Cortical Excitability Parameters Research Articles

Effect of Propranolol on Motor Cortex Excitability in Essential Tremor: An Exploratory Study.

Essential tremor, the world's most prevalent movement disorder, lacks a clear understanding of its pathophysiology. Propranolol, a non-specific beta-blocker capable of crossing the blood-brain barrier, is a primary choice for essential tremor treatment. While its tremor-reducing effects are generally attributed to peripheral actions, various uses hint at central adrenergic effects. Nevertheless, propranolol's precise impact on the central nervous system in essential tremor subjects remains unexplored. In this study, we employed transcranial magnetic stimulation to assess the influence of propranolol on the excitability of the primary motor cortex (M1) in patients with essential tremor, compared to an age- and sex-matched control group. Cortical excitability parameters were measured following placebo and propranolol administration, encompassing resting and active motor thresholds, motor evoked potential characteristics, cortical silent period, and the input/output curve. Distinct effects were observed across the two cortical hemispheres. Essential tremor patients displayed inhibition of the left M1 cortex and heightened excitability in the right M1 cortex four hours after propranolol administration, but not following placebo. These findings suggest potential differential noradrenergic excitatory and inhibitory modulation. However, comprehensive understanding necessitates further investigations, including left-handed participants and more diverse essential tremor subpopulations. This study underscores the need for continued exploration to unravel propranolol's complex effects on motor cortex excitability in essential tremor.

Effects of Clozapine on Cortical Inhibition

Abstract Background Preclinical and clinical investigations have revealed deficits in cortical inhibition in individuals with schizophrenia. Transcranial magnetic stimulation, a commonly used noninvasive measurement technique, is used for assessing these deficits. Limited research has been conducted on the effects of antipsychotic medications on cortical inhibition. This study aimed to evaluate the effects of clozapine on cortical inhibition with transcranial magnetic stimulation longitudinally and compare it with unaffected controls. Methods Ten patients who started clozapine were assessed at baseline, with 8 reassessed after 4 months. Eight age- and sex-matched unaffected controls were included. Psychopathology, neurocognitive performance, formal thought disorder, and disability were assessed, and the cortical excitability parameters (resting motor threshold, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, and short-latency afferent inhibition [SAI]) were measured at baseline and four months after clozapine treatment. Results Resting motor threshold, ICF, and SAI were significantly different between patients and controls at baseline, whereas resting motor threshold, SAI, and ICF became similar to controls after clozapine with only ICF having a trend for significance. Clozapine prolonged cortical silent period significantly in the patients. Conclusions This is the first study to investigate the effect of clozapine on SAI, a potential cholinergic biomarker, and the first follow-up study to investigate the relationship between the effects of clozapine on cortical inhibition and cognition. Clozapine seems to cause an increase in cortical inhibition through GABAergic and possibly cholinergic mechanisms. However, additional follow-up studies with larger sample sizes are required to reach more robust conclusions.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy

ObjectiveTo elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. MethodsParticipants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. ResultsLTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. ConclusionsLTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SignificanceThe degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

Cortical excitability in patients with REM sleep behavior disorder with abnormal TRODAT-1 SPECT scan: an insight into prodromal Parkinson's disease.

REM Sleep Behavior Disorder (RBD) has been highlighted to identify a patient with prodromal Parkinson's disease (PD). Although many studies focus on biomarkers to predict an RBD patient's evolution from prodromal PD to clinical PD, the neurophysiological perturbation of cortical excitability has not yet been well elucidated. Moreover, no study describes the difference between RBD with and without abnormal TRODAT-1 SPECT. By measuring the amplitude of motor evoked potentials (MEP), the cortical excitability changes after transcranial magnetic stimulation (TMS) were evaluated in 14 patients with RBD and eight healthy controls (HC). Seven of the 14 patients with RBD showed abnormal TRODAT-1 (TRA-RBD), and seven were normal (TRN-RBD). The tested parameters of cortical excitability include resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), contralateral silence period (CSP), and input-output recruitment curve. The RMT and AMT showed no difference among the three studied groups. There was only SICI at inter-stimuli-interval 3 ms revealing group differences. The TRA-RBD demonstrated significant differences to HC in these aspects: decreased SICI, increased ICF, shortening of CSP, and augmented MEP amplitude at 100% RMT. Moreover, the TRA-RBD had a smaller MEP facilitation ratio at 50% and 100% of maximal voluntary contraction when compared to TRN-RBD. The TRN-RBD did not present any difference to HC. We showed that TRA-RBD shared similar cortical excitability changes with clinical PD. These findings would provide further insight into the concept that RBD is the highly prevalent entity in prodromal PD.

