Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Investigating the effects of dopamine on short- and long-latency afferent inhibition.

Short- and long-latency afferent inhibition (SAI and LAI respectively) are phenomenon whereby the motor evoked potential induced by transcranial magnetic stimulation (TMS) is inhibited by a sensory afferent volley consequent to nerve stimulation. It remains unclear whether dopamine participates in the genesis or modulation of SAI and LAI. The present study aimed to determine if SAI and LAI are modulated by levodopa (l-DOPA). In this placebo-controlled, double-anonymized study Apo-Levocarb (100 mg l-DOPA in combination with 25 mg carbidopa) and a placebo were administered to 32 adult males (mean age 24 ± 3 years) in two separate sessions. SAI and LAI were evoked by stimulating the median nerve and delivering single-pulse TMS over the motor hotspot corresponding to the first dorsal interosseous muscle of the right hand. SAI and LAI were quantified before and 1 h following ingestion of drug or placebo corresponding to the peak plasma concentration of Apo-Levocarb. The results indicate that Apo-Levocarb increases SAI and does not significantly alter LAI. These findings support literature demonstrating increased SAI following exogenous dopamine administration in neurodegenerative disorders. KEY POINTS: Short- and long-latency afferent inhibition (SAI and LAI respectively) are measures of corticospinal excitability evoked using transcranial magnetic stimulation. SAI and LAI are reduced in conditions such as Parkinson's disease which suggests dopamine may be involved in the mechanism of afferent inhibition. 125 mg of Apo-Levocarb (100 mg dopamine) increases SAI but not LAI. This study increases our understanding of the pharmacological mechanism of SAI and LAI.

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

BACKGROUND: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. METHODS: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. RESULTS: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. CONCLUSIONS: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

Always expect the unexpected: eye position modulates visual cortex excitability in a stimulus-free environment.

Stimuli that potentially require a rapid defensive or avoidance action can appear from the periphery at any time in natural environments. de Wit et al. (Cortex 127: 120-130, 2020) recently reported novel evidence suggestive of a fundamental neural mechanism that allows organisms to effectively deal with such situations. In the absence of any task, motor cortex excitability was found to be greater whenever gaze was directed away from either hand. If modulation of cortical excitability as a function of gaze location is a fundamental principle of brain organization, then one would expect its operation to be present outside of motor cortex, including brain regions involved in perception. To test this hypothesis, we applied single-pulse transcranial magnetic stimulation (TMS) to the right lateral occipital lobe while participants directed their eyes to the left, straight-ahead, or to the right, and reported the presence or absence of a phosphene. No external stimuli were presented. Cortical excitability as reflected by the proportion of trials on which phosphenes were elicited from stimulation of the right visual cortex was greater with eyes deviated to the right as compared with the left. In conjunction with our previous findings of change in motor cortex excitability when gaze and effector are not aligned, this eye position-driven change in visual cortex excitability presumably serves to facilitate the detection of stimuli and subsequent readiness to act in nonfoveated regions of space. The existence of this brain-wide mechanism has clear adaptive value given the unpredictable nature of natural environments in which human beings are situated and have evolved.NEW & NOTEWORTHY For many complex tasks, humans focus attention on the site relevant to the task at hand. Humans evolved and live in dangerous environments, however, in which threats arise from outside the attended site; this fact necessitates a process by which the periphery is monitored. Using single-pulse transcranial magnetic stimulation (TMS), we demonstrated for the first time that eye position modulates visual cortex excitability. We argue that this underlies at least in part what we term "surveillance attention."

Spontaneous and optogenetically induced cortical spreading depolarization in familial hemiplegic migraine type 1 mutant mice.

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant CaV2.1 Ca2+ channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients. Very rarely, spontaneous CSDs were observed in mutant but never in wildtype mice. In homozygous Cacna1aR192Q mice exclusively single-wave CSDs were observed whereas heterozygous Cacna1aS218L mice displayed multiple-wave events, seemingly in line with the more severe clinical phenotype associated with the S218L mutation. Spontaneous CSDs were associated with body stretching, one-directional slow head turning, and rotating movement of the body. Spontaneous CSD events were compared with those induced in a controlled manner using minimally invasive optogenetics. Also in the optogenetic experiments single-wave CSDs were observed in Cacna1aR192Q and Cacna1aS218L mice (whereas the latter also showed multiple-wave events) with movements similar to those observed with spontaneous events. Compared to wildtype mice, FHM1 mutant mice exhibited a reduced threshold and an increased propagation speed for optogenetically induced CSD with a more profound CSD-associated dysfunction, as indicated by a prolonged suppression of transcallosal evoked potentials and a reduction of unilateral forepaw grip performance. When induced during sleep, the optogenetic CSD threshold was particularly lowered, which may explain why spontaneous CSD events predominantly occurred during sleep. In conclusion, our data show that key neurophysiological and behavioural features of optogenetically induced CSDs mimic those of rare spontaneous events in FHM1 R192Q and S218L mutant mice with differences in severity in line with FHM1 clinical phenotypes seen with these mutations.

Spatial sensorimotor mismatch between the motor command and somatosensory feedback decreases motor cortical excitability. A transcranial magnetic stimulation-virtual reality study.

Effective control of movement predominantly depends on the exchange and integration between sensory feedback received by our body and motor command. However, the precise mechanisms governing the adaptation of the motor system's response to altered somatosensory signals (i.e., discrepancies between an action performed and feedback received) following movement execution remain largely unclear. In order to address these questions, we developed a unique paradigm using virtual reality (VR) technology. This paradigm can induce spatial incongruence between the motor commands executed by a body district (i.e., moving the right hand) and the resulting somatosensory feedback received (i.e., feeling touch on the left ankle). We measured functional sensorimotor plasticity in 17 participants by assessing the effector's motor cortical excitability (right hand) before and after a 10-min VR task. The results revealed a decrease in motor cortical excitability of the movement effector following exposure to a 10-min conflict between the motor output and the somatosensory input, in comparison to the control condition where spatial congruence between the moved body part and the area of the body that received the feedback was maintained. This finding provides valuable insights into the functional plasticity resulting from spatial sensorimotor conflict arising from the discrepancy between the anticipated and received somatosensory feedback following movement execution. The cortical reorganization observed can be attributed to functional plasticity mechanisms within the sensorimotor cortex that are related to establishing a new connection between somatosensory input and motor output, guided by temporal binding and the Hebbian plasticity rule.

Motor-evoked potentials as biomarkers for sexual arousal?

BACKGROUND: Motor cortex excitability may represent the neuronal endpoint of motivational processes and was shown to be modulated by both sexual arousal and deceptive behavior. AIM: This is the first study to investigate the influence of lying and sex in heterosexual women and men based on motor-evoked potentials (MEPs) measured while viewing sexually arousing pictures. METHODS: Sixteen heterosexual couples were shown 360 trials consisting of pictures displaying both almost naked females and males and neutral control images. In a subsequent forced-choice question about wanting to see the respective pictures fully naked, they were instructed to either answer in agreement with or opposite to their sexual preference. Participants went through 2 blocks of answering truthfully and 2 blocks of lying, with these 4 blocks being shown in a randomized alternating order. OUTCOMES: To measure cortical excitability, MEPs were used, evoked by single transcranial magnetic stimulation pulses between image presentation and response. RESULTS: In normalized MEPs, women and men showed higher amplitudes for preferred over non-preferred sexual stimuli, but only on a descriptive level. Planned contrasts showed higher non-normalized MEPs for lying in all picture categories. Direct comparisons to a preliminary study showed overall lower effect sizes. CLINICAL IMPLICATIONS: Both sexes tend to show higher MEPs in response to their sexually preferred stimuli. MEPs are not stable markers for willful volitionally controlled deception although lying does increase cortical excitability. The present experimental design does not seem valid enough to serve as a diagnostic marker for sexual preference or paraphilia and malingering. STRENGTHS AND LIMITATIONS: This is the first study investigating whether sexual motivational stimuli modulate MEPs in women, while also examining the influence of lying for both sexes. The sample was too small for some found effects to be significant. Also, the experimental setup may have been less suited for female participants in comparison to male ones. CONCLUSION: The operationalization of sexual motivation via MEPs seems to highly depend on different experimental factors including the sex of the participants, induced motivation, and lying.

Transcutaneous auricular vagus nerve stimulation modifies cortical excitability in middle-aged and older adults.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABAAergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation.

Correlation of bilateral M1 hand area excitability and overall functional recovery after spinal cord injury: protocol for a prospective cohort study.

BACKGROUND: After spinal cord injury (SCI), a large number of survivors suffer from severe motor dysfunction (MD). Although the injury site is in the spinal cord, excitability significantly decreases in the primary motor cortex (M1), especially in the lower extremity (LE) area. Unfortunately, M1 LE area-targeted repetitive transcranial magnetic stimulation (rTMS) has not achieved significant motor improvement in individuals with SCI. A recent study reported that the M1 hand area in individuals with SCl contains a compositional code (the movement-coding component of neural activity) that links matching movements from the upper extremities (UE) and the LE. However, the correlation between bilateral M1 hand area excitability and overall functional recovery is unknown. OBJECTIVE: To clarify the changes in the excitability of the bilateral M1 hand area after SCI and its correlation with motor recovery, we aim to specify the therapeutic parameters of rTMS for SCI motor rehabilitation. METHODS: This study is a 12-month prospective cohort study. The neurophysiological and overall functional status of the participants will be assessed. The primary outcomes included single-pulse and paired-pulse TMS. The second outcome included functional near-infrared spectroscopy (fNIRS) measurements. Overall functional status included total motor score, modified Ashworth scale score, ASIA Impairment Scale grade, spinal cord independence measure and modified Barthel index. The data will be recorded for individuals with SCI at disease durations of 1 month, 2 months, 4 months, 6 months and 12 months. The matched healthy controls will be measured during the same period of time after recruitment. DISCUSSION: The present study is the first to analyze the role of bilateral M1 hand area excitability changes in the evaluation and prediction of overall functional recovery (including motor function and activities of daily living) after SCI, which will further expand the traditional theory of the predominant role of M1, optimize the current rTMS treatment, and explore the brain-computer interface design for individuals with SCI. TRIAL REGISTRATION NUMBER: ChiCTR2300068831.

Low-intensity ultrasound stimulation modulates cortical neurovascular coupling in an attention deficit hyperactivity disorder rat model.

Attention deficit hyperactivity disorder is accompanied by changes in cranial nerve function and cerebral blood flow (CBF). Low-intensity ultrasound stimulation can modulate brain neural activity in attention deficit hyperactivity disorder. However, to date, the modulatory effects of low-intensity ultrasound stimulation on CBF and neurovascular coupling in attention deficit hyperactivity disorder have not been reported. To address this question, Sprague-Dawley, Wistar-Kyoto, and spontaneously hypertensive (attention deficit hyperactivity disorder (ADHD) rat model) rats were divided into the control and low-intensity ultrasound stimulation (LIUS) groups. Cortical electrical stimulation was used to induce cortical excitability in different types of rats, and a penetrable laser speckle contrast imaging (LSCI) system and electrodes were used to evaluate the electrical stimulation-induced CBF, cortical excitability, and neurovascular coupling in free-moving rats. The CBF, cortical excitability, and neurovascular coupling (NVC) under cortical electrical stimulation in the attention deficit hyperactivity disorder rats were significantly different from those in the Sprague-Dawley and Wistar-Kyoto rats. We also found that low-intensity ultrasound stimulation significantly interfered with the cortical excitability and neurovascular coupling induced by cortical electrical stimulation in rats with attention deficit hyperactivity disorder. Our findings suggest that neurovascular coupling is a potential biomarker for attention deficit hyperactivity disorder. Furthermore, low-intensity ultrasound stimulation can improve abnormal brain function in attention deficit hyperactivity disorder and lay a research foundation for its application in the clinical treatment of attention deficit hyperactivity disorder.

The neurophysiological aftereffects of brain stimulation in human primary motor cortex: a Sham-controlled comparison of three protocols.

Paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are non-invasive brain stimulation methods that are used to modulate cortical excitability. Whether one technique is superior to the others in achieving this outcome and whether individuals that respond to one intervention are more likely to respond to another remains largely unknown. In the present study, the neurophysiological aftereffects of three excitatory neurostimulation protocols were measured with transcranial magnetic stimulation (TMS). Twenty minutes of PAS at an ISI of 25 ms, anodal tDCS, 20-Hz tACS, and Sham stimulation were administered to 31 healthy adults in a repeated measures design. Compared with Sham, none of the stimulation protocols significantly modulated corticospinal excitability (input/ouput curve and slope, TMS stimulator intensity required to elicit MEPs of 1-mV amplitude) or intracortical excitability (short- and long-interval intracortical inhibition, intracortical facilitation, cortical silent period). Sham-corrected responder analysis estimates showed that an average of 41 (PAS), 39 (tDCS), and 39% (tACS) of participants responded to the interventions with an increase in corticospinal excitability. The present data show that three stimulation protocols believed to increase cortical excitability are associated with highly heterogenous and variable aftereffects that may explain a lack of significant group effects.

Acute pain drives different effects on local and global cortical excitability in motor and prefrontal areas: insights into interregional and interpersonal differences in pain processing.

Pain-related depression of corticomotor excitability has been explored using transcranial magnetic stimulation-elicited motor-evoked potentials. Transcranial magnetic stimulation-electroencephalography now enables non-motor area cortical excitability assessments, offering novel insights into cortical excitability changes during pain states. Here, pain-related cortical excitability changes were explored in the dorsolateral prefrontal cortex and primary motor cortex (M1). Cortical excitability was recorded in 24 healthy participants before (Baseline), during painful heat (Acute Pain), and non-noxious warm (Warm) stimulation at the right forearm in a randomized sequence, followed by a pain-free stimulation measurement. Local cortical excitability was assessed as the peak-to-peak amplitude of early transcranial magnetic stimulation evoked potential, whereas global-mean field power measured the global excitability. Relative to the Baseline, Acute Pain decreased the peak-to-peak amplitude in M1 and dorsolateral prefrontal cortex compared with Warm (both P < 0.05). A reduced global-mean field power was only found in M1 during Acute Pain compared with Warm (P = 0.003). Participants with the largest reduction in local cortical excitability under Acute Pain showed a negative correlation between dorsolateral prefrontal cortex and M1 local cortical excitability (P = 0.006). Acute experimental pain drove differential pain-related effects on local and global cortical excitability changes in motor and non-motor areas at a group level while also revealing different interindividual patterns of cortical excitability changes, which can be explored when designing personalized treatment plans.

Efficacy of dual-task augmented reality rehabilitation in non-hospitalized adults with self-reported long COVID fatigue and cognitive impairment: a pilot study.

BACKGROUND: Cognitive impairment and chronic fatigue represent common characteristics of the long COVID syndrome. Different non-pharmacological treatments have been proposed, and physiotherapy has been proposed to improve the symptoms. This study aimed to evaluate the effects of a dual-task augmented reality rehabilitation protocol in people with long COVID fatigue and cognitive impairment. METHODS AND MATERIALS: Ten non-hospitalized adults with reported fatigue and "brain fog" symptoms after COVID (7/10 females, 50 years, range 41-58) who participated in 20 sessions of a 1-h "dual-task" training, were compared to 10 long COVID individuals with similar demographics and symptoms (9/10 females, 56 years, range 43-65), who did not participate to any rehabilitation protocol. Cognitive performance was assessed with the Trail Making Test (TMT-A and -B) and Frontal Assessment Battery (FAB), and cardiovascular and muscular fatigue were assessed with the fatigue severity scale (FSS), six-minute walking test and handgrip endurance. Finally, transcranial magnetic stimulation (TMS) investigated cortical excitability. RESULTS: The mixed-factors analysis of variance found a significant interaction effect only in cognitive performance evaluation, suggesting TMT-B execution time decreased (- 15.9 s, 95% CI 7.6-24.1, P = 0.001) and FAB score improved (1.88, 95% CI 2.93-0.82, P = 0.002) only in the physiotherapy group. For the remaining outcomes, no interaction effect was found, and most parameters similarly improved in the two groups. CONCLUSION: The preliminary results from this study suggest that dual-task rehabilitation could be a feasible protocol to support cognitive symptoms recovery after COVID-19 and could be helpful in those individuals suffering from persisting and invalidating symptoms.

Immediate Effects of Preconditioning Intermittent Theta Burst Stimulation on Lower Extremity Motor Cortex Excitability in Healthy Participants.

BACKGROUND: Previous studies have found that inhibitory priming with continuous theta burst stimulation (cTBS) can enhance the effect of subsequent excitatory conditioning stimuli with intermittent theta burst stimulation (iTBS) in the upper limbs. However, whether this combined stimulation approach elicits a comparable compensatory response in the lower extremities remains unclear. This study aimed to investigate how cTBS preconditioning modulated the effect of iTBS on motor cortex excitability related to the lower limb in healthy individuals. METHODS: Using a randomised cross-over design, a total of 25 healthy participants (19 females, mean age = 24.80 yr) were recruited to undergo three different TBS protocols (cTBS + iTBS, sham cTBS + iTBS, sham cTBS + sham iTBS) in a random order. Each TBS intervention was administered with one-week intervals. cTBS and iTBS were administered at an intensity of 80% active motor threshold (AMT) delivering a total of 600 pulses. Before intervention (T0), immediately following intervention (T1), and 20 min after intervention (T2), the corticomotor excitability was measured for the tibialis anterior muscle of participants' non-dominant leg using a Magneuro100 stimulator and matched double-cone coil. The average amplitude of the motor-evoked potential (MEP) induced by applying 20 consecutive monopulse stimuli at an intensity of 130% resting motor threshold (RMT) was collected and analysed. RESULTS: Compare with T0 time, the MEP amplitude (raw and normalised) at T1 and T2 showed a statistically significant increase following the cTBS + iTBS protocol (p < 0.01), but no significant differences were observed in amplitude changes following other protocols (sham cTBS + iTBS and sham cTBS + sham iTBS) (p > 0.05). Furthermore, no statistically significant difference was found among the three protocols at any given time point (p > 0.05). CONCLUSIONS: Preconditioning the lower extremity motor cortex with cTBS prior to iTBS intervention can promptly enhance its excitability in healthy participants. This effect persists for a minimum duration of 20 min. CLINICAL TRIAL REGISTRATION: No: ChiCTR2300069315. Registered 13 March, 2023, https://www.chictr.org.cn.

An investigation of the acute effects of aerobic exercise on executive function and cortical excitability in adolescents with attention deficit hyperactivity disorder (ADHD).

Previous studies have shown that aerobic exercise has beneficial effects on executive function in adolescents with attention-deficit hyperactivity disorder (ADHD). The underlying mechanisms could be partially due to aerobic exercise-induced cortical excitability modulation. The aim of this study was to explore the effects of acute aerobic exercise on executive functions and cortical excitability and the association between these phenomena in adolescents with ADHD. The study was conducted using a complete crossover design. Executive functions (inhibitory control, working memory, and planning) and cortical excitability were assessed in twenty-four drug-naïve adolescents with ADHD before and after acute aerobic exercise or a control intervention. Inhibitory control, working memory, and planning improved after acute aerobic exercise in adolescents with ADHD. Moreover, cortical excitability monitored by transcranial magnetic stimulation (TMS) decreased after intervention in this population. Additionally, improvements in inhibitory control and working memory performance were associated with enhanced cortical inhibition. The findings provide indirect preliminary evidence for the assumption that changes in cortical excitability induced by aerobic exercise partially contribute to improvements in executive function in adolescents with ADHD.

Feasibility of Simultaneous Anodal Transcranial Direct Current Stimulation During Gait Training in Chronic Stroke Patients: A Randomized Double-Blind Pilot Clinical Trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a therapeutic tool for improving post-stroke gait disturbances, with ongoing research focusing on specific protocols for its application. We evaluated the feasibility of a rehabilitation protocol that combines tDCS with conventional gait training. METHODS: This was a randomized, double-blind, single-center pilot clinical trial. Patients with unilateral hemiplegia due to ischemic stroke were randomly assigned to either the tDCS with gait training group or the sham stimulation group. The anodal tDCS electrode was placed on the tibialis anterior area of the precentral gyrus while gait training proceeded. Interventions were administered 3 times weekly for 4 weeks. Outcome assessments, using the 10-meter walk test, Timed Up and Go test, Berg Balance Scale, Functional Ambulatory Scale, Modified Barthel Index, and European Quality of Life 5 Dimensions 3 Level Version, were conducted before and after the intervention and again at the 8-week mark following its completion. Repeated-measures analysis of variance (ANOVA) was used for comparisons between and within groups. RESULTS: Twenty-six patients were assessed for eligibility, and 20 were enrolled and randomized. No significant differences were observed between the tDCS with gait training group and the sham stimulation group in gait speed after the intervention. However, the tDCS with gait training group showed significant improvement in balance performance in both within-group and between-group comparisons. In the subgroup analysis of patients with elicited motor-evoked potentials, comfortable pace gait speed improved in the tDCS with gait training group. No serious adverse events occurred throughout the study. CONCLUSIONS: Simultaneous anodal tDCS during gait training is a feasible rehabilitation protocol for chronic stroke patients with gait disturbances. CLINICAL TRIAL REGISTRATION: URL: https://cris.nih.go.kr; Registration number: KCT0007601; Date of registration: 11 July 2022.

Impact of repetitive transcranial magnetic stimulation on cortical activity: a systematic review and meta-analysis utilizing functional near-infrared spectroscopy evaluation.

BACKGROUND: Repeated transcranial magnetic stimulation (rTMS) could induce alterations in cortical excitability and promote neuroplasticity. To precisely quantify these effects, functional near-infrared spectroscopy (fNIRS), an optical neuroimaging modality adept at detecting changes in cortical hemodynamic responses, has been employed concurrently alongside rTMS to measure and tailor the impact of diverse rTMS protocols on the brain cortex. OBJECTIVE: This systematic review and meta-analysis aimed to elucidate the effects of rTMS on cortical hemodynamic responses over the primary motor cortex (M1) as detected by fNIRS. METHODS: Original articles that utilized rTMS to stimulate the M1 cortex in combination with fNIRS for the assessment of cortical activity were systematically searched across the PubMed, Embase, and Scopus databases. The search encompassed records from the inception of these databases up until April, 2024. The assessment for risk of bias was also conducted. A meta-analysis was also conducted in studies with extractable raw data. RESULTS: Among 312 studies, 14 articles were eligible for qualitative review. 7 studies were eligible for meta-analysis. A variety of rTMS protocols was employed on M1 cortex. In inhibitory rTMS, multiple studies observed a reduction in the concentration of oxygenated hemoglobin [HbO] at the ipsilateral M1, contrasted by an elevation at the contralateral M1. Meta-analysis also corroborated this consistent trend. Nevertheless, certain investigations unveiled diminished [HbO] in bilateral M1. Several studies also depicted intricate inhibitory or excitatory interplay among distinct cortical regions. CONCLUSION: Diverse rTMS protocols led to varied patterns of cortical activity detected by fNIRS. Meta-analysis revealed a trend of increasing [HbO] in the contralateral cortices and decreasing [HbO] in the ipsilateral cortices following low frequency inhibitory rTMS. However, due to the heterogeneity between studies, further research is necessary to comprehensively understand rTMS-induced alterations in brain activity.

Number of conditioning trials, but not stimulus intensity, influences operant conditioning of brain responses after total knee arthroplasty.

PURPOSE: The primary purpose of this randomized, cross-sectional study was to determine whether operant conditioning of motor evoked torque (MEPTORQUE) in individuals with total knee arthroplasty (TKA) increases quadriceps MEPTORQUE responses within a single session and induces acute corticospinal adaptations by producing sustained increases in MEPTORQUE after training. A secondary purpose was to determine if these changes were affected by the stimulus intensity and number of training trials. METHODS: Thirty participants were block-randomized into one of three groups based on the participant's active motor threshold (100%, 120%, and 140%) to evaluate the effect of stimulus intensity. Participants received three blocks of conditioning trials (COND), where they trained to increase their MEPTORQUE. Control (CTRL) transcranial magnetic stimulation pulses were provided before and after each COND block to establish baseline corticospinal excitability and to evaluate the effect of the number of training trials. Two MEPTORQUE recruitment curves were collected to evaluate the effect of up-conditioning on acute corticospinal adaptations. RESULTS: TKA participants were able to successfully increase their MEPTORQUE in a single session (F3,81 = 10.719, p < 0.001) and induce acute corticospinal adaptations (F1,27 = 20.029, p < 0.001), indicating sustained increases in quadriceps corticospinal excitability due to operant conditioning. While the stimulus intensity used during training did not affect the ability to increase MEPTORQUE (F2,26 = 0.021, n.s.) or its associated acute adaptations (F2,27 = 0.935, n.s.), the number of training trials significantly influenced these outcomes (F3,81 = 10.719, p < 0.001; F3,81 = 4.379, p = 0.007, respectively). CONCLUSION: Operant conditioning is a feasible approach for improving quadriceps corticospinal excitability following TKA. While any of the three stimulus intensities evaluated in this study may be used in future operant conditioning interventions, using a low or moderate stimulus intensity and 150 training trials are recommended to improve treatment efficiency and patient adherence. LEVEL OF EVIDENCE: Level II.

Repetitive transcranial magnetic stimulation in new daily persistent headache patients: a single arm open label study.

BACKGROUND: New daily persistent headache (NDPH) is a continuous, unremitting headache from onset that yields suboptimal results with traditional medicines. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive treatment for other headache disorders, such as migraine, and neuromodulation has not been well-studied in NDPH. The objective of the study was to evaluate the efficacy of rTMS in reducing the frequency and severity of headaches, and associated anxiety and depressive symptoms in NDPH patients. METHODS: This was an open label prospective, single arm, interventional pilot study conducted between October 2022 and September 2023. All eligible participants received 10 Hz rTMS (600 pulses, 10 trains), delivered to the left prefrontal cortex for three consecutive days. The post-rTMS headache severity was recorded weekly for four weeks and headache free days/functional disability, PHQ-9, and GAD-7 scores at the end of four weeks and compared with pre-rTMS parameters. The primary outcome was defined by ≥ 50% reduction in headache severity on Visual Analogue Scale (VAS) score, decrease in headache days from the baseline and secondary outcome was ≥ 6 point reduction in HIT-6 score at 4 weeks. RESULTS: Fifty NDPH patients (mean [SD] age, 35.06 [13.91] years; 31 females [62%]) participated in this study. Thirty-five patients (70%) reported ≥ 50% improvement in pain severity (p-value < 0.001), with a mean reduction of 10.84 (4.88) headache days per 28 days from a baseline of 28 headache days (p-value < 0.001). Thirty-eight patients (76%) reported a ≥ 6 point's reduction in HIT score at 4 weeks. Maximum improvement in the above parameters was observed in NDPH patients with chronic migraine. Two patients reported intolerance to the sound of the rTMS. The median (IQR) PHQ-9 and GAD-7 scores reduced from 11.5(3.75,20) to 7(2,15) (p-value < 0.001) and 10(3,14) to 5.5(0,9) (p-value < 0.001) respectively. CONCLUSION: rTMS was well tolerated and effective in reducing pain severity, headache days and headache related disability, depressive and anxiety symptoms. TRIAL REGISTRATION: CTRI/2023/05/053247.

A comparative transcranial magnetic stimulation study: Assessing cortical excitability and plasticity in Alzheimer's disease, dementia with Lewy bodies and Frontotemporal dementia.

BACKGROUND: Here, we aimed to investigate the roles of long-term potentiation-like (LTP-like) plasticity using intermittent theta burst (iTBS) protocol and resting motor threshold (rMT) in the differential diagnosis of Alzheimer's disease (AD), diffuse dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). METHOD: We enrolled 21 subjects with AD, 28 subjects with DLB, 14 subjects with FTD, and 33 elderly subjects with normal cognitive functions into the study. We recorded rMT and percentage amplitude change of motor evoked potentials (MEPs) after the iTBS protocol in each group. RESULTS: In patients with AD and DLB, the percentage amplitude change of MEPs, and rMTs were significantly lower than in healthy subjects. However, no significant difference was observed in individuals with FTD. CONCLUSION: Our findings showed that transcranial magnetic stimulation measures, particularly rMTs and LTP-like plasticity, may be potential biomarkers to distinguish between different dementia subtypes. Impaired motor cortical excitability and synaptic plasticity were more prominent in AD and DLB than in FTD. This aligns with the evidence that cortical motor networks are usually spared in FTDs in early-to-middle stages.