Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS–EEG study

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.     

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS‐evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage‐gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma‐aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double‐blinded randomized placebo‐controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco‐physiological characterization of TEPs will facilitate utilization of TMS‐EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.     

Assessing cortical network properties using TMS–EEG

The past decade has seen significant developments in the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess cortical network properties such as excitability and connectivity in humans. New hardware solutions, improved EEG amplifier technology, and advanced data processing techniques have allowed substantial reduction of the TMS‐induced artifact, which had previously rendered concurrent TMS–EEG impossible. Various physiological artifacts resulting from TMS have also been identified, and methods are being developed to either minimize or remove these sources of artifact. With these developments, TMS–EEG has unlocked regions of the cortex to researchers that were previously inaccessible to TMS. By recording the TMS‐evoked response directly from the cortex, TMS–EEG provides information on the excitability, effective connectivity, and oscillatory tuning of a given cortical area, removing the need to infer such measurements from indirect measures. In the following review, we investigate the different online and offline methods for reducing artifacts in TMS–EEG recordings and the physiological information contained within the TMS‐evoked cortical response. We then address the use of TMS–EEG to assess different cortical mechanisms such as cortical inhibition and neural plasticity, before briefly reviewing studies that have utilized TMS–EEG to explore cortical network properties at rest and during different functional brain states. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Alterations of motor cortical excitability and anatomy in Unverricht‐Lundborg disease

Unverricht‐Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp‐to‐cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease‐related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp‐to‐cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht‐Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms. © 2013 International Parkinson and Movement Disorder Society     

Sensorimotor cortex excitability and connectivity in Alzheimer's disease: A TMS‐EEG Co‐registration study

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083–2096, 2016. © 2016 Wiley Periodicals, Inc.     

Neuroplasticity and network connectivity of the motor cortex following stroke: A transcranial direct current stimulation study

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has potential for clinical utility in neurorehabilitation. However, recent evidence indicates that the responses to tDCS are highly variable. This study investigated whether electroencephalographic (EEG) measures of functional connectivity of the target network were associated with the response to ipsilesional anodal tDCS in stroke survivors. Ten chronic stroke patients attended two experimental sessions in a randomized cross‐over trial and received anodal or sham tDCS. Single‐pulse transcranial magnetic stimulation was used to quantify change in corticospinal excitability following tDCS. At the beginning of each session, functional connectivity was estimated using the debiased‐weighted phase lag index from EEG recordings at rest. Magnetic resonance imaging identified lesion location and lesion volume. Partial least squares regression identified models of connectivity which maximally accounted for variance in anodal tDCS responses. Stronger connectivity of a network with a seed approximating the stimulated ipsilesional motor cortex, and clusters of electrodes approximating the ipsilesional parietal cortex and contralesional frontotemporal cortex in the alpha band (8–13 Hz) was strongly associated with a greater increase of corticospinal excitability following anodal tDCS. This association was not observed following sham stimulation. Addition of a structural measure(s) of injury (lesion volume) provided an improved model fit for connectivity between the seed electrode and ipsilesional parietal cortex, but not the contralesional frontotemporal cortex. TDCS has potential to greatly assist stroke rehabilitation and functional connectivity appears a robust and specific biomarker of response which may assist clinical translation of this therapy.     

导航经颅磁刺激定位国人右利手汉字示图书写功能区

目的运用导航经颅磁刺激探索国人右利手汉字图示书写功能区的皮层定位,并分析研究该技术下与手运动中枢的皮层位置关系。方法对10例健康受试者完成汉字示图书写的任务,在进行书写的同时予以导航下经颅磁刺激,根据出现书写障碍的阳性位点,测绘书写功能区的区域和面积;通过导航经颅磁刺激刺激右手运动功能区出现运动诱发电位,记录右手肌肉肌电数据和阳性刺激坐标,计算右手运动功能区面积,进行书写功能区与右手运动功能区大小和距离的对比。结果 10例健康汉语母语受试者均可以在导航经颅磁刺激下定位书写中枢。书写功能区的皮层定位较为固定,阳性位点主要位于额中回后部(86%,55/64)。书写功能区面积小于右手运动功能区的面积,差异具有统计学意义(161.03 mm~2±62.58 mm~2 vs.589.50 mm~2±227.34 mm~2,t=-4.050,P0.001)。书写功能区的位置与手运动区的皮层定位存在一定距离(d=12.58 mm±2.71 mm),并没有功能区的重合。结论导航经颅磁刺激技术可以辅助定位示图书写功能区位置,并且书写功能区与手运动功能区没有重合。     

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5‐day repeated sessions study

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a “build‐up” effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30 min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5 days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day‐to‐day was low in both groups, implying high within‐subject variability of both active and sham iTBS after‐effects. In contrast, we found a high within‐subject repeatability of resting and active motor threshold, and baseline motor‐evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5 days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.     

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.     

GABA and cortical inhibition in motor and non-motor regions using combined TMS–EEG: A time analysis

ObjectiveThe 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 GABA_B 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).MethodsppTMS 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.ResultsIn the motor cortex, LICI resulted in significant suppression in mean cortical evoked activity on EEG between 75 and 250 ms following delivery of the test stimulus. Maximal inhibition was seen from 50 to 250 ms in DLPFC, and between 50 and 175 ms in the parietal lobe.ConclusionsppTMS may be used to produce LICI in several cortical regions with a time course similar to known GABA_B activity.SignificanceppTMS induction of LICI can be recorded by combining TMS with EEG and seems to relate to GABA_B activity.     

ARTIST: A fully automated artifact rejection algorithm for single‐pulse TMS‐EEG data

Concurrent single‐pulse TMS‐EEG (spTMS‐EEG) is an emerging noninvasive tool for probing causal brain dynamics in humans. However, in addition to the common artifacts in standard EEG data, spTMS‐EEG data suffer from enormous stimulation‐induced artifacts, posing significant challenges to the extraction of neural information. Typically, neural signals are analyzed after a manual time‐intensive and often subjective process of artifact rejection. Here we describe a fully automated algorithm for spTMS‐EEG artifact rejection. A key step of this algorithm is to decompose the spTMS‐EEG data into statistically independent components (ICs), and then train a pattern classifier to automatically identify artifact components based on knowledge of the spatio‐temporal profile of both neural and artefactual activities. The autocleaned and hand‐cleaned data yield qualitatively similar group evoked potential waveforms. The algorithm achieves a 95% IC classification accuracy referenced to expert artifact rejection performance, and does so across a large number of spTMS‐EEG data sets (n = 90 stimulation sites), retains high accuracy across stimulation sites/subjects/populations/montages, and outperforms current automated algorithms. Moreover, the algorithm was superior to the artifact rejection performance of relatively novice individuals, who would be the likely users of spTMS‐EEG as the technique becomes more broadly disseminated. In summary, our algorithm provides an automated, fast, objective, and accurate method for cleaning spTMS‐EEG data, which can increase the utility of TMS‐EEG in both clinical and basic neuroscience settings.     

Cortical inhibition within motor and frontal regions in alcohol dependence post-detoxification: A pilot TMS-EEG study

Objectives. Preclinical studies suggest that cortical alterations within the prefrontal cortex (PFC) are critical to the pathophysiology of alcohol dependence. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows direct assessment of cortical excitability and inhibition within the PFC of human subjects. We report the first application of TMS-EEG to measure these indices within the PFC of alcohol-dependent (ALD) patients post-detoxification. Methods. Cortical inhibition was assessed in 12 ALD patients and 14 healthy controls through single and paired-pulse TMS paradigms. Long-interval cortical inhibition indexed cortical inhibition in the PFC. In the motor cortex (MC), short- interval intracortical inhibition and cortical silent period determined inhibition, while intracortical facilitation measured facilitation, resting and active motor threshold indexed cortical excitability. Results. ALD patients demonstrated altered cortical inhibition across the bilateral frontal cortices relative to controls. There was evidence of altered cortical excitability in ALD patients; however, no significant differences in MC inhibition. Conclusions. Our study provides first direct evidence of reduced cortical inhibition in the PFC of ALD patients post-detoxification. Altered cortical excitability in the MC may reflect hyper-excitability within the cortex associated with chronic alcohol consumption. These findings provide initial neurophysiological evidence of disrupted cortical excitability within the PFC of ALD patients.     

A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition

Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.     

Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation‐evoked potentials: A systematic review

Transcranial magnetic stimulation (TMS) can depolarize the neurons directly under the coil when applied to the cerebral cortex, and modulate the neural circuit associated with the stimulation site, which makes it possible to measure the neurophysiological index to evaluate excitability and inhibitory functions. Concurrent TMS and electroencephalography (TMS‐EEG) has been developed to assess the neurophysiological characteristics of cortical regions other than the motor cortical region noninvasively. The aim of this review is to comprehensively discuss TMS‐EEG research in the healthy brain focused on excitability, inhibition, and plasticity following neuromodulatory TMS paradigms from a neurophysiological perspective. A search was conducted in PubMed to identify articles that examined humans and that were written in English and published by September 2018. The search terms were as follows: (TMS OR ‘transcranial magnetic stimulation’) AND (EEG OR electroencephalog*) NOT (rTMS OR ‘repetitive transcranial magnetic stimulation’ OR TBS OR ‘theta burst stimulation’) AND (healthy). The study presents an overview of TMS‐EEG methodology and neurophysiological indices and reviews previous findings from TMS‐EEG in healthy individuals. Furthermore, this review discusses the potential application of TMS‐EEG neurophysiology in the clinical setting to study healthy and diseased brain conditions in the future. Combined TMS‐EEG is a powerful tool to probe and map neural circuits in the human brain noninvasively and represents a promising approach for determining the underlying pathophysiology of neuropsychiatric disorders.     

Focal enhancement of motor cortex excitability during motor imagery: a transcranial magnetic stimulation study

OBJECTIVES: In order to learn more about the physiology of the motor cortex during motor imagery, we evaluated the changes in excitability of two different hand muscle representations in the primary motor cortex (M1) of both hemispheres during two imagery conditions. MATERIALS AND METHODS: We applied focal transcranial magnetic stimulation (TMS) over each M1, recording motor evoked potentials (MEPs) from the contralateral abductor pollicis brevis (APB) and first dorsal interosseus (FDI) muscles during rest, imagery of contralateral thumb abduction (C-APB), and imagery of ipsilateral thumb abduction (I-APB). We obtained measures of motor threshold (MT), MEP recruitment curve (MEP-rc) and F waves. RESULTS: Motor imagery compared with rest significantly decreased the MT and increased MEPs amplitude at stimulation intensities clearly above MT in condition C-APB, but not in condition I-APB. These effects were not significantly different between right and left hemisphere. MEPs simultaneously recorded from the FDI, which was not involved in the task, did not show facilitatory effects. There were no significant changes in F wave amplitude during motor imagery compared with rest. CONCLUSIONS: Imagery of unilateral simple movements is associated with increased excitability only of a highly specific representation in the contralateral M1 and does not differ between hemispheres.     

Central fatigue and motor cortical excitability during repeated shortening and lengthening actions

A decline in voluntary muscle activation and adaptations in motor cortical excitability contribute to the progressive decline in voluntary force during sustained isometric contractions. However, the neuronal control of muscle activation differs between isometric and dynamic contractions. This study was designed to investigate voluntary activation, motor cortex excitability, and intracortical inhibition during fatiguing concentric and eccentric actions. Eight subjects performed 143 torque motor-controlled, repeated shortening and lengthening actions of the elbow flexor muscles. Transcranial magnetic stimulation (TMS) was applied three times every 20 cycles. Magnetic evoked motor potentials (MEP), duration of the silent period (SP), and the torque increase due to TMS were analyzed. TMS resulted in a small torque increase in unfatigued actions. With repeated actions, voluntary torque dropped rapidly and the amplitude of the TMS-induced twitches increased, especially during repeated lengthening actions. MEP area of biceps brachii and brachioradialis muscles increased during repeated actions to a similar extent during lengthening and shortening fatigue. The duration of biceps and brachioradialis SP did not change with fatigue. Thus, voluntary activation became suboptimal during fatiguing dynamic actions and motor cortex excitability increased without any changes in intracortical inhibition. The apparent dissociation of voluntary activation and motor cortex excitability suggests that the central fatigue observed, especially during lengthening actions, did not result from changes in motor cortex excitability.