Effects of a single session of cathodal transcranial direct current stimulation primed intermittent theta-burst stimulation on heart rate variability and cortical excitability measures

Objectives: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been used as neuromodulators in neuropsychiatric conditions. This study is aimed to find the effects of a single session of priming cathodal tDCS with intermittent theta-burst stimulation (iTBS) over left dorsolateral prefrontal cortex on heart rate variability (HRV) and cortical excitability parameters before and after perturbation. Materials and Methods: The neuromodulatory techniques used in the study were Cathodal tDCS for 20 min followed by iTBS for 3 min on the left dorsolateral prefrontal cortex (DLPFC). HRV variables and TMS parameters were recorded before and after this intervention of combined neuromodulation in 31 healthy volunteers (20 males and 11 females; age range of 19–35 years with Mean ± SD = 24.2 ± 4.7 years). Results: The results showed an overall increase in cortical excitability and parasympathetic dominance in healthy volunteers. Other measures of cortical excitability and HRV did not change significantly following single session of combined neuromodulation. Conclusion: This study showed that there is an overall increase in cortical excitability and parasympathetic dominance in the cohort of healthy volunteers following a combination of neuromodulation involving cathodal tDCS followed by iTBS over left DLPFC. Future studies exploring the effects of other possible combinations with sham stimulation could be carried out to explore the utility of dual stimulation as add-on therapy in disorders.

Are there differences in cortical excitability between akinetic-rigid and tremor-dominant subtypes of Parkinson's disease?

ObjectiveTo assess by transcranial magnetic stimulation (TMS) the excitability of various cortical circuits in akinetic-rigid and tremor-dominant subtypes of Parkinson's disease (PD). MethodsThe study included 92 patients with PD according to UK Brain Bank criteria, with akinetic-rigid (n = 64) or tremor-dominant (n = 28) subtype. Cortical excitability study, including resting and active motor thresholds (rMT and aMT), input—output curve of motor evoked potentials, contralateral and ipsilateral silent periods (cSP and iSP), short and long-interval intracortical inhibition (SICI and LICI), and intracortical facilitation (ICF) were measured. The results obtained were compared to a control group of 30 age- and sex-matched healthy subjects. ResultsThe patients in the tremor group had significantly lower rMT and aMT compared to controls and akinetic-rigid patients and significantly shorter iSP duration compared to akinetic-rigid patients, while iSP latency tended to be longer in akinetic-rigid patients compared to controls. There were no significant differences between the two PD subgroups regarding other cortical excitability parameters, including paired-pulse TMS parameters. ConclusionsOnly subtle differences of cortical excitability were found between patients with akinetic-rigid vs. tremor-dominant subtype of PD. SignificanceThe clinical heterogeneity of PD patients probably has an impact on cortical excitability measures, far beyond the akinetic-rigid versus tremor-dominant profile.

Reduced Occipital Cortex Excitability in Amyotrophic Lateral Sclerosis.

In addition to motor cortex involvement, sensory abnormalities have been demonstrated in amyotrophic lateral sclerosis (ALS), including structural and metabolic alterations in the occipital cortex. The aim of this study was to examine occipital excitability changes in ALS. Twenty-one patients with ALS and 16 healthy subjects were enrolled into the study. Phosphene experience and phosphene threshold were studied to assess occipital excitability. Cognitive function was evaluated in both groups by means of Montreal Cognitive Assessment and Addenbrooke's Cognitive Examination-Revised visuospatial score tests. Phosphene was experienced in 13 (81.3%) healthy subjects and 9 (42.9%) patients with ALS ( P = 0.04). The mean phosphene threshold was not significantly different between the two groups. No correlation existed between phosphene threshold and motor cortical excitability parameters, ALS Functional Rating Scale Revised, Montreal Cognitive Assessment, and Addenbrooke's Cognitive Examination-Revised scores. Visual cortex is affected, and the occipital excitability is reduced in ALS, without any relation to motor cortical excitability changes, providing another clue suggestive of sensory involvement in ALS.

Effect of home-based transcranial direct current stimulation associated with nutritional counseling therapy on clinical and electrophysiological measures in Binge eating disorder: a study protocol for a blind, randomized, controlled clinical trial

Background: Binge Eating Disorder (BED) is a psychiatric disorder that has several medical and social consequences. Cognitive Behavioral Therapy (CBT) is the reference treatment, but presents significant dropout rates and elevated failure of therapeutic response. Therefore, new therapies targeting Central Nervous System (CNS) modulation, such as transcranial direct current stimulation (tDCS), might improve therapeutical responses, by modulating cognitive control over eating behavior and/or by enhancing inhibitory control due to synergistic action when combined with the current treatments available. Methods: Women with moderated BED, aged between 18 and 65 years and BMI ? 25 Kg/m² will be included. The participants will be divided into one of four groups: (1) Active tDCS; (2) Nutritional Counseling Therapy (NCT); (3) Active tDCS + NCT; (4) Sham tDCS + NCT. The electrodes of the tDCS will be positioned over the right Dorsolateral Pre-Frontal Cortex (DLPFC) - anode and left DLPFC - cathode. The participants will have a weekly appointment for 8 weeks where they will undergo the stimulation and/or the NCT. The groups that have the tDCS therapy will also receive the stimulation at home 4x/week in the first 5 weeks. The follow up is 8 weeks. The primary outcomes are the severity of symptoms, measured by the Binge Eating Scale (BES), and the inhibitory parameters of cortical excitability, measured by Transcranial Magnetic Stimulation (TMS) - Short Intracortical Inhibition (SICI). The secondary outcomes are weight loss, eating behavior, inhibitory control (Go/No-go), parameters of cortical excitability (Intracortical Facilitation (ICF) and cortical silent period (CSP)), and serum levels of leptin. Discussion: Cumulative research has provided evidence that tDCS improves disordered eating behaviors. Nevertheless, studies investigating the efficacy of long-term tDCS combined to standard treatment to BED are scarce. Based on exciting findings in trials that have associated tDCS and cognitive-behavioral approaches in Major Depressive Disorder (MDD), we hypothesize that the proposed protocol will be able to amplify therapeutical responses by reducing the severity of BED symptoms and enhancing inhibitory pathways assessed by cortical excitability parameters.

P83-T ONAMIG: Effect of BOTOX® over cortical excitability (measured by transcranial magnetic stimulation) in chronic migraine

Background Several transcranial magnetic stimulation (TMS) studies have demonstrated cortical excitability changes in patients with migraine. It has been suggested that central sensitization may be associated with poor response to treatment. The recognition of these phenomena and the effect of different treatments on them may have clinical relevance. The aim of the study is to evaluate changes in cortical excitability parameters in patients with chronic migraine (CM) after treatment with BOTOX®. Material and methods Patients with CM and candidates for treatment with BOTOX® were included. In addition, patients with episodic migraine (EM) were recruited as controls. Clinical data and disability scales were collected as well as cortical excitability parameters measured by TMS: motor threshold at rest (RMT), cortical silence period (CSP) and intracortical inhibition (SICI) ). A baseline clinical and neurophysiological study was performed and repeated after two cycles of botox treatment. Results We included 19 patients with CM and 16 with EM. After treatment with BOTOX® in CM the RMT was reduced (58.9 ± 13.3% vs 55.1 ± 11.9%, p = 0.004) approaching the values of controls (53.75 ± 9.88%, p = 0.019); increased CSP (85.6 ± 26.4 ms and 100.9 ± 33.0 ms, p = 0.004) approaching the values of controls (121.53 ± 39.92, p = 0003). In addition, parameters of greater inhibition in the SICI predicted an improvement in frequency and intensity >50%. Conclusions Treatment with BOTOX® is associated with changes in the cortical excitability of patients with CM who can translate mechanisms of central cortical modulation.

TDCS effects on cortical excitability in multiple sclerosis fatigue

Objectives Fatigue could affect up to 90% of patients with multiple sclerosis (MS) [1] . Facing the modest benefits and numerous side effects of pharmacological therapies, transcranial direct current stimulation (tDCS) has recently emerged as an appealing tool to treat several neuropsychiatric complaints, including MS fatigue [3] . Previous tDCS protocols did not assess long-term effects of tDCS on MS fatigue, neither did they investigate its potential mechanism of action in this context. Methods We hereby present the case of a 37-year-old MS patient who sought medical attention for debilitating fatigue. The patient has previously participated in a sham-controlled tDCS trial and was found to be among responders to real but not sham stimulation [3] . At presentation, he did not have secondary causes of fatigue. The protocol lasted for 9 weeks (5 consecutive daily sessions in week 1; 4 sessions per week in week 2 and 3; 3 sessions in week 4; 2 sessions in week 5; 1 session in week 6 and a follow-up in week 9). We tested tDCS effects over fatigue as well as other neuropsychological symptoms. Cortical excitability measures were obtained at baseline [2] and then at the end of week 1, week 3 and week 6. Results tDCS resulted in a significant improvement of fatigue which was obtained after the first week, but the most important anti-fatigue effects were documented after week 5. This effect was paralleled by amelioration of cognition and mood scores as well as changes in cortical excitability parameters (increase in short-interval intracortical inhibition and decrease in short-interval intracortical facilitation). Conclusion This is the first report that presents long-term assessment of tDCS effects in the context of fatigue and other MS-related symptoms. Left prefrontal tDCS appears to improve MS fatigue and seems to have a modulatory effect on inhibitory and facilitatory intracortical circuits.

T46. Correlates of motor disability and fatigue with alterations of cortical excitability and quantitative MRI parameters in relapsing remitting multiple sclerosis and neuromyelitis optica

Introduction Relapsing Remitting Multiple sclerosis(RRMS) and Neuromyelitis optica(NMO) are primary demyelinating disorders with almost similar clinical symptoms but have varied etiology and response to treatment. Methods To study and compare clinical (fatigue depression and disability scores), electrophysiological and imaging characteristics of RRMS and NMO including correlation of (Transcranial magnetic stimulation) TMS parameters with clinical scores and imaging;and improvement in TMS parameters pre and post steroids.23 RRMS and 14 NMO patients were recruited over a period of 5 years and all parameters were done pre and post steroid therapy. Results Mean age at presentation-RRMS-31.1 ± 12.2 years;NMO-34.8 ± 10.9 years. Mean duration of illness- RRMS-50.9 ± 58.1 months; NMO-42.9 ± 48.6 months. Age at onset of illness -RRMS-26.9 ± 10.7 years; NMO-31.9 ± 9.2 years. Frequency of episodes were high in NMO (predominantly myelopathy) as opposed to RRMS (Brainstem syndrome). Disability, fatigue scores and Cerebrospinal fluid pleocytosis were significantly high in NMO than RRMS. Somatosensory Evoked Potentials (EPs) showed significant prolongation in RRMS while Visual EPs showed no difference between both entities. Duration of illness correlated positively with total T1, T2 lesion load and disability scores with T1 lesion load in RRMS. No correlation was found in any clinical scores and lesion load in NMO. As compared to NMO right uncus, insula and anterior cingulate gyrus were relatively preserved in RRMS with atrophy of left pre cuneus,cuneus,occipital gyrus,cerebellum and bilateral pulvinar as identified by voxel based morphometric analysis. Both RRMS and NMO showed significant prolongation of Central motor conduction time (CMCT) whereas reduction in Motor Evoked Potential (MEP) amplitudes and prolongation of contralateral silent periods was significant only in RRMS. In paired stimulation studies, none of the patients in RRMS and NMO group had intracortical facilitation (ICF) and Short interval intracortical inhibition (SICI) was found to be elevated in both group of patients, with more inhibition compared to controls. Trend towards improvement was noted in both the groups post steroids, in Resting Motor Threshold, MEP amplitude and ICF. Disability was found to have negative correlation with SICI in RRMS patients. Conclusion Patients of NMO were of later age at onset with more disability and fatigue compared to RRMS. Duration of illness correlated with total MRI lesion load and disability with T1 lesion load in RRMS.TMS parameters were found to be significantly abnormal in RRMS than NMO with significant CMCT prolongation in both the groups which improved post steroid therapy.Lack of cortical excitability was noted in both the groups with increased cortical inhibition.Negative correlation of disability with SICI was also noted only in RRMS and not NMO with no correlation of TMS parameters with fatigue and depression.TMS thereby helps in evaluation and assessment of response to therapy in both RRMS and NMO.

The effect of the anodal transcranial direct current stimulation over the cerebellum on the motor cortex excitability

This study was designed to investigate whether the cerebellum has an inhibitory effect on motor cortical excitability.Sixteen healthy adults (age range, 25–50 years, five female) participated in the study. Anodal cerebellar transcranial direct current stimulation (a-cTDCS) was used to modulate cerebellar excitability. A-cTDCS was given for 20 min at 1 mA intensity. The automatic threshold tracking method was used to investigate cortical excitability. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), intracortical facilitation (ICF), and the input output curve (I-O curve) were motor cortical excitability parameters.a-cTDCS caused a reduction in overall SICI and the reduced SICF for interstimulus intervals (ISIs) to 2.4–4.4 ms. a-cTDCS has no effect on ICF, RMT, and the I-O curve. There were no significant changes in any of these cortical excitability parameters after sham cTDCS.Results of the study indicate that a-cTDCS has a dual (both inhibitory and excitatory) effect on motor cortical excitability, rather than a simple inhibitory effect. The cerebellum modulates both the inhibitory and facilitatory activities of motor cortex (M1) and suggest that cerebello–cerebral motor connectivity is more complex than solely inhibitory or facilitatory connections.

A reappraisal of the mechanisms of action of ketamine to treat complex regional pain syndrome in the light of cortical excitability changes

ObjectiveTo evaluate the changes in glutamate/GABA balance of intracortical excitability produced by ketamine, delivered at subanaesthetic dose to treat patients with complex regional pain syndrome (CRPS). MethodsIn 19 patients with CRPS, we assessed the effect of a 5-day ketamine protocol on various clinical aspects, including pain and depression, and on cortical excitability parameters provided by transcranial magnetic stimulation testing. ResultsThe rest motor threshold (RMT) and the amplitude of the motor evoked potentials at 120% of RMT were not modified after ketamine therapy. In contrast, ketamine reduced intracortical facilitation (ICF) in both hemispheres and increased short-interval intracortical inhibition (SICI), which was defective at baseline only in the hemisphere corresponding to the painful side. These changes positively correlated with pain relief. ConclusionThis study shows for the first time that the remarkable analgesic effects produced by ketamine in CRPS patients is associated with cortical excitability changes in favour of an enhanced GABAergic transmission in the hemisphere corresponding to the painful side and an overall reduction of excitability in the contralateral hemisphere. SignificanceAnalgesic effects of ketamine cannot be resumed to its classical antigutamatergic action related to N-methyl-d-aspartate receptor blockade.

Higher Cortical Facilitation and Serum BDNF Are Associated with Increased Sensitivity to Heat Pain and Reduced Endogenous Pain Inhibition in Healthy Males.

Although the brain-derived neurotrophic factor (BDNF) has been intensively investigated in animal models of chronic pain, its role in human pain processing is less understood. To study the neurophysiology of BDNF modulation on acute experimental pain, we performed a cross-sectional study. We recruited 20 healthy male volunteers (19-40 years old) and assessed their serum BDNF levels, quantitative sensory testing, and cortical excitability parameters using transcranial magnetic stimulation. Linear regression models demonstrated that the BDNF (β = -5.245, P = 0.034) and intracortical facilitation (β = -3.311, P = 0.034) were inversely correlated with heat pain threshold (adjusted R2 = 44.26). The BDNF (β = -3.719, P ≤ 0.001) was also inversely correlated with conditioned pain modulation (adjusted R2 = 56.8). Our findings indicate that higher serum BDNF and intracortical facilitation of the primary motor cortex are associated with increased sensitivity to heat pain and high serum BDNF with reduced pain inhibition during noxious heterotopic stimulation.

P287 Longitudinal study of cortical excitability in treated versus untreated patients with progressive multiple sclerosis

