Heightened Reticulospinal Excitability after Severe Corticospinal Damage in Chronic Stroke.

OBJECTIVE: After severe corticospinal tract damage poststroke in humans, some recovery of strength and movement proximally is evident. It is possible that alternate motor pathways, such as the reticulospinal tract, may be upregulated to compensate for the loss of corticospinal tract input. We investigated the extent of reticulospinal tract excitability modulation and its inter-dependence on the severity of corticospinal tract damage after stroke in humans. METHODS: We used a novel startle conditioned transcranial magnetic stimulation paradigm to elicit ipsilateral motor evoked potentials, an index of reticulospinal tract excitability, in 22 chronic stroke participants with mild to severe corticospinal tract damage and 14 neurotypical age-matched controls. RESULTS: We found that ipsilateral motor evoked potential presence was higher in the paretic arm of people with severe corticospinal tract damage compared to their non-paretic arm, people with mild corticospinal tract damage, and age-matched controls. Interestingly, ipsilateral motor evoked potential presence was correlated with motor impairment across the entire stroke cohort, whereby individuals with worse impairment exhibited more frequent ipsilateral motor evoked potentials (ie, higher reticulospinal tract excitability). INTERPRETATION: Following severe corticospinal tract damage, upregulated reticulospinal tract activity may compensate for a loss of corticospinal tract input, providing some proximal recovery of isolated and within-synergy movements, but deficits in performing out of synergy movements and finger fractionation remain. Interventions aimed at modulating the reticulospinal tract could be beneficial or detrimental to ameliorating motor impairment depending on the degree of reliance on this pathway for residual motor output. ANN NEUROL 2024.

Cerebellar Excitability Regulates Physical Fatigue Perception.

Fatigue is the subjective sensation of weariness, increased sense of effort, or exhaustion and is pervasive in neurologic illnesses. Despite its prevalence, we have a limited understanding of the neurophysiological mechanisms underlying fatigue. The cerebellum, known for its role in motor control and learning, is also involved in perceptual processes. However, the role of the cerebellum in fatigue remains largely unexplored. We performed two experiments to examine whether cerebellar excitability is affected after a fatiguing task and its association with fatigue. Using a crossover design, we assessed cerebellar inhibition (CBI) and perception of fatigue in humans before and after "fatigue" and "control" tasks. Thirty-three participants (16 males, 17 females) performed five isometric pinch trials with their thumb and index finger at 80% maximum voluntary capacity (MVC) until failure (force <40% MVC; fatigue) or at 5% MVC for 30 s (control). We found that reduced CBI after the fatigue task correlated with a milder perception of fatigue. In a follow-up experiment, we investigated the behavioral consequences of reduced CBI after fatigue. We measured CBI, perception of fatigue, and performance during a ballistic goal-directed task before and after the same fatigue and control tasks. We replicated the observation that reduced CBI after the fatigue task correlated with a milder perception of fatigue and found that greater endpoint variability after the fatigue task correlated with reduced CBI. The proportional relation between cerebellar excitability and fatigue indicates a role of the cerebellum in the perception of fatigue, which might come at the expense of motor control.SIGNIFICANCE STATEMENT Fatigue is one of the most common and debilitating symptoms in neurologic, neuropsychiatric, and chronic illnesses. Despite its epidemiological importance, there is a limited understanding of the neurophysiological mechanisms underlying fatigue. In a series of experiments, we demonstrate that decreased cerebellar excitability relates to lesser physical fatigue perception and worse motor control. These results showcase the role of the cerebellum in fatigue regulation and suggest that fatigue- and performance-related processes might compete for cerebellar resources.

Neurochemical balance and inhibition at the subacute stage after stroke.

Stroke is a leading cause of death and disability worldwide with many people left with impaired motor function. Evidence from experimental animal models of stroke indicates that reducing motor cortex inhibition may facilitate neural plasticity and motor recovery. This study compared primary motor cortex (M1) inhibition measures over the first 12 wk after stroke with a cohort of age-similar healthy controls. The excitation-inhibition ratio and gamma-aminobutyric acid (GABA) neurotransmission within M1 were assessed using magnetic resonance spectroscopy and threshold hunting paired-pulse transcranial magnetic stimulation respectively. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Patients with a functional corticospinal pathway had motor-evoked potentials on the paretic side and exhibited better recovery from upper limb impairment and recovery of function than patients without a functional corticospinal pathway. Compared with age-similar controls, the neurochemical balance in terms of the excitation-inhibition ratio was greater within contralesional M1 in patients with a functional corticospinal pathway. There was evidence for elevated long-interval inhibition in both ipsilesional and contralesional M1 compared with controls. Short-interval inhibition measures differed between the first and second phases, with evidence for elevation of the former only in ipsilesional M1 and no evidence of disinhibition for the latter. Overall, findings from transcranial magnetic stimulation indicate an upregulation of GABA-mediated tonic inhibition in M1 early after stroke. Therapeutic approaches that aim to normalize inhibitory tone during the subacute period warrant further investigation.NEW & NOTEWORTHY Magnetic resonance spectroscopy indicated higher excitation-inhibition ratios within motor cortex during subacute recovery than age-similar healthy controls. Measures obtained from adaptive threshold hunting paired-pulse transcranial magnetic stimulation indicated greater tonic inhibition in patients compared with controls. Therapeutic approaches that aim to normalize motor cortex inhibition during the subacute stage of recovery should be explored.

Primary motor cortex function and motor skill acquisition: insights from threshold-hunting TMS.

Modulation of GABA-mediated inhibition in primary motor cortex (M1) is important for the induction of training-induced plasticity. The downregulation of inhibition during acquisition may promote cortical reorganization, whereas an upregulation once performance has plateaued may promote consolidation of the newly acquired skill. GABA-related inhibition in human M1 is routinely assessed using the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI). However, modulation of SICI with motor skill learning is not a consistent finding and may be influenced by TMS parameters. The aim of this study was to compare the modulation of SICI by motor skill learning between conventional and adaptive threshold-hunting techniques with an anterior-posterior and posterior-anterior induced current. Sixteen participants (21-33 years) trained with their dominant (right) hand on a sequential visual isometric pinch task. Electromyographic recordings were obtained from the right first dorsal interosseous muscle. Corticomotor excitability and SICI were examined before and immediately after 12 blocks of training. Skill increased throughout the training, with performance plateauing before completion. Corticomotor excitability increased after motor training for both current directions. The amount of SICI was greater with anterior-posterior stimulation than posterior-anterior for both conventional and adaptive threshold-hunting techniques. SICI increased after motor training, but only for adaptive threshold-hunting with an anterior-posterior-induced current. The increased GABA-mediated inhibition evident after motor skill learning may promote consolidation of the newly acquired skill. The findings also support the notion that adaptive threshold-hunting SICI using an anterior-posterior current provides an effective assessment in interventional studies.

Neurophysiological mechanisms underlying motor skill learning in young and older adults.

The ability to acquire and retain novel motor skills is preserved with advancing age. However, the neurophysiological mechanisms underlying skill acquisition in older adults have received little systematic investigation. The aim of the present study was to assess the modulation of primary motor cortex excitability and inhibition after skill acquisition in young and older adults. Sixteen young and sixteen older adults trained on a sequential visual isometric wrist extension task. Anodal or sham transcranial direct current stimulation was applied during training in a pseudorandomized crossover design. Skill was quantified before, immediately after, 24 h and 7 days post-training. Transcranial magnetic stimulation protocols were used to examine corticomotor excitability and intracortical inhibition pre- and post-training. Corticomotor excitability increased and intracortical inhibition decreased after skill acquisition in both age groups. Anodal transcranial direct current stimulation did not enhance skill acquisition or the modulation of neurophysiological variables. These findings indicate potential neurophysiological mechanisms relevant for motor learning in neurorehabilitation contexts involving older adults, such as after stroke.

Adaptive threshold hunting reveals differences in interhemispheric inhibition between young and older adults.

Interhemispheric inhibition between bilateral motor cortices is important for the performance of unimanual activities and may be compromised with advancing age. Conventionally, interhemispheric inhibition is assessed using paired-pulse transcranial magnetic stimulation (TMS) with constant conditioning and test stimulation parameters. Adaptive threshold hunting TMS, whereby a target motor-evoked potential amplitude is maintained in the presence of the conditioning, may provide an alternative means of assessment. Furthermore, interhemispheric inhibition may suppress late indirect-waves more so than early indirect-waves which can be preferentially elicited using anterior-posterior (AP) and posterior-anterior (PA) induced currents, respectively. The aim of this study was to assess age-related effects on interhemispheric inhibition using both conventional and threshold hunting techniques with PA- and AP-induced current. In 15 young and 15 older adults, short (10 ms) and long (40 ms) interval interhemispheric inhibition was examined in the nondominant extensor carpi radialis muscle at rest and during voluntary extension of the contralateral wrist. With the conventional technique, there were no age-related differences in short-interval interhemispheric inhibition. With threshold hunting and AP-induced current, young adults exhibited greater short-interval interhemispheric inhibition during contralateral activation compared with rest and compared with older adults. Furthermore, long-interval interhemispheric inhibition was greater in older adults compared with young for both conventional and threshold hunting techniques. Age-related differences in interhemispheric inhibition are evident with threshold hunting using PA- and AP-induced current.

Adaptive threshold hunting for the effects of transcranial direct current stimulation on primary motor cortex inhibition.

Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA)-mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior-anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior-posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 ± 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICIAP was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICIAP and LICIAP modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after-effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA-mediated inhibitory circuits.

GABA and primary motor cortex inhibition in young and older adults: a multimodal reliability study.

The effects of healthy aging on γ-aminobutyric acid (GABA) within primary motor cortex (M1) remain poorly understood. Studies have reported contrasting results, potentially due to limitations with the common assessment technique. The aim of the present study was to investigate the effect of healthy aging on M1 GABA concentration and neurotransmission using a multimodal approach. Fifteen young and sixteen older adults participated in this study. Magnetic resonance spectroscopy (MRS) was used to measure M1 GABA concentration. Single-pulse and threshold-tracking paired-pulse transcranial magnetic stimulation (TMS) protocols were used to examine cortical silent period duration, short- and long-interval intracortical inhibition (SICI and LICI), and late cortical disinhibition (LCD). The reliability of TMS measures was examined with intraclass correlation coefficient analyses. SICI at 1 ms was reduced in older adults (15.13 ± 2.59%) compared with young (25.66 ± 1.44%; P = 0.002). However, there was no age-related effect for cortical silent period duration, SICI at 3 ms, LICI, or LCD (all P > 0.66). The intersession reliability of threshold-tracking measures was good to excellent for both young (range 0.75-0.96) and older adults (range 0.88-0.93). Our findings indicate that extrasynaptic inhibition may be reduced with advancing age, whereas GABA concentration and synaptic inhibition are maintained. Furthermore, MRS and threshold-tracking TMS provide valid and reliable assessment of M1 GABA concentration and neurotransmission, respectively, in young and older adults.NEW & NOTEWORTHY γ-Aminobutyric acid (GABA) in primary motor cortex was assessed in young and older adults using magnetic resonance spectroscopy and threshold-tracking paired-pulse transcranial magnetic stimulation. Older adults exhibited reduced extrasynaptic inhibition (short-interval intracortical inhibition at 1 ms) compared with young, whereas GABA concentration and synaptic inhibition were similar between age groups. We demonstrate that magnetic resonance spectroscopy and threshold-tracking provide valid and reliable assessments of primary motor cortex GABA concentration and neurotransmission, respectively.

Acute aerobic exercise modulates primary motor cortex inhibition.

