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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]

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]

• 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]

• 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]

Objective: The study aimed to investigate short-interval intracortical inhibition (SICI) in burns survivors and non-injured controls, and establish whether paired-pulse transcranial magnetic stimulation (TMS) is a sensitive tool to investigate SICI after burn-injury.Methods: Burn survivors underwent experimental assessments at 6- and 12-weeks after injury, and control participants underwent two equivalent sessions 6 weeks apart. Single-pulse transcranial magnetic stimulation (TMS) was used to record motor-evoked potentials (MEPs) from a hand muscle and paired-pulse TMS was used to measure SICI. Functional measures were obtained for comparison at 12-weeks after injury.Results: There was no significant difference in SICI between burns survivors and non-injured controls at either 6- or 12-weeks after burn injury. There was no evidence of correlations between SICI and functional outcome measures in burns survivors.Conclusions: These results show that paired-pulse TMS is a useful method for investigating cortical inhibition following burn injury, and that SICI circuits in the primary motor cortex are not affected by minor burn injury. This study presents details for definitive future studies of primary motor cortex function after minor burn injury. [ABSTRACT FROM AUTHOR]

Background: Suicide is a leading cause of death among youth. Prior research using transcranial magnetic stimulation (TMS) has implicated deficits in GABAergic cortical inhibition in adolescent suicidal behavior, yet no studies have assessed whether cortical inhibition varies over time in conjunction with changes in suicidal ideation (SI). This study examined dynamic changes in long-interval intracortical inhibition (LICI), a TMS measure of GABAB-mediated inhibition, and their relationship with changes in SI in a small sample of adolescents undergoing pharmacologic treatment for depression.Methods: Ten depressed adolescents (aged 13-17) underwent clinical assessment and TMS testing at baseline and again at follow-up. All were treated with antidepressant medication in the interim. SI was measured with the Columbia Suicide Severity Rating Scale (C-SSRS) Intensity of Ideation subscale. LICI was measured at interstimulus intervals of 100 and 150 ms.Results: There was a significant partial correlation, controlling for change in depression severity, between ΔLICI-100 and change in SI as measured by ΔC-SSRS (ρ = .746, df = 7, p = .021), which remained after also controlling for time to follow-up assessment (ρ = .752, df = 6, p = .032). No significant correlation was observed between ΔLICI-150 and change in SI.Limitations: Sample size; variable follow-up interval; inability to control for age, sex, and potential treatment effects.Conclusions: These data offer preliminary signal of an association between increases in GABAB-mediated cortical inhibition and reduction in SI over time in adolescents treated for depression. Further studies are warranted to explore the role of cortical inhibition in adolescent suicidal ideation and behavior. [ABSTRACT FROM AUTHOR]

Background Alterations in inhibitory processes mediated by gamma-aminobutyric acid type B (GABA B ) receptors may contribute to age-related functional impairments. However, investigation of these circuits using conventional paired-pulse transcranial magnetic stimulation (TMS) at long interstimulus intervals (∼100-200ms) have produced conflicting results in older adults, possibly due to the indirect nature of the TMS motor evoked potential (MEP). Objective To utilise electroencephalography and TMS coregistration (TMS-EEG) to more directly assess age-related changes in GABA B -mediated long-interval intracortical inhibition (LICI). Methods In 17 young (24.2 ± 1.1 years) and 17 older (71.4 ± 1.4 years) subjects, the TMS-evoked potential (TEP) was used to assess the global scalp response to single-pulse TMS and LICI applied at two interstimulus intervals of 100 ms (LICI 100 ) and 150 ms (LICI 150 ). Results For single-pulse stimulation, P30 amplitude was unaffected by age. Despite this, N45 amplitude was increased in older adults and both N100 and P180 showed altered spatial distributions. Furthermore, the latency of P30 was shorter, while the latency of P180 was longer, in the elderly. In addition, inhibition of the N100 and P180 was increased in older adults following both LICI 100 and LICI 150 . Conclusions These findings with TMS-EEG suggest that the ageing process is associated with a potentiation of GABAergic inhibition, particularly for the GABA B -receptor subtype. [ABSTRACT FROM AUTHOR]

Objectives The present aging study investigated the impact of a multisession anodal-tDCS protocol applied over the primary motor cortex (M1) during motor sequence learning on generalization of motor learning and plasticity-dependent measures of cortical excitability. Methods A total of 32 cognitively-intact aging participants performed five consecutive daily 20-min sessions of the serial-reaction time task (SRTT) concomitant with either anodal ( n  = 16) or sham ( n  = 16) tDCS over M1. Before and after the intervention, all participants performed the Purdue Pegboard Test (PPT) and Transcranial Magnetic Stimulation (TMS) measures of cortical excitability were collected. Results Relative to sham, participants assigned to the anodal-tDCS intervention revealed significantly greater performance gains on both the trained SRTT and the untrained PPT as well as a greater disinhibition of long-interval cortical inhibition (LICI). Generalization effects of anodal-tDCS significantly correlated with LICI disinhibition. Conclusion Anodal-tDCS facilitates motor learning generalisation in an aging population through intracortical disinhibition effects. Significance The current findings demonstrate the potential clinical utility of a multisession anodal-tDCS over M1 protocol as an adjuvant to motor training in alleviating age-associated motor function decline. This study also reveals the pertinence of implementing brain stimulation techniques to modulate age-associated intracortical inhibition changes in order to facilitate motor function gains. [ABSTRACT FROM AUTHOR]

