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.

Repetitive Transcranial Magnetic Stimulation with Sensorimotor Training for the Treatment of Complex Regional Pain Syndrome Type 2 of the Upper Limb Case Report.

This case report describes the use of repetitive transcranial magnetic stimulation (rTMS) combined with sensorimotor training (SMT) to treat an individual with complex regional pain syndrome (CRPS) type 2 with allodynia of the right hand/wrist. After the 9-week intervention, there was a clinically meaningful reduction in pain intensity which continued to 3 months after intervention. Further, clinically meaningful improvements in wrist and hand function and allodynia were observed. Although the use of rTMS for CRPS has been reported, this unique report provides valuable insight into the clinical utility of rTMS plus SMT for the treatment of CRPS and related symptoms.

Experimental environment improves the reliability of short-latency afferent inhibition.

Evidence indicates attention can alter afferent inhibition, a Transcranial Magnetic Stimulation (TMS) evoked measure of cortical inhibition following somatosensory input. When peripheral nerve stimulation is delivered prior to TMS, a phenomenon known as afferent inhibition occurs. The latency between the peripheral nerve stimulation dictates the subtype of afferent inhibition evoked, either short latency afferent inhibition (SAI) or long latency afferent inhibition (LAI). While afferent inhibition is emerging as a valuable tool for clinical assessment of sensorimotor function, the reliability of the measure remains relatively low. Therefore, to improve the translation of afferent inhibition within and beyond the research lab, the reliability of the measure must be improved. Previous literature suggests that the focus of attention can modify the magnitude of afferent inhibition. As such, controlling the focus of attention may be one method to improve the reliability of afferent inhibition. In the present study, the magnitude and reliability of SAI and LAI was assessed under four conditions with varying attentional demands focused on the somatosensory input that evokes SAI and LAI circuits. Thirty individuals participated in four conditions; three conditions were identical in their physical parameters and varied only in the focus of directed attention (visual attend, tactile attend, non- directed attend) and one condition consisted of no external physical parameters (no stimulation). Reliability was measured by repeating conditions at three time points to assess intrasession and intersession reliability. Results indicate that the magnitude of SAI and LAI were not modulated by attention. However, the reliability of SAI demonstrated increased intrasession and intersession reliability compared to the no stimulation condition. The reliability of LAI was unaffected by the attention conditions. This research demonstrates the impact of attention/arousal on the reliability of afferent inhibition and has identified new parameters to inform the design of TMS research to improve reliability.

Investigating the intra-session reliability of short and long latency afferent inhibition.

Objective: To establish the intrasession relative and absolute reliability of Short (SAI) and Long-Latency Afferent Inhibition (LAI). These findings will allow us to guide future explorations of changes to these measures. Methods: 31 healthy individuals (21.06 ±â€¯2.85 years) had SAI and LAI obtained thrice at 30-minute intervals in one session. To identify the minimum number of trials required to reliably elicit SAI and LAI, relative reliability was assessed at running intervals of 5 trials. Results: SAI had moderate-high, and LAI had high-excellent relative reliability. Both SAI and LAI had high amounts of measurement error. LAI had high relative reliability when only 5 frames of data were included, whereas SAI required ∼20-30 frames of data for the same. For both SAI and LAI, individual smallest detectable change was large but was reduced at the group level. Conclusions: SAI and LAI can be used for both diagnostic purposes and to assess group level change but have limited utility in assessing within-individual changes. Significance: These results can be used to inform future work regarding the utility of SAI and LAI, particularly in terms of their ability to identify particularly high or low values of afferent inhibition.

Tactile sensorimotor training does not alter short- and long-latency afferent inhibition.

Sensorimotor integration refers to the process of combining incoming sensory information with outgoing motor commands to control movement. Short-latency afferent inhibition (SAI), and long-latency afferent inhibition (LAI) are neurophysiological measures of sensorimotor integration collected using transcranial magnetic stimulation. No studies to date have investigated the influence of tactile discrimination training on these measures. This study aimed to determine whether SAI and LAI are modulated following training on a custom-designed tactile discrimