral measure of cortical inhibition. We recruited 217 participants in a test battery that included bistable perception paradigms as well as a center-surround suppression paradigm. While we were able to successfully replicate the correlations between binocular rivalry and bistable moving plaid perception, we did not find a correlation between center-surround suppression strength and percept durations for any form of bistable perception. Moreover, the results from a mediation analysis indicate that center-surround suppression is not the mediating factor in the correlation between binocular rivalry and bistable moving plaids. These results do not support the idea that cortical inhibition can explain the between-observer correlation in mean percept duration between binocular rivalry and bistable moving plaid perception. [ABSTRACT FROM AUTHOR]

Long-interval intracortical inhibition (LICI) is a paired-pulse transcranial magnetic stimulation (TMS) paradigm mediated in part by gamma-aminobutyric acid receptor B (GABAB) inhibition. Prior work has examined LICI as a putative biomarker in an array of neuropsychiatric disorders. This review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sought to examine existing literature focused on LICI as a biomarker in neuropsychiatric disorders. There were 113 articles that met the inclusion criteria. Existing literature suggests that LICI may have utility as a biomarker of GABAB functioning but more research with increased methodologic rigor is needed. The extant LICI literature has heterogenous methodology and inconsistencies in findings. Existing findings to date are also non-specific to disease. Future research should carefully consider existing methodological weaknesses and implement high-quality test-retest reliability studies. [ABSTRACT FROM AUTHOR]

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of c oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry. [ABSTRACT FROM AUTHOR]

Summary Intractable epilepsy is commonly associated with developmental cortical malformations. Using the rodent freeze lesion model, we have sought the underlying circuit abnormalities contributing to the epileptiform activity that occurs in association with the structural pathology of four‐layered microgyria. We showed previously that within the epileptogenic paramicrogyral region (PMR) surrounding the malformation, non–fast‐spiking neurons commonly containing somatostatin (SSt) exhibit alterations, including having a greater maximum firing rate. Here we examined the output of SSt interneurons with optogenetics, using SSt‐Cre mice mated to mice with floxed channelrhodopsin‐2. Voltage clamp recordings from layer V pyramidal neurons in ex vivo slices had significantly enhanced SSt‐evoked inhibitory postsynaptic currents in PMR cortex compared to control. In addition, under conditions of low‐Mg2+ artificial cerebral spinal fluid (aCSF), light activation of the SSt neurons evoked field potential epileptiform activity in the PMR cortex, but not in control. These data suggest that within the PMR cortex, SSts have a significantly larger effect on excitatory neurons. Surprisingly, the network effect of this enhanced inhibition is hyperexcitability with propagating epileptiform activity, perhaps due to disinhibition of other interneuron cell types or to enhanced synchrony of excitatory cortical elements. This identification creates a new locus for potential modulation of epileptiform activity associated with cortical malformation.

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI.

Corticospinal excitability, and particularly the balance between cortical inhibitory and excitatory processes (assessed in a muscle using single and paired-pulse transcranial magnetic stimulation), are affected by neurodegenerative pathologies or following a stroke. This review describes how locomotor exercises may counterbalance these neuroplastic alterations, either when performed under its conventional form (e.g., walking or cycling) or when comprising eccentric (i.e., active lengthening) muscle contractions. Non-fatiguing conventional locomotor exercise decreases intracortical inhibition and/or increases intracortical facilitation. These modifications notably seem to be a consequence of neurotrophic factors (e.g., brain-derived neurotrophic factor) resulting from the hemodynamic solicitation. Furthermore, it can be inferred from non-invasive brain and peripheral stimulation studies that repeated activation of neural networks can endogenously shape neuroplasticity. Such mechanisms could also occur following eccentric exercises (lengthening of the muscle), during which motor-related cortical potential (electroencephalography) is of greater magnitude and lasts longer than during concentric exercises (i.e., muscle shortening). As single-joint eccentric exercise decreased short- and long-interval intracortical inhibition and increased intracortical facilitation, locomotor eccentric exercise (e.g., downhill walking or eccentric cycling) may be even more potent by adding hemodynamic-related neuroplastic processes to endogenous processes. Besides, eccentric exercise is especially useful to develop relatively high force levels at low cardiorespiratory and perceived intensities, which can be a training goal alongside the induction of neuroplastic changes. Even though indirect evidence let us think that locomotor eccentric exercise could shape neuroplasticity in ways relevant to neurorehabilitation, its efficacy remains speculative. We provide future research directions on the neuroplastic effects and underlying mechanisms of locomotor exercise. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a mental illness with high socio-economic burden, but its pathophysiology has not been fully elucidated. Recently, the cortical excitatory and inhibitory imbalance hypothesis and neuroplasticity hypothesis have been proposed for MDD. Although several studies have examined the neurophysiological profiles in MDD using transcranial magnetic stimulation (TMS), a meta-analysis of TMS neurophysiology has not been performed. The objective of this study was to compare TMS-electromyogram (TMS-EMG) findings between patients with MDD and healthy controls (HCs). To this end, we examined whether patients with MDD have lower short-interval cortical inhibition (SICI) which reflects gamma-aminobutyric acid (GABA)A receptor-mediated activity, lower cortical silent period (CSP) which represents GABAB receptor-mediated activity, higher intracortical facilitation (ICF) which reflects glutamate N-methyl-D-aspartate receptor-mediated activity, and the lower result of paired associative stimulation (PAS) paradigm which shows the level of neuroplasticity in comparison with HC. Further, we explored the effect of clinical and demographic factors that may influence TMS neurophysiological indices. We first searched and identified research articles that conducted single- or paired-pulse TMS-EMG on patients with MDD and HC. Subsequently, we extracted the data from the included studies and meta-analyzed the data with the comprehensive meta-analysis software. Patients with MDD were associated with lower SICI, lower CSP, potentially higher ICF, and lower PAS compared with HC. Our results confirmed the proposed hypotheses, suggesting the usefulness of TMS neurophysiology as potential diagnostic markers of MDD. [ABSTRACT FROM AUTHOR]

In schizophrenia and related disorders, a deeper mechanistic understanding of neocortical dysfunction will be essential to developing new diagnostic and therapeutic techniques. To this end, combined transcranial magnetic stimulation and electroencephalography (TMS/EEG) provides a non-invasive tool to simultaneously perturb and measure neurophysiological correlates of cortical function, including oscillatory activity, cortical inhibition, connectivity, and synchronization. In this review, we summarize the findings from a variety of studies that apply TMS/EEG to understand the fundamental features of cortical dysfunction in schizophrenia. These results lend to future applications of TMS/EEG in understanding the pathophysiological mechanisms underlying cognitive deficits in schizophrenia.

Context: Current research into the etiology of joint instability has yielded inconsistent results, limiting our understanding of how to prevent and treat ligamentous injury effectively. Recently, cortical reorganization was demonstrated in patients with ligamentous injury; however, these neural changes have not been assessed relative to joint laxity. Objective: The purpose of the current study was to determine if changes in cortical excitability and inhibition occur in subjects with functional ankle instability, as well as to investigate the relationship between these measures and joint laxity. Design: Posttest only with control group. Setting: University laboratory. Subjects: 12 subjects with no history of ankle sprain (CON) and 12 subjects with a history of unilateral functional ankle instability (UNS). Interventions: Subjects were tested for joint laxity using an instrumented ankle arthrometer. Cortical excitability and inhibition were assessed using transcranial magnetic stimulation (TMS) to obtain motor-evoked potentials and the cortical silent period from the lower leg muscles. Main Outcome Measures: Joint laxity was quantified as peak anterior displacement and inversion rotation. Active motor threshold, slope, and intensity at 50% of peak slope of TMS-derived recruitment curves were used to quantify cortical excitability from lower leg muscles, while the cortical silent period from the peroneus longus was used to represent intracortical inhibition. Results: No significant differences were observed between groups for laxity or cortical measures. CON demonstrated a significant relationship between laxity and tibialis anterior excitability, as well as laxity and silent period, while UNS ankles demonstrated significant relationships between peroneal and soleus excitability and laxity measures. Conclusion: Our results support relationships between laxity and measures of excitability and inhibition that differ between healthy and unstable subjects. Future research should further investigate the mechanisms behind these findings and consider cortical influences when investigating altered joint laxity. [ABSTRACT FROM AUTHOR]

In schizophrenia and related disorders, a deeper mechanistic understanding of neocortical dysfunction will be essential to developing new diagnostic and therapeutic techniques. To this end, combined transcranial magnetic stimulation and electroencephalography (TMS/EEG) provides a non-invasive tool to simultaneously perturb and measure neurophysiological correlates of cortical function, including oscillatory activity, cortical inhibition, connectivity, and synchronization. In this review, we summarize the findings from a variety of studies that apply TMS/EEG to understand the fundamental features of cortical dysfunction in schizophrenia. These results lend to future applications of TMS/EEG in understanding the pathophysiological mechanisms underlying cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM +) interneurons, in mice of both sexes. We found that inactivating SOM+ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM+ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features. [ABSTRACT FROM AUTHOR]

Motor cortical contribution was shown to be important for balance control and for ballistic types of movements. However, little is known about the role of cortical inhibitory mechanisms and even less about long(er)‐term adaptations of these inhibitory processes. Therefore, the aim of the present study was to investigate the role of intracortical inhibition before and after four weeks of explosive or balance training. Two groups of subjects participated for four weeks either in an explosive training programme of the plantar flexor muscles or in a balance training programme on unstable devices. Adaptations in short‐interval intracortical inhibition (SICI) were assessed by applying paired‐pulse TMS to the soleus muscle during dynamic plantar flexions, balance perturbations and at rest. Furthermore, SICI was assessed for the untrained tibialis anterior muscle. The results show task‐, muscle‐ and group‐specific adaptations in SICI after the training (p =.021) with significantly increased SICI after balance training in the balance task and decreased SICI after explosive training in the ballistic task. The training also caused task‐ and group‐specific behavioural adaptations indicated by improved balance performance after balance training and increased ballistic performance after explosive training. There were no changes in SICI when measured at rest or in the untrained tibialis anterior muscle. This study shows that long(er)‐term training improves the ability to modulate cortical inhibitory processes in a task‐ and muscle‐specific manner. [ABSTRACT FROM AUTHOR]

• Variability exists in the duration of ipsilesional and contralesional cortical silent period durations in children with congenital hemiparesis. • EMG breakthrough activity was consistently observed during ipsilesional CSP assessment. • The amplitude of ipsilesional EMG breakthrough was higher than contralesional EMG breakthrough. The cortical silent period is a transient suppression of electromyographic activity after a transcranial magnetic stimulation pulse, attributed to spinal and supraspinal inhibitory mechanisms. Electromyographic breakthrough activity has been observed in healthy adults as a result of a spinal reflex response within the cortical silent period. The objective of this case series is to report the ipsilesional and contralesional cortical silent period and the electromyographic breakthrough activity of 7 children with congenital hemiparesis. TMS was delivered over the ipsilesional and contralesional primary motor cortices with resting motor threshold and cortical silent period measures recorded from first dorsal interosseous muscle. Seven children (13 ± 2 years) were included. Ipsilesional and contralesional resting motor thresholds ranged from 49 to 80% and from 38 to 63% of maximum stimulator output, respectively. Ipsilesional (n = 4) and contralesional (n = 7) cortical silent period duration ranged from 49 to 206 ms and 81 to 150 ms, respectively. Electromyographic breakthrough activity was observed ipsilesionally in 3/4 (75%) and contralesionally in 3/7 (42.8%) participants. In the 3 children with ipsilesional breakthrough activity during the cortical silent period, all testing trials showed breakthrough. Contralesional breakthrough activity was observed in only one of the analyzable trials in each of those 3 participants. The mean peak amplitude of breakthrough activity ranged from 45 to 214 μV (ipsilesional) and from 23 to 93 μV (contralesional). Further research is warranted to understand the mechanisms and significance of electromyographic breakthrough activity within the cortical silent period in congenital hemiparesis. Understanding these mechanisms may lead to the design of tailored neuromodulation interventions for physical rehabilitation. NCT02250092 (https://clinicaltrials.gov/ct2/show/NCT02250092) [ABSTRACT FROM AUTHOR]

• Phosphene tracing can be used to assess visual cortex inhibition (VCI). • Stimulation parameters that yield inhibition are different in visual than motor cortex. • A weak conditioning intensity (45% of threshold) yields phosphene suppression across all interstimulus intervals (2–200 ms). • A stronger conditioning intensity (75% of threshold) yields phosphene suppression only at long intervals (50–200 ms). Paired-pulse transcranial magnetic stimulation (ppTMS) has been used extensively to probe local facilitatory and inhibitory function in motor cortex. We previously developed a reliable ppTMS method to investigate these functions in visual cortex and found reduced thresholds for net intracortical inhibition compared to motor cortex. The current study used this method to investigate the temporal dynamics of local facilitatory and inhibitory networks in visual cortex in 28 healthy subjects. We measured the size of the visual disturbance (phosphene) evoked by stimulating visual cortex with a fixed intensity, supra-threshold test stimulus (TS) when that TS was preceded by a sub-threshold conditioning stimulus (CS). We manipulated the inter-stimulus interval (ISI) and assessed how the size of the phosphene elicited by the fixed-intensity TS changed as a function of interval for two different CS intensities (45% and 75% of phosphene threshold). At 45% of threshold, the CS produced uniform suppression of the phosphene elicited by the TS across ISIs ranging from 2 to 200 ms. At 75% of threshold, the CS did not have a significant effect on phosphene size across the 2–15 ms intervals. Intervals of 50–200 ms exhibited statistically significant suppression of phosphenes, however, suppression was not uniform with some subjects demonstrating no change or facilitation. This study demonstrates that the temporal dynamics of local inhibitory and facilitatory networks are different across motor and visual cortex and that optimal parameters to index local inhibitory and facilitatory influences in motor cortex are not necessarily optimal for visual cortex. We refer to the observed inhibition as visual cortex inhibition (VCI) to distinguish it from the phenomenon reported in motor cortex. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to reveal the effects of intermittent theta burst stimulation (iTBS) in modulating cortical networks using transcranial magnetic stimulation and electroencephalography (TMS-EEG) recording. Methods: Eighteen young adults participated in our study and received iTBS to the primary motor cortex (M1), supplementary motor area, and the primary visual cortex in three separate sessions. A finger tapping task and ipsilateral single-pulse TMS-EEG recording for the M1 were administrated before and after iTBS in each session. The effects of iTBS in motor performance and TMS-evoked potentials (TEPs) were investigated. Results: The results showed that iTBS to the M1, but not supplementary motor area or the primary visual cortex, significantly reduced the N100 amplitude of M1 TEPs in bilateral hemispheres (p = 0.019), with a more prominent effect in the contralateral hemisphere than in the stimulated hemisphere. Moreover, only iTBS to the M1 decreased global mean field power (corrected ps < 0.05), interhemispheric signal propagation (t = 2.53, p = 0.030), and TMS-induced early α-band synchronization (p = 0.020). Conclusion: Our study confirmed the local and remote after-effects of iTBS in reducing cortical inhibition in the M1. TMS-induced oscillations after iTBS for changed cortical excitability in patients with various neurological and psychiatric conditions are worth further exploration.

The so-called cortical silent period (CSP) refers to the temporary interruption of electromyographic signal from a muscle following a motor-evoked potential (MEP) triggered by transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). The neurophysiological origins of the CSP are debated. Previous evidence suggests that both spinal and cortical mechanisms may account for the duration of the CSP. However, contextual factors such as cortical fatigue, experimental procedures, attentional load, as well as neuropathology can also influence the CSP duration. The present paper summarizes the most relevant evidence on the mechanisms underlying the duration of the CSP, with a particular focus on the central role of the basal ganglia in the “direct” (excitatory), “indirect” (inhibitory), and “hyperdirect” cortico-subcortical pathways to manage cortical motor inhibition. We propose new methods of interpretation of the CSP related, at least partially, to the inhibitory hyperdirect and indirect pathways in the basal ganglia. This view may help to explain the respective shortening and lengthening of the CSP in various neurological disorders. Shedding light on the complexity of the CSP’s origins, the present review aims at constituting a reference for future work in fundamental research, technological development, and clinical settings.

Schizophrenia (SCZ) is a serious mental disorder, and its pathogenesis is complex. Recently, the glutamate hypothesis and the excitatory/inhibitory (E/I) imbalance hypothesis have been proposed as new pathological hypotheses for SCZ. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a non-invasive novel method that enables us to investigate the cortical activity in humans, and this modality is a suitable approach to evaluate these hypotheses. In this study, we systematically reviewed TMS-EEG studies that investigated the cortical dysfunction of SCZ to examine the emerging hypotheses for SCZ. The following search terms were set in this systematic review: (TMS or ‘transcranial magnetic stimulation’) and (EEG or electroencephalog*) and (schizophrenia). We inspected the articles written in English that examined humans and were published by March 2020 via MEDLINE, Embase, PsycINFO, and PubMed. The initial search generated 379 studies, and 14 articles were finally identified. The current review noted that patients with SCZ demonstrated the E/I deficits in the prefrontal cortex, whose dysfunctions were also associated with cognitive impairment and clinical severity. Moreover, TMS-induced gamma activity in the prefrontal cortex was related to positive symptoms, while theta/delta band activities were associated with negative symptoms in SCZ. Thus, this systematic review discusses aspects of the pathophysiological neural basis of SCZ that are not explained by the traditional dopamine hypothesis exclusively, based on the findings of previous TMS-EEG research, mainly in terms of the E/I imbalance hypothesis. In conclusion, TMS-EEG neurophysiology can be applied to establish objective biomarkers for better diagnosis as well as to develop new therapeutic strategies for patients with SCZ.

Aging is associated with declines in motor and somatosensory function. Some of these motor declines have been linked to age-related reductions in inhibitory function. Here we examined whether tactile surround inhibition also changes with age and whether these changes are associated with those in the motor domain. We tested a group of 56 participants spanning a wide age range (18–76 years old), allowing us to examine when age differences emerge across the lifespan. Participants performed tactile and motor tasks that have previously been linked to inter- and intra-hemispheric inhibition in the somatosensory and motor systems. The results showed that aging is associated with reductions in inhibitory function in both the tactile and motor systems starting around 40 years of age; however, age effects in the two systems were not correlated. The independent effects of age on tactile and motor inhibitory function suggest that distinct mechanisms may underlie age-related reductions in inhibition in the somatosensory and motor systems.