Objective To assess the specificity of cortical inhibitory deficits in cervical dystonia patients. Methods A systematic test battery was developed to assess spatial and temporal aspects of cortical inhibition, in motor and somatosensory systems of the hand. We tested 17 cervical dystonia (CD) patients and 19 controls assessing somatosensory spatial inhibition (grating orientation test, interdigital feedforward subliminal inhibition), somatosensory temporal inhibition (temporal discrimination threshold, feedforward subliminal inhibition), motor spatial inhibition (surround inhibition), and motor temporal inhibition (short interval intracortical inhibition). Results A significant deficit in CD was observed in both measures of somatosensory spatial inhibition, with a trend in the same direction in our measure of motor spatial inhibition. We found no significant group differences in temporal inhibition measures. Importantly, statistical comparison of effect sizes across the different measures showed that deficits in tests of spatial inhibition were greater than those in tests of temporal inhibition. Conclusion Our results suggest that CD is associated with abnormal function of local inhibitory cortical circuits subserving spatial sensory processing. Importantly, this abnormality relates to the somatotopic representation of an unaffected body part. Significance These results clarify the nature of deficits in cortical inhibitory function in dystonia. [ABSTRACT FROM AUTHOR]

Motor cortex is important for motor skill learning, particularly the dexterous skills necessary for our favorite sports and careers. We are especially interested in understanding how plasticity in motor cortex contributes to skill learning. Although human studies have been helpful in understanding the importance of motor cortex in learning skilled tasks, animal models are necessary for achieving a detailed understanding of the circuitry underlying these behaviors and the changes that occur during training. We review data from these models to try to identify sites of plasticity in motor cortex, focusing on rodents as a model system. Rodent neocortex contains well-differentiated motor and sensory regions, as well as neurons expressing similar genetic markers to many of the same circuit components in human cortex. Furthermore, rodents have circuit mapping tools for labeling, targeting, and manipulating these cell types as circuit nodes. Crucially, the projection from rodent primary somatosensory cortex to primary motor cortex is a well-studied corticocortical projection and a model of sensorimotor integration. We first summarize some of the descending pathways involved in making dexterous movements, including reaching. We then describe local and long-range circuitry in mouse motor cortex, summarizing structural and functional changes associated with motor skill acquisition. We then address which specific connections might be responsible for plasticity. For insight into the range of plasticity mechanisms employed by cortex, we review plasticity in sensory systems. The similarities and differences between motor cortex plasticity and critical periods of plasticity in sensory systems are discussed. [ABSTRACT FROM AUTHOR]

Objectives To examine the effects of intermittent TBS (iTBS) and continuous TBS (cTBS) on cortical reactivity in the dorsolateral prefrontal cortex. Methods 10 healthy participants were stimulated with either iTBS, cTBS or sham at F3 electrode. Single- and paired-pulse TMS and concurrent electroencephalography (EEG) were used to assess change in cortical reactivity and long-interval intracortical inhibition (LICI) via TMS-evoked potentials (TEPs) and TMS-evoked oscillations. Results Significant increases in N120 amplitudes ( p < 0.01) were observed following iTBS over prefrontal cortex. Changes in TMS-evoked theta oscillations and LICI of theta oscillations were also observed following iTBS (increase) and cTBS (decrease). Change in LICI of theta oscillations correlated with change in N120 amplitude following TBS ( r = −0.670, p = 0.001). Conclusions This study provides preliminary evidence that TBS produces direct changes in cortical reactivity in the prefrontal cortex. Combining TBS with TMS-EEG may be a useful approach to optimise stimulation paradigms prior to the conduct of clinical trials. Significance TBS is able to modulate cortical reactivity and cortical inhibition in the prefrontal cortex. [ABSTRACT FROM AUTHOR]

Objective High frequency repetitive somatosensory stimulation (HF-RSS), which is a patterned electric stimulation applied to the skin through surface electrodes, improves two-point discrimination, somatosensory temporal discrimination threshold (STDT) and motor performance in humans. However, the mechanisms which underlie these changes are still unknown. In particular, we hypothesize that refinement of inhibition might be responsible for the improvement in spatial and temporal perception. Methods Fifteen healthy subjects underwent 45 min of HF-RSS. Before and after the intervention several measures of inhibition in the primary somatosensory area (S1), such as paired-pulse somatosensory evoked potentials (pp-SEP), high-frequency oscillations (HFO), and STDT were tested, as well as tactile spatial acuity and short intracortical inhibition (SICI). Results HF-RSS increased inhibition in S1 tested by pp-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Conclusions These findings suggest that HF-RSS can improve spatial and temporal tactile abilities by increasing the effectiveness of inhibitory interactions in the somatosensory system. Moreover, HF-RSS induces changes in cortical sensorimotor interaction. Significance HF-RSS is a repetitive electric stimulation technique able to modify the effectiveness of inhibitory circuitry in the somatosensory system and primary motor cortex. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) of the globus pallidus interna is an effective tool for the treatment of dystonia with possible distant effects reaching beyond the basal ganglia network. Aim We analyzed the cortical silent period (CoSP) to test inhibitory circuits at the cortical level, and the cutaneous silent period (CuSP) and the H-reflex to test inhibitory circuits at the spinal level. Methods The upper limb muscles of 16 patients (9F, aged 54 ± (SD)16 years) with generalized (N = 9) and cervical (N = 7) dystonia treated with DBS bilaterally were examined by the CoSP, CuSP and H-reflex in two states with random order: (i) in DBS ON and (ii) in DBS OFF condition two hours later, and compared with healthy controls. Results While the CuSP and H-Reflex did not differ between groups and remained unaffected by DBS, the CoSP was influenced significantly in dystonia. The CoSP onset latency was shortened (p < 0.05 corrected) and the CoSP duration prolonged (p < 0.01 corrected) in ON versus OFF condition. This effect was especially larger in generalized or phasic type of dystonia. Compared to healthy controls, the CoSP latency and duration became shorter in patients during the OFF condition only. Conclusion The pallidal DBS did not affect the spinal inhibitory circuitry in dystonia. However, the abnormally low cortical inhibition was normalized after DBS possibly offering more efficient suppression of aberrant dystonic movements. [ABSTRACT FROM AUTHOR]