Aerobic exercise can enhance neuroplasticity although presently the neural mechanisms underpinning these benefits remain unclear. One possible mechanism is through effects on primary motor cortex (M1) function via down-regulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The aim of the present study was to examine how corticomotor excitability (CME) and M1 intracortical inhibition are modulated in response to a single bout of moderate intensity aerobic exercise. Ten healthy right-handed adults were participants. Single- and paired-pulse transcranial magnetic stimulation was applied over left M1 to obtain motor-evoked potentials in the right flexor pollicis brevis. We examined CME, cortical silent period (SP) duration, short- and long-interval intracortical inhibition (SICI, LICI), and late cortical disinhibition (LCD), before and after acute aerobic exercise (exercise session) or an equivalent duration without exercise (control session). Aerobic exercise was performed on a cycle ergometer for 30 min at a workload equivalent to 60 % of maximal cardiorespiratory fitness (VO2 peak; heart rate reserve = 75 ± 3 %, perceived exertion = 13.5 ± 0.7). LICI was reduced at 10 (52 ± 17 %, P = 0.03) and 20 min (27 ± 8 %, P = 0.03) post-exercise compared to baseline (13 ± 4 %). No significant changes in CME, SP duration, SICI or LCD were observed. The present study shows that GABAB-mediated intracortical inhibition may be down-regulated after acute aerobic exercise. The potential effects this may have on M1 plasticity remain to be determined.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

Mapping subcortical motor pathways in humans with startle-conditioned TMS.

Subcortical motor pathways, such as the reticulospinal tract, are critical for producing and modulating voluntary movements and have been implicated in neurological conditions. Previous research has described the presence of ipsilateral motor evoked potentials (iMEPs) in the arm to transcranial magentic stimulation (TMS), and suggested they could be mediated by the uncrossed corticospinal tract or by ipsilateral cortico-reticulospinal connections. Here, we sought to elucidate the role of the reticulospinal tract in mediating iMEPs by assessing their modulation by a startling acoustic stimulus and mapping these responses across multiple upper limb effectors. In a first experiment, we delivered TMS at various intervals (1, 5, 10 and 15 ms) after a startling acoustic stimulus, known to excite the reticular formation, to elicit iMEPs in the arm. We observed robust facilitation of iMEP area when startle conditioning preceded TMS at the 10 ms interval. In a second experiment, we replicated our findings showing that both the area and number of iMEPs in the arm increases with startle conditioning. Using this technique, we observed that iMEPs are more prominent in the arm compared with the hand. In a third experiment, we also observed greater presence of iMEPs in flexor compared with extensor muscles. Together, these findings are consistent with properties of the reticulospinal tract observed in animals, suggesting that iMEPs primarily reflect reticulospinal activity. Our findings imply that we can use this approach to track modulation of cortico-reticulospinal excitability following interventions or neurological conditions where the reticulospinal tract may be involved in motor recovery.

Anodal cerebellar t-DCS impacts skill learning and transfer on a robotic surgery training task.

The cerebellum has demonstrated a critical role during adaptation in motor learning. However, the extent to which it can contribute to the skill acquisition of complex real-world tasks remains unclear. One particularly challenging application in terms of motor activities is robotic surgery, which requires surgeons to complete complex multidimensional visuomotor tasks through a remotely operated robot. Given the need for high skill proficiency and the lack of haptic feedback, there is a pressing need for understanding and improving skill development. We investigated the effect of cerebellar transcranial direct current stimulation applied during the execution of a robotic surgery training task. Study participants received either real or sham stimulation while performing a needle driving task in a virtual (simulated) and a real-world (actual surgical robot) setting. We found that cerebellar stimulation significantly improved performance compared to sham stimulation at fast (more demanding) execution speeds in both virtual and real-world training settings. Furthermore, participants that received cerebellar stimulation more effectively transferred the skills they acquired during virtual training to the real world. Our findings underline the potential of non-invasive brain stimulation to enhance skill learning and transfer in real-world relevant tasks and, more broadly, its potential for improving complex motor learning.

Age-related strengthening of cerebello-cortical motor circuits.