Objectives Transcranial magnetic stimulation (TMS) paradigms could be of help to get information on cortical excitability. This would enable a better understanding of pathophysiological mechanisms of various diseases and testing therapeutic responses. The objective of this study was to evaluate the cortical excitability of treated and untreated patients with progressive multiple sclerosis (MS). Methods 34 patients were initially included and separated in two groups based on whether they are receiving or not disease-modifying therapies. Evaluation took place at baseline, 6 months and 12 months. Clinical evaluation included the expanded disability status scale (EDSS). Cortical excitability was assessed by TMS via various measures. Results 25 patients completed the study. At baseline, treated patients had significantly higher motor evoked potentials (MEP) amplitude, and EDSS scores were inversely correlated with the resting MEP amplitude. At one year, contrarily to treated patients who did not experience any significant clinical or neurophysiological changes, untreated patients exhibited significant increase in resting motor threshold (rMT) and a reduction of short-interval intracortical inhibition (SICI). These changes were accompanied by an increase in EDSS score. Discussion This pilot study illustrates the changes in cortical excitability parameters in untreated patients with progressive MS over a one-year follow-up. Conclusions Disease modifying therapies might stabilize cortical excitability during the progressive phase of MS. Significance Some cortical excitability measures may constitute biomarkers for monitoring the disease progression in MS.

P344 Motor cortical excitability changes in early stage ALS patients using automatic threshold tracking method

Objectives to determine motor cortical excitability changes in early stage ALS patients. Methods Twenty-seven ALS patients were recruited the study. The mean age was 55.2 years and seven patients were female. Cortical excitability tests performed on the diagnostic stage of the disease. Investigated cortical excitability parameters were; resting motor threshold: (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF). Results Mean RMT was 60.1 ± 2.2% MSO for ALS patients, 52.9 ± 3.1% for control group. There was not significant difference between two groups ( p > 0.05 ). Factor analysis of SICI resulted in two factors with eigenvalues more than 1. In the calculation of factor 1 (SICI1-2.5 ms) values, short ISI values have more weight than long ISI values. The opposite was true for factor 2. (SICI2.5-5 ms). Mean SICI1-2.5 msvalues were 11.3 ± 11.7 in ALS group and 74.3 ± 9.9 in control group ( p 0.05 ) while mean SICI2.5-5 ms were 10.6 ± 9.7 in ALS group and 67.8 ± 9.8 in control group ( p 0.05 ). Factor analysis of SICF and ICF resulted in two factor with eigenvalues more than 1. There were no significant difference between two groups any of these two factors both for SICF and ICF ( p > 0.05 ). Comment SICI values are significantly reduced in ALS patients at the early stage of the disease. Significance SICI analysis with automatic threshold tracking method may have potential role for diagnosis of ALS. Reliability and reproducibility of this test should be performed before using it as a diagnostic test.

P224 Effect of the anodal transcranial direct current stimulation over the cerebellum on the motor cortex excitability

Introduction The aim of this study was to elucidate effect of the cerebellum on the motor cortex excitability and connectivity. We used cerebellar direct current stimulation (ctDCS) to modulate cerebellar excitability and hypothesized that anodal ctDCS would increase cerebellar excitability that will be cause to decrease motor cortical excitability via suppression of the dentato-thalamo-cortcal activity. Method Sixteen healthy adults participated to study. Motor cortex was stimulated with figure-of-eight- shaped coil of 9 cm diameter connected to two Magstim 200 stimulator linked with a Bistim module. Data acquisition and magnetic stimulus output were controlled by QTRAC software. Anodal stimulation was given for 20 min at 1 mA intensity. Investigated motor cortical excitability parameters were; resting motor threshold: (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF). Results Factor analysis of SICI resulted in one factor with an eugenvealue over 1 which explained 86% of variance. SICI factors significantly decreased after anodal ctDCS ( p = 0.01) while there were no changes after sham ctDCS ( p = 0.96). Two factor with an eigenvalue over 1 were extracted from SICF factor analysis (SICF 2.4−4.4 and SICF 1.2−1.6. ). SICF 2.4−4.4 significantly decreased after anodalctDCS ( p = 0.01). There were no significant anodal ctDCS effect on RMT, ICF and I-O curve ( p > 0.05 ). Conclusion The cerebellum modulates both inhibitory and facilitator activities in the motor cortex. Significance Anodal ctDCS has dual effect on the motor cortex excitability. We hypothesized that this dual effect may be depends on its polarizing effect of both afferent facilitator, end efferent inhibitory systems.

Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study.

To evaluate changes in DNA methylation profiles in patients with fibromyalgia (FM) compared to matched healthy controls (HCs). All individuals underwent full clinical and neurophysiological assessment by cortical excitability (CE) parameters measured by transcranial magnetic stimulation. DNA from the peripheral blood of patients with FM (n = 24) and HC (n = 24) were assessed using the Illumina-HumanMethylation450 BeadChips. We identified 1610 differentially methylated positions (DMPs) in patients with FM displaying a nonrandom distribution in regions of the genome. Sixty-nine percent of DMP in FM were hypomethylated compared to HC. Differentially methylated positions were enriched in 5 genomic regions (1p34; 6p21; 10q26; 17q25; 19q13). The functional characterization of 960 genes related to DMPs revealed an enrichment for MAPK signaling pathway (n = 18 genes), regulation of actin cytoskeleton (n = 15 genes), and focal adhesion (n = 13 genes). A gene-gene interaction network enrichment analysis revealed the participation of DNA repair pathways, mitochondria-related processes, and synaptic signaling. Even though DNA was extracted from peripheral blood, this set of genes was enriched for disorders such as schizophrenia, mood disorders, bulimia, hyperphagia, and obesity. Remarkably, the hierarchical clusterization based on the methylation levels of the 1610 DMPs showed an association with neurophysiological measurements of CE in FM and HC. Fibromyalgia has a hypomethylation DNA pattern, which is enriched in genes implicated in stress response and DNA repair/free radical clearance. These changes occurred parallel to changes in CE parameters. New epigenetic insights into the pathophysiology of FM may provide the basis for the development of biomarkers of this disorder.

Cortical Plasticity in Depression.

Neural plasticity is considered the neurophysiological correlate of learning and memory, although several studies have also noted that it plays crucial roles in a number of neurological and psychiatric diseases. Indeed, impaired brain plasticity may be one of the pathophysiological mechanisms that underlies both cognitive decline and major depression. Moreover, a degree of cognitive impairment is frequently observed throughout the clinical spectrum of mood disorders, and the relationship between depression and cognition is often bidirectional. However, most evidence for dysfunctional neural plasticity in depression has been indirect. Transcranial magnetic stimulation has emerged as a noninvasive tool for investigating several parameters of cortical excitability with the aim of exploring the functions of different neurotransmission pathways and for probing in vivo plasticity in both healthy humans and those with pathological conditions. In particular, depressed patients exhibit a significant interhemispheric difference in motor cortex excitability, an imbalanced inhibitory or excitatory intracortical neurochemical circuitry, reduced postexercise facilitation, and an impaired long-term potentiation-like response to paired-associative transcranial magnetic stimulation, and these symptoms may indicate disrupted plasticity. Research aimed at disentangling the mechanism by which neuroplasticity plays a role in the pathological processes that lead to depression and evaluating the effects of modulating neuroplasticity are needed for the field to facilitate more powerful translational research studies and identify novel therapeutic targets.

Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients.

Cerebral plasticity-inducing approaches like repetitive transcranial magnetic stimulation (rTMS) are of high interest in situations where reorganization of neural networks can be observed, e.g., after stroke. However, an increasing number of studies suggest that improvements in motor performance of the stroke-affected hand following modulation of primary motor cortex (M1) excitability by rTMS shows a high interindividual variability. We here tested the hypothesis that in stroke patients the interindividual variability of behavioral response to excitatory rTMS is related to interindividual differences in network connectivity of the stimulated region. Chronic stroke patients (n = 14) and healthy controls (n = 12) were scanned with functional magnetic resonance imaging (fMRI) while performing a simple hand motor task. Dynamic causal modeling (DCM) was used to investigate effective connectivity of key motor regions. On two different days after the fMRI experiment, patients received either intermittent theta-burst stimulation (iTBS) over ipsilesional M1 or control stimulation over the parieto-occipital cortex. Motor performance and TMS parameters of cortical excitability were measured before and after iTBS. Our results revealed that patients with better motor performance of the affected hand showed stronger endogenous coupling between supplemental motor area (SMA) and M1 before starting the iTBS intervention. Applying iTBS to ipsilesional M1 significantly increased ipsilesional M1 excitability and decreased contralesional M1 excitability as compared to control stimulation. Individual behavioral improvements following iTBS specifically correlated with neural coupling strengths in the stimulated hemisphere prior to stimulation, especially for connections targeting the stimulated M1. Combining endogenous connectivity and behavioral parameters explained 82% of the variance in hand motor performance observed after iTBS. In conclusion, the data suggest that the individual susceptibility to iTBS after stroke is influenced by interindividual differences in motor network connectivity of the lesioned hemisphere.