Past studies have shown consistent evidence that body position significantly affects brain activity, revealing that both head-down and horizontal bed-rest are associated with cortical inhibition and altered perceptual and cognitive processing. The present study investigates the effects of body position on spontaneous, open-eyes, resting-state EEG cortical activity in 32 young women randomly assigned to one of two conditions, seated position (SP) or horizontal bed rest (BR). A between-group repeated-measure experimental design was used, EEG recordings were made from 38 scalp locations, and low-frequency (delta and alpha) amplitudes of the two groups were compared in four different conditions: when both groups (a) were seated (T0), (b) assumed two different body positions (seated vs. supine conditions, immediate [T1] and 120 min later [T2]), and (c) were seated again (T3). Overall, the results showed no a priori between-group differences (T0) before experimental manipulation. As expected, delta amplitude, an index of cortical inhibition in awake resting participants, was significantly increased in group BR, revealing both rapid (T1) and mid-term (T2) inhibitory effects of supine or horizontal positions. Instead, the alpha band was highly sensitive to postural transitions, perhaps due to baroreceptor intervention and, unlike the delta band, underwent habituation and decreased after a 2-h bed rest. These results indicate clear-cut differences at rest between the seated and supine positions, thus supporting the view that the role of body position in the differences found between brain metabolic methods (fMRI and PET) in which participants lie horizontally, and EEG-MEG-TMS techniques with participants in a seated position, has been largely underestimated so far. [ABSTRACT FROM AUTHOR]

Background: Although altered gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathophysiology of schizophrenia, it is unclear whether the influence of GABA on working memory processes is confounded by nicotine use in this population. It is therefore crucial to evaluate working memory and its underlying mechanisms in non-smokers with schizophrenia to eliminate the confounding effects of nicotine on behavior and neurophysiology.Methods: In this cross-sectional study, working memory was assessed using the verbal N-back task, while GABAergic function was assessed through motor cortical inhibition using single and paired-pulse transcranial magnetic stimulation (TMS) to the left primary motor cortex in 11 non-smokers with schizophrenia and 13 non-smoker healthy subjects.Results: Similar to previously published studies, working memory performance was significantly impaired in the 3-back condition in patients with schizophrenia compared to healthy subjects (p=0.036). In addition, GABAA receptor function was significantly reduced in schizophrenia as assessed by short interval cortical inhibition (SICI) (p=0.005). A positive correlation was found between GABAA inhibition and working memory performance on the 3-back task (r(23)=0.55, p=0.006), suggesting that greater GABAA inhibition is associated with better performance on tasks of working memory.Conclusions: Our findings highlight the role of GABAA receptor dysfunction in working memory and the pathophysiology of schizophrenia, and may represent a selective characteristic of schizophrenia. Moreover, these findings suggest a potential therapeutic role for targeting GABA receptor activity to improve cognition and quality of life in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives: Neurophysiologic correlates of depression severity potentially have great utility in diagnosis and treatment planning. Transcranial magnetic stimulation (TMS) measures of cortical inhibition and excitability have shown promise as biomarkers in psychiatry, but no prior work has examined correlates of illness severity in pediatric mood disorders. This study sought to examine the relationship between depression severity and TMS measures of cortical inhibition and excitability in children and adolescents.Methods: Twenty-four depressed and 22 healthy control youth underwent TMS testing (cortical silent period [CSP], short-interval intracortical inhibition at 2-ms and 4-ms interstimulus intervals (ISIs) [SICI-2,-4], resting motor threshold [RMT] and intracortical facilitation at 10-, 15-, and 20-ms ISIs [ICF-10,-15,-20]). Symptom severity was assessed with the Quick Inventory of Depressive Symptomatology (QIDS-A17-SR) and the Children's Depression Rating Scale-Revised (CDRS-R).Results: In the overall sample, the following significant negative correlations were observed: CDRS-R and CSP (right hemisphere, ρ=-0.35, p=0.021); QIDS-A17-SR and CSP (left, ρ=-0.33, p=0.031; right, ρ=-0.42, p=0.004); and CDRS-R and SICI-4 (right, ρ=-0.30, p=0.042). Among healthy control participants, additional significant negative correlations were observed between QIDS-A17-SR and right ICF-10; QIDS-A17-SR and right ICF-15; and QIDS-A17-SR and left ICF-20. Among depressed participants, significant negative correlations were observed between QIDS-A17-SR and bilateral CSP; CDRS-R and bilateral ICF-10; CDRS-R and bilateral ICF-15; QIDS-A17-SR and left ICF-10; and QIDS-A17-SR and bilateral ICF-15.Limitations: Small sample, potential developmental/age- and sex-related effects.Conclusions: These preliminary results provide evidence for a relationship between depression severity and dysfunction in GABAergic and glutamatergic cortical processes in a pediatric population. [ABSTRACT FROM AUTHOR]

Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington’s disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short-interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long-interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype. [ABSTRACT FROM AUTHOR]

Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata . While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic–clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABA A receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA-induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition. [ABSTRACT FROM AUTHOR]

Objective The pathophysiology of migraine with or without aura (MA, MO) is still a matter of debate. We thus studied patients with MA and MO by means of paired-pulse flash-visual evoked potentials (paired F-VEPs). This technique, recently revived, analyses the overall excitability of visual system as detected from the cortical occipital signal. Methods We enrolled 13 adult patients with MO and 13 with MA. Twenty-two normal subjects of similar age and sex acted as controls. Stimuli were single flashes, intermingled at random to flash pairs at critical interstimulus intervals (ISIs, 16.5–125 ms) with closed and open eyes. The “single”(unconditioned) F-VEP was split into a “main complex” (50–200 ms after the flash) and a “late response” (200–400 ms). As for paired stimulation, the “test” F-VEP emerged from electronic subtraction of the “single” F-VEP to the “paired” F-VEP. Its size was expressed as “test”/“single”F-VEP∗100. Results As for paired F-VEPs, the “main complex” of the “test” F-VEP in the MA group did not show the size reduction (at ISIs 50–62.5 ms) which was typical among the control and MO groups ( p ⩽ 0.016) in the “eyes-closed” state. Conclusions Paired F-VEPs document a defective neural inhibition in the visual system of patients with MA. Significance Paired F-VEPs may warrant inclusion in future preclinical/clinical studies, to evaluate its potential role in the pathophysiology and management of MA. [ABSTRACT FROM AUTHOR]

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

Systemic lipopolysaccharide (LPS) is widely used to induce a neuroinflammatory response that is associated with short-term ‘sickness’-behavior that can include fever, loss of activity, loss of appetite, impaired cognition, anxiety and depression. If large enough or left unchecked, this neuroinflammatory response can become self-perpetuating and lead to long-term neurodegenerative processes. In this study, we assess the longer-term effects of a single systemic LPS injection on electrophysiological neuromodulator effects and basic behavioral analysis in mice. Five months after LPS injection, we find a mild reduction in cortical inhibition and altered temporal dynamics of acetylcholine but not norepinephrine or serotonin neuromodulator effects. Consistent with electrophysiological findings, LPS treated mice showed a deficit in memory performance in the novel object recognition test with no effect on measures of anxiety or despair as measured in the open field test and tail suspension test, respectively. Furthermore, LPS-treated mice showed an increase in acetylcholinesterase activity. As increased acetylcholinesterase activity is associated with reduced acetylcholine signaling and impaired cognitive ability, these studies demonstrate the potential for a single inflammatory event to initiate processes that may lead to long-term neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Insufficient cortical inhibition is a key pathophysiological finding in dystonia. Subliminal sensory stimuli were reported to transiently inhibit somatosensory processing. Here we investigated whether such subliminal feedforward inhibition is reduced in patients with cervical dystonia.Methods: Sixteen cervical dystonia patients and 16 matched healthy controls performed a somatosensory detection task. We measured the drop in sensitivity to detect a threshold-level digital nerve shock when it was preceded by a subliminal conditioning shock, compared to when it was not.Results: Subliminal conditioning shocks reduced sensitivity to threshold stimuli to a similar extent in both patients and controls, suggesting that somatosensory subliminal feedforward inhibition is normal in cervical dystonia.Conclusion: Somatosensory feedforward inhibition was normal in this group of cervical dystonia patients. Our results qualify previous concepts of a general dystonic deficit in sensorimotor inhibitory processing. [ABSTRACT FROM AUTHOR]

Background Deficits in gamma-aminobutyric acid (GABA) inhibitory neurotransmission have been associated with pathophysiological mechanisms underlying schizophrenia. However, little is known about whether these deficits occur before or after the onset of psychosis. Method We recruited 16 drug-naive subjects at ultra-high risk of psychosis (UHR), 17 schizophrenia patients and 28 healthy controls. Cortical inhibition was determined using transcranial magnetic stimulation (TMS) over the left primary motor cortex. TMS markers such as short-interval cortical inhibition (SICI), cortical silent period (CSP) and intracortical facilitation (ICF) were obtained from each subject. While SICI can reflect GABA type A (GABA A ) mediated inhibition, CSP is thought to indicate GABA type B (GABA B ) mediated inhibitory circuits. Results As compared with healthy controls, UHR subjects showed a prolonged CSP with no change in SICI, whereas schizophrenia patients demonstrated both a prolonged CSP and a reduced SICI. No group differences were found for ICF. CSP in schizophrenia patients also had a positive correlation with positive symptom score of the positive and negative symptom scale (PANSS). Conclusions Cortical inhibitory deficits among UHR subjects were relatively limited compared to those among schizophrenia patients. Alterations might occur in some subgroup of GABA-mediated neurotransmitter systems before the onset of psychosis, while alterations in both GABA A and GABA B networks might contribute to full-blown psychosis. [ABSTRACT FROM AUTHOR]

Abnormal cortical-inhibition has been hypothesized to underlie social-cognition deficits in schizophrenia. Studies using transcranial magnetic stimulation (TMS) as a neurophysiological probe have demonstrated cortical-inhibition deficits in this group. We compared TMS-measured short- and long-interval intracortical-inhibition (SICI & LICI) in antipsychotic-naïve (n = 33) and medicated (n = 21) schizophrenia patients and in healthy comparison subjects (n = 45). We also studied the association between cortical-inhibition and social-cognition deficits in the patients. Antipsychotic-naïve patients had significant deficits in SICI (i.e., less inhibitory response). In this group, SICI had significant inverse correlations with emotion processing and a global social-cognition score. Impaired intracortical-inhibition may thus contribute to social-cognition deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Highlights: [•] Repetitive transcranial magnetic stimulation (rTMS) can potentiate cortical inhibition in healthy human subjects. [•] Our findings break with convention that high frequency stimulation results in excitation whereas low frequency stimulation results in inhibition. [•] Our results suggest that longer sessions of rTMS with increased number of pulses are more effective in producing changes on cortical inhibition. [Copyright &y& Elsevier]

Abstract: Background: Transcranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions. Objective: To provide a systematic review of TMS studies (1985–2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). Methods: Systematic literature-based review. Results: Across disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction. Conclusions: The results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters. [Copyright &y& Elsevier]

Highlights: [•] Neuroimaging tools have been critical for understanding pre- and symptomatic HD. [•] The relationship between pathophysiology and phenotype in HD is poorly understood. [•] TMS can inform causal relationships between neural circuitry and behaviour. [•] TMS–EEG can assess the integrity of neural networks in non-motor brain areas. [•] Neurophysiological measures may prove sensitive markers of progression in HD. [ABSTRACT FROM AUTHOR]

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

Abstract: Recent progress in cognitive neuroscience suggests that alpha activity may reflect selective cortical inhibition involved in signal amplification, rather than neural idling. Unfortunately, these theoretical advances remain largely ignored in affective neuroscience. To address this limitation the present paper proposes a novel research avenue aimed at using alpha to elucidate cortical inhibitory mechanisms involved in affective processes. The proposal is illustrated by developing inhibitory accounts of affective attention and affective tuning phenomena. The emergent predictions were tested using event-related perturbations from 73 students evaluating affective and nonaffective aspects of five types of emotional images. The results revealed that upper alpha power was increased by affective content in general and aversive stimuli in particular from 350ms at posterior and from 575ms at central sites. The evaluation task interacted with affective content only at a liberal statistical significance level in late posterior alpha. These results are generally in line with the proposed inhibitory accounts of affective attention and tuning, although the evidence is preliminary rather than conclusive. As confirmation of functional origins of alpha in affect remains beyond the scope of a single study, this paper aims to inspire further extrapolation of the inhibitory account of alpha within affective neuroscience. [Copyright &y& Elsevier]

Abstract: Background: Cognitive impairments are present during the early course of schizophrenia, and the contribution of GABAergic dysfunction to these cognitive impairments has received increasing attention. Cortical GABAergic inhibition can be assessed using short-interval intracortical inhibition (SICI) in a paired-pulse transcranial magnetic stimulation (ppTMS). The aim of this study was to examine the relationship between cortical GABAergic inhibition and cognitive function in recent onset schizophrenia patients using ppTMS and a neuropsychological battery. Methods: The subjects were 20 healthy controls (HC group) and 20 patients with schizophrenia whose duration of illness was less than three years (SZ group). All subjects underwent ppTMS measurements of SICI and intracortical facilitation (ICF), and cognitive performance of the SZ group was assessed using the Brief Assessment of Cognition in Schizophrenia Japanese-language version. We examined group differences in ppTMS measurements (resting motor threshold, SICI, and ICF). In the SZ group, we assessed the relationship between SICI and cognitive performance, and the relationships between SICI and age, duration of illness, medications, and psychopathology. Results: The SZ group showed a significant reduction of SICI compared to the HC group, and demonstrated a significant correlation between the reduction of SICI and impaired performance of a working memory task. The HC and the SZ groups did not differ significantly in resting motor threshold and ICF. The SZ group did not show any significant correlations between SICI and age, duration of illness, medications, or psychopathology. Conclusions: Our results suggest that the reduction of cortical GABAergic inhibition is related to impairment of working memory in patients with recent onset schizophrenia. [Copyright &y& Elsevier]

Background: Impaired cortical inhibition is a well-established finding in schizophrenia patients and has been linked to dysfunctional gamma-aminobutyric acid (GABA)ergic transmission. However, there have been no previous studies investigating cortical excitability with particular regard to intracortical inhibitory networks in antipsychotic-naive subjects at risk of developing first-episode psychosis. Methods: A total of 18 subjects at risk, 18 first-episode schizophrenia patients, and 18 healthy control subjects were included in this study. Transcranial magnetic stimulation over the left primary motor cortex was used to determine short-latency intracortical inhibition, intracortical facilitation, and the contralateral silent period (CSP). Short-latency intracortical inhibition can be considered as a parameter of GABA type A (GABAA)-mediated inhibition and it has been proposed that CSP can test GABA type B (GABAB)-mediated inhibitory intracortical networks. Results: Subjects at risk and first-episode patients showed a reduced short-latency intracortical inhibition compared with healthy control subjects, suggesting reduced GABAA-mediated inhibition. First-episode patients had a prolonged CSP duration compared with the other two groups, implying a GABAB imbalance only in patients with full-blown psychosis. Analyses did not reveal group differences for intracortical facilitation. Conclusions: These results indicate specific alterations in inhibitory cortical networks in subjects at risk and in first-episode patients. It appears that there is already a cortical inhibitory deficit in at-risk individuals. These results suggest a possible GABAA dysfunction early in the disease course, whereas alterations in GABAB functionality seem to occur later in the disease''s progression. Future longitudinal studies will be needed to clarify this inhibitory deficit and its relation to the transition to psychosis. [Copyright &y& Elsevier]

Abstract: The objective of this study was to investigate premotor modulation of motor cortical excitability between rhythmic unimanual finger contractions. Applying TMS at rest prior to an anticipated contraction provides a measure of cortical excitability that reflects premotor modulatory drive and is uncontaminated by the alterations in spinal and cortical excitability that occur during muscle activation. We hypothesized that premotor structures contribute to unimanual movement through the modulation of intracortical and interhemispheric inhibitory circuits within the primary motor cortex and that this premotor modulation would be evident at rest between contractions. Thus, we used transcranial magnetic stimulation (TMS) to assess short interval intracortical inhibition (SICI) and interhemispheric inhibition (IHI) in a 500-ms epoch prior to a planned contraction of the right FDI in 10 participants (21.4±1.9 years). These measures of inhibition were made in three different states: (1) at complete rest (with no plan to contract), (2) at rest between rhythmic contractions, and (3) during low level contractions. Cortical excitability was enhanced prior to a contraction and during a contraction compared to at rest (F (2,18) =758.3, p <0.001). IHI was also increased prior to a contraction compared to at rest and during a contraction while SICI was only reduced during a contraction (F (2,38) =30.3, p <0.001).We used this pre-contraction protocol to investigate the cortical mechanisms of unimanual control. However, this protocol would be a useful tool to investigate any neuromuscular adaptation that may occur as a result of altered premotor modulation of cortical excitability, such as neuromuscular fatigue, training and movement disorders. [Copyright &y& Elsevier]

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

Abstract: Objective: Long-term potentiation (LTP)-like plasticity induced by paired associative stimulation (PAS) is impaired in Parkinson’s disease (PD). Intermittent theta burst stimulation (iTBS) is another rTMS protocol that produces LTP-like effects and increases cortical excitability but its effects are independent of afferent input. The aim of the present study was to examine the effects of iTBS on cortical excitability in PD. Methods: iTBS was applied to the motor cortex in 10 healthy subjects and 12 PD patients ON and OFF dopaminergic medications. Motor evoked potential (MEP) before and for 60min after iTBS were used to examine the changes in cortical excitability induced by iTBS. Paired-pulse TMS was used to test whether intracortical circuits, including short interval intracortical inhibition, intracortical facilitation, short and long latency afferent inhibition, were modulated by iTBS. Results: After iTBS, the control, PD ON and OFF groups had similar increases in MEP amplitude compared to baseline over the course of 60min. Changes in intracortical circuits induced by iTBS were also similar for the different groups. Conclusions: iTBS produced similar effects on cortical excitability for PD patients and controls. Significance: Spike-timing dependent heterosynaptic LTP-like plasticity induced by PAS may be more impaired in PD than frequency dependent homosynaptic LTP-like plasticity induced by iTBS. [Copyright &y& Elsevier]

Background: Several lines of evidence suggest that cognitive behavioral therapy (CBT) is an effective treatment for depression and anxiety disorders. Evidence suggests that the therapeutic effects of CBT are related to neurophysiologic changes in the cortex, particularly γ-aminobutyric acid (GABA) potentiation. Transcranial magnetic stimulation (TMS) represents a noninvasive method of measuring cortical inhibition, which is a neurophysiologic mechanism associated with the pathophysiology of several psychiatric disorders. Objective/Hypothesis: To demonstrate the effectiveness of a 12-week CBT intervention compared with a wait list control group measuring cortical inhibition in participants with pathologic perfectionism. Participants within the CBT group would demonstrate increases in cortical inhibition and improvements on clinical outcomes relative to the wait list control group. Methods: Twenty-four right-handed perfectionists were randomly assigned to a 12-week CBT intervention or a wait list control group. Cortical inhibition was measured at pre- and postintervention with TMS paradigms specifically short-interval cortical inhibition and the cortical silent period, which index GABAA and GABAB receptor-mediated inhibitory neurotransmission, respectively. Results: The CBT group demonstrated a significant potentiation of the cortical silent period when compared with the wait list control group. The CBT group demonstrated a decrease in anxiety sensitivity and automatic thoughts relative to the control group. Conclusions: These findings demonstrate that CBT tailored for perfectionism is accompanied by an increase in cortical inhibition of the motor cortex and positive changes on clinical outcomes. These findings provide compelling evidence for an association between positive CBT effects and a potentiation of GABAergic inhibitory neurotransmission. [Copyright &y& Elsevier]

Abstract: Objective: Concentration changes in hemoglobin following single and paired pulse (2 and 15ms inter-stimulus interval) transcranial magnetic stimulation (TMS) was investigated using near infra-red spectroscopy (NIRS). Methods: TMS was delivered to left pre-frontal cortex at typical intensities used in neuroscience research and concentrations of deoxyhemoglobin (Hb), oxyhemoglobin (HbO) and total hemoglobin (HbT) were measured. Results: Significant drops in concentration of HbO and HbT were observed and while there was no effect of the different pulse types on amplitude, there was a difference in the time taken to return to baseline. Conclusions: The changes observed imply that in pre-frontal cortex, the different TMS pulse types result in differential effects on oxygen consumption. Significance: This study aids our understanding of the physiological effects of single and paired pulse TMS. [ABSTRACT FROM AUTHOR]

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

Abstract: The 40-Hz steady state response (SSR) reflects early sensory processing and can be measured with electroencephalography (EEG). The current study compared the 40-Hz SSR in groups consisting of mild Alzheimer''s disease patients (AD) (n =15), subjects with mild cognitive impairment (MCI) (n =20) and healthy elderly control subjects (n =20). All participants were naïve for psychoactive drugs. Auditory click trains at a frequency of 40-Hz evoked the 40-Hz SSR. To evaluate test–retest reliability (TRR), subjects underwent a similar assessment 1 week after the first. The results showed a high TRR and a significant increase of 40-Hz SSR power in the AD group compared to MCI and controls. Furthermore a moderate correlation between 40-Hz SSR power and cognitive performance as measured by ADAS-cog was shown. The results suggest that 40-Hz SSR might be an interesting candidate marker of disease progression. [Copyright &y& Elsevier]

Abstract: Perception of visual motion declines during healthy aging, and evidence suggests that this reflects decreases in cortical GABA inhibition that increase neural noise and motion bandwidths. This is supported by neurophysiological data on motion perception in senescent monkeys. Much less is known about deficits in higher level form vision. For example, face perception of frontal views remains relatively constant from adolescence through age 70 with a modest decline thereafter. However, we have shown recently that the elderly have a specific deficit in face matching when a transformation must be made between frontal and left or right side views. Here we use face view adaptation to demonstrate that this deficit results from significant broadening of cortical bandwidths for face orientation along with increased internal noise. A neural model shows that these bandwidths increase by a factor of 1.74 between age 26 and age 67years. This is similar to the increase reported for motion bandwidths in senescent monkeys. Furthermore, the neural model demonstrates that head orientation bandwidth increases can arise from decreased cortical inhibition. Thus, high levels of form vision degrade in parallel with higher levels of motion perception and likely result from similar causes. [ABSTRACT FROM AUTHOR]

Background & Aims: Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally, we determine the relationship of these indices to the symptoms of PBC. Methods: 16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF). Results: PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p <0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF. Conclusions: PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC). [ABSTRACT FROM AUTHOR]

Abstract: We addressed how spatial frequency and orientation selectivity coexist and co-vary in Macaque primary visual cortex (V1) by simulating cortical layer 4Cα of V1 with a large-scale network model and then comparing the model’s behavior with a population of cells we recorded in layer 4Cα. We compared the distributions of orientation and spatial frequency selectivity, as well as the correlation between the two, in the model with what we observed in the 4Cα population. We found that (1) in the model, both spatial frequency and orientation selectivity of neuronal firing are greater and more diverse than the LGN inputs to model neurons; (2) orientation and spatial frequency selectivity co-vary in the model in a way very similar to what we observed in layer 4Cα neurons; (3) in the model, orientation and spatial frequency selectivity co-vary because of intra-cortical inhibition. The results suggest that cortical inhibition provides a common mechanism for selectivity in multiple dimensions. [ABSTRACT FROM AUTHOR]

Abstract: Practicing skilled tasks that involve the use of the hand and fingers has been shown to lead to adaptations within the central nervous system (CNS) underpinning improvements in the performance of the acquired task. However, neural adaptations following a period of strength training in the hand is not well understood. In order to determine the neural adaptations to strength training, we compared the effect of isometric strength training of the right first dorsal interosseous (FDI) muscle on the electromyographic (EMG) responses to transcranial magnetic stimulation (TMS) over left M1. The specific aim of the study was to investigate the corticospinal responses, including latency, motor-evoked potential amplitude (MEP), and silent period duration (SP) following 4 week of strength training of the FDI muscle. Sixteen healthy adults (13 male, three female; 24.12±5.21years), were randomly assigned into a strength training (n =8) or control group (n =8). Corticospinal measures of active motor threshold (AMT), MEP amplitude, and SP duration were obtained using TMS during 5% and 20% of maximal voluntary contraction force (MVC) pre and post 4 week strength training. Following training, MVC force increased by 33.8% (p =.01) in the training group compared to a 13% increase (p =.2) in the untrained group. There were no significant differences in AMT, latency, or MEP amplitude between groups following training. However, in the trained group, there was a 16ms reduction in SP duration at 5% of MVC (p =.01) and 25ms reduction in SP duration at 20% of MVC (p =.03). These results demonstrate a task dependent adaptation in corticospinal inhibition via a reduction in cortical SP duration that may in part underpin the strength increases observed following strength training. [Copyright &y& Elsevier]

Abstract: Trancranial magnetic stimulation (TMS) provides a non-invasive means for exploring physiological alterations of central motor control in a variety of neuropsychiatric diseases. The present study aimed to assess the neurophysiological profile of muscle evoked responses to a standard TMS procedure in 51 medicated patients with schizophrenia and 51 age- and sex-matched healthy subjects. Motor evoked potentials (MEPs) from the abductor pollicis brevis muscle were elicited by stimulation of the contralateral motor cortex with a circular coil. The hot spot was marked, and the resting motor threshold (RMTh), the stimulus intensity for maximum MEP (SI-max), the post-stimulus silent period of voluntary muscle activity, and MEP latency and amplitude were measured. The main findings were the significantly higher than normal values for RMTh and SI-max, which are both indices of neuronal excitability. In particular, patients who had ziprasidone in their therapeutic regimen demonstrated the highest SI-max for both hemispheres, and the highest RMTh for the left hemisphere, patients receiving olanzapine demonstrated the lowest RMTh for the left hemisphere, and those on quetiapine showed intermediate values. The silent period was longer in the patients than in the controls when a RMTh-related SI was used and did not differ between the two groups when a fixed SI was used. We concluded that the observed TMS changes could be interpreted as primary alterations of intracortical motor excitability followed by defects of cortical inhibition and should be attributed to schizophrenia, antipsychotic medication or the interaction between the two factors. [Copyright &y& Elsevier]

Abstract: Objective: Previous studies have revealed a surprising decrease in spike counts and Teager energy between on- and off-AEDs states during intracranial EEG (icEEG) monitoring. Here, we expand the measures evaluated to icEEG power and frequency band power. Methods: Two icEEG epochs, on- and off-AEDs, each 1h in duration, were studied for each of 21 unselected adult patients. Spike counts, Teager energy and total power were evaluated for each electrode contact. Power was also evaluated for delta (0–4Hz), theta (4–8Hz), alpha (8–13Hz), beta (13–25Hz), gamma (25–55Hz) and high (65–128Hz) frequency bands. Results: A decrease in power accompanies AED taper and the previously reported decrease in spike counts and Teager energy. The decrease in power was underpinned by a spatially widespread and broadband decrease in power in delta through gamma frequency bands with maximum decrease in the lowest frequency bands. An increase in high-frequency power was observed in some patients. Conclusions: There is a decrease in spike counts, Teager energy and power from on- to off-AEDs state during intracranial monitoring. The decrease in power is spatially widespread and broadband including power in the delta through gamma frequency bands. Significance: The decrease in cortical activity with AED taper suggests that seizure generation during intracranial monitoring may not be mediated solely by poorly regulated cortical excitation. [Copyright &y& Elsevier]

Summary: Objective: During intracranial EEG (icEEG) monitoring the likelihood of observing a seizure is increased by tapering anti-epileptic drugs (AEDs). Presumably AED taper results in an increase in cortical excitation which in turn promotes seizure emergence. We measured change in signal energy of icEEGs in response to AED taper to quantify changes in excitation which accompany the increased propensity for seizures. Methods: Twelve consecutive adult patients who completed intracranial monitoring were studied. Two icEEG epochs from before and after AED taper, each 1h in duration, during wake, matched by time-of-day and removed from seizures were selected for each patient. Teager energy, a frequency weighted measure of signal energy, was estimated for both the seizure onset region as well as all other brain areas monitored. Results: Considerable changes in Teager energy, evaluated at a 1-h time-resolution, occur during intracranial monitoring. The most dominant trend is a decrease to lower values than those when the patient is on AEDs. A decrease of 35% was observed for both all the brain areas monitored and the seizure onset region. Conclusions: A decrease in signal energy occurs during intracranial EEG monitoring, possibly accompanying AED taper. If the decrease is due to AED taper this would suggest that AEDs prevent seizures in ways other than reduction of cortical excitation and seizure generation may be influenced by factors other than poorly regulated cortical excitation. [Copyright &y& Elsevier]

Abstract: Objective: The induction of long interval cortical inhibition (LICI) in motor cortex with paired pulse transcranial magnetic stimulation (ppTMS) is an established paradigm for the assessment of cortical inhibition, proposed to be related to GABAB receptor inhibitory neurotransmission. This study aimed to further evaluate recent methods of the assessment of LICI in non motor regions with ppTMS and electroencephalography (EEG). Methods: ppTMS was applied using a single coil to the motor and dorsolateral prefrontal cortex (DLPFC) in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. Results: In the motor cortex, LICI resulted in significant suppression in mean cortical evoked activity on EEG between 75 and 250ms following delivery of the test stimulus. Maximal inhibition was seen from 50 to 250ms in DLPFC, and between 50 and 175ms in the parietal lobe. Conclusions: ppTMS may be used to produce LICI in several cortical regions with a time course similar to known GABAB activity. Significance: ppTMS induction of LICI can be recorded by combining TMS with EEG and seems to relate to GABAB activity. [Copyright &y& Elsevier]

Abstract: Voluntary movement is often perturbed by the external forces in the environment. Because corticospinal (CS) control of wrist muscles during preparation of voluntary movement has been extensively studied without variation in the external forces, very little is known about the way CS control adapts when subjects expect motor perturbations. Here, we studied the CS control of wrist muscles during expectation of an imposed wrist extension. Subjects were instructed either to compensate (COMP) the perturbation (applied at variable delays) or not to intervene (NINT). In a quarter of all trials at random, in the time window when perturbation might occur, TMS was applied over contralateral M1. Motor evoked potentials (MEPs) were measured in the FCR (flexor carpi radialis) and ECR (extensor carpi radialis) muscles, as well as the silent period (SP) in the FCR. Following the perturbation, we found a larger long-latency stretch reflex in COMP than in NINT. During the expectation of the perturbation, MEP amplitudes did not differ across conditions in FCR. However, those evoked in ECR were greater in COMP than in NINT condition. Moreover in the FCR, the silent period lasted longer in NINT. Thus, we showed a selective effect of the prepared reaction on the anticipatory tuning of CS excitability and cortical inhibition in the agonist/antagonist muscles. This tuning clearly differed from the tuning during voluntary movement preparation without variation in the external forces. This shows that the tuning of the CS system during motor preparation depends on the dynamical context of movement production. [Copyright &y& Elsevier]

Background: Cortical inhibition (CI) deficits assessed by transcranial magnetic stimulation paradigms, short-interval cortical inhibition (SICI), and cortical silent period (CSP) have been demonstrated in schizophrenia (SCZ) patients. Antipsychotic treatments can modify CI and improve clinical symptoms, suggesting a neurophysiological link between the two. Previous studies have demonstrated that clozapine is associated with prolongation in CSP, a γ-hydroxybutyric acid (GABA)B-mediated phenomenon. Furthermore, SICI deficits were associated with psychotic symptom severity, suggesting alternation in GABAA-mediated neurotransmission. Such differential association patterns between clinical symptoms and CI deficits and their relationship to antipsychotic treatment thus might provide insights to the pathophysiology of schizophrenia. Methods: CI was assessed in 78 SCZ patients and 38 healthy subjects. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Subjects were grouped according to antipsychotic medication status: unmedicated (n = 7), clozapine (n = 19), olanzapine/quetiapine (n = 32), and risperidone/typical antipsychotics (n = 20). Results: Relative to control subjects, patients receiving clozapine had longer CSP and reduced SICI, whereas patients receiving other antipsychotics and unmedicated patients had shorter CSP. Across all subjects with SCZ, CSP was inversely associated with negative symptoms, and SICI was inversely associated with positive symptoms. Conclusions: These results confirm that unmedicated SCZ patients have CI deficits and that clozapine treatment is associated with potentiation of GABAB-inhibitory neurotransmission and reduced GABAA inhibitory neurotransmission. Also, the differential associations among SICI, CSP, and clinical symptom dimensions suggest that GABAA- and GABAB-mediated CI might have different roles in the pathophysiology of symptoms of schizophrenia. [Copyright &y& Elsevier]

Abstract: Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p =0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p =0.059 for right motor cortex; Mann–Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis. [Copyright &y& Elsevier]