Effective connectivity between the cerebellum and primary motor cortex (M1) is critical for motor learning and motor control. Despite evidence of cerebellar atrophy and declines in motor learning and motor control with advanced age, recent behavioral studies indicate that cerebellar-dependent motor learning processes are preserved or even enhanced in older adults. However, physiological evidence of heightened cerebellar excitability leading to strengthened cerebellar-M1 connectivity with advanced age is lacking. Here, we used transcranial magnetic stimulation to assess age-related effects on cerebellar inhibition, a measure of cerebellar-M1 connectivity, in 20 young and 19 older adults. We observed stronger cerebellar inhibition in older compared with young adults. The behavioral implications of strengthened cerebellar inhibition with advanced age found in this study remain to be determined.

Training at asymptote stabilizes motor memories by reducing intracortical excitation.

Learning similar motor skills in close succession is limited by interference, a phenomenon that takes place early after acquisition when motor memories are unstable. Interference can be bidirectional, as the first memory can be disrupted by the second (retrograde interference), or the second memory can be disrupted by the first (anterograde interference). The heightened plastic state of primary motor cortex after learning is thought to underlie interference, as unstable motor memories compete for neural resources. While time-dependent consolidation processes reduce interference, the passage of time (~6 h) required for memory stabilization limits our capacity to learn multiple motor skills at once. Here, we demonstrate in humans that prolonged training at asymptote of an initial motor skill reduces both retrograde and anterograde interference when a second motor skill is acquired in close succession. Neurophysiological assessments via transcranial magnetic stimulation reflect this online stabilization process. Specifically, excitatory neurotransmission in primary motor cortex increased after short training and decreased after prolonged training at performance asymptote. Of note, this reduction in intracortical excitation after prolonged training was proportional to better skill retention the following day. Importantly, these neurophysiological effects were not observed after motor practice without learning or after a temporal delay. Together, these findings indicate that prolonged training at asymptote improves the capacity to learn multiple motor skills in close succession, and that downregulation of excitatory neurotransmission in primary motor cortex may be a marker of online motor memory stabilization.

The reliability of cerebellar brain inhibition.

OBJECTIVE: Connectivity between the cerebellum and primary motor cortex (M1) can be assessed by using transcranial magnetic stimulation to measure cerebellar brain inhibition (CBI). The aim of the present study was to determine the intra- and inter-day measurment error and relative reliability of CBI. The former informs the degree to which repeated measurements vary, whereas the latter informs how well the measure can distinguish individuals from one another within a sample. METHODS: We obtained CBI data from 83 healthy young participants (n = 55 retrospective). Intra-day measurements were separated by ~ 30 min. Inter-day measurmenets were separated by a minimum of 24 h. RESULTS: We show that CBI has low measurement error (~15%) within and between sessions. Using the measurment error, we demonstrate that change estimates which exceed measurment noise are large at an individual level, but can be detected with modest sample sizes. Finally, we demonstrate that the CBI measurement has fair to good relative reliability in healthy individuals, which may be deflated by low sample heterogeneity. CONCLUSIONS: CBI has low measurement error supporting its use for tracking intra- and inter-day changes in cerebellar-M1 connectivity. SIGNIFICANCE: Our findings provide clear reliability guidelines for future studies assessing modulation of cerebellar-M1 connectivity with intervention or disease progression.

Neurophysiology of motor skill learning in chronic stroke.

OBJECTIVE: Motor learning is relevant in chronic stroke for acquiring compensatory strategies to motor control deficits. However, the neurophysiological mechanisms underlying motor skill acquisition with the paretic upper limb have received little systematic investigation. The aim of this study was to assess the modulation of corticomotor excitability and intracortical inhibition within ipsilesional primary motor cortex (M1) during motor skill learning. METHODS: Ten people at the chronic stage after stroke and twelve healthy controls trained on a sequential visuomotor isometric wrist extension task. Skill was quantified before, immediately after, 24 hours and 7 days post-training. Transcranial magnetic stimulation was used to examine corticomotor excitability and short- and long-interval intracortical inhibition (SICI and LICI) pre- and post-training. RESULTS: The patient group exhibited successful skill acquisition and retention, although absolute skill level was lower compared with controls. In contrast to controls, patients' ipsilesional corticomotor excitability was not modulated during skill acquisition, which may be attributed to excessive ipsilesional LICI relative to controls. SICI decreased after training for both patient and control groups. CONCLUSIONS: Our findings indicate distinct inhibitory networks within M1 that may be relevant for motor learning after stroke. SIGNIFICANCE: These findings have potential clinical relevance for neurorehabilitation adjuvants aimed at augmenting the recovery of motor function.

The Influence of Primary Motor Cortex Inhibition on Upper Limb Impairment and Function in Chronic Stroke: A Multimodal Study.

BACKGROUND: Stroke is a leading cause of adult disability owing largely to motor impairment and loss of function. After stroke, there may be abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory function within primary motor cortex (M1), which may have implications for residual motor impairment and the potential for functional improvements at the chronic stage. OBJECTIVE: To quantify GABA neurotransmission and concentration within ipsilesional and contralesional M1 and determine if they relate to upper limb impairment and function at the chronic stage of stroke. METHODS: Twelve chronic stroke patients and 16 age-similar controls were recruited for the study. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Threshold tracking paired-pulse transcranial magnetic stimulation protocols were used to examine short- and long-interval intracortical inhibition and late cortical disinhibition. Magnetic resonance spectroscopy was used to evaluate GABA concentration. RESULTS: Short-interval intracortical inhibition was similar between patients and controls ( P = .10). Long-interval intracortical inhibition was greater in ipsilesional M1 compared with controls ( P < .001). Patients who did not exhibit late cortical disinhibition in ipsilesional M1 were those with greater upper limb impairment and worse function ( P = .002 and P = .017). GABA concentration was lower within ipsilesional ( P = .009) and contralesional ( P = .021) M1 compared with controls, resulting in an elevated excitation-inhibition ratio for patients. CONCLUSION: These findings indicate that ipsilesional and contralesional M1 GABAergic inhibition are altered in this small cohort of chronic stroke patients. Further study is warranted to determine how M1 inhibitory networks might be targeted to improve motor function.

Conventional or threshold-hunting TMS? A tale of two SICIs.

BACKGROUND: In human primary motor cortex (M1), the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI) can be expressed conventionally as a percent change in the relative amplitude of a conditioned motor evoked potential to non-conditioned; or adaptive threshold-hunting a target motor evoked potential amplitude in the absence or presence of a conditioning stimulus, and noting the relative change in stimulation intensity. The suitability of each approach may depend on the induced current direction, which probe separate M1 interneuronal populations. OBJECTIVE: To examine the influence of conditioning stimulus intensity, interstimulus interval (ISI) and current direction for adaptive threshold-hunting and conventional SICI using equivalent TMS intensities. METHODS: In 16 participants (21-32 years), SICI was examined using adaptive threshold-hunting and conventional paired-pulse TMS with posterior-anterior and anterior-posterior stimulation, ISIs of 2 and 3 ms, and a range of conditioning intensities. RESULTS: Inhibition with adaptive threshold-hunting was greater for anterior-posterior stimulation with an ISI of 3 ms (23.6 ±â€¯9.0%) compared with 2 ms (7.5 ±â€¯7.8%, P < 0.001) and posterior-anterior stimulation at both ISIs (2 ms 8.6 ±â€¯8.7%, 3 ms 5.9 ±â€¯4.8%; P < 0.001). There was an association between inhibition obtained with conventional and adaptive threshold-hunting for posterior-anterior but not anterior-posterior stimulation (2 ms only, r = 0.68, P = 0.03). CONCLUSIONS: More inhibition was evident with anterior-posterior than posterior-anterior current for both adaptive threshold-hunting and conventional paired-pulse TMS. Assessment of SICI with anterior-posterior stimulation was not directly comparable between the two approaches. However, the amount of inhibition was dependent on conditioning stimulus intensity and ISI for both SICI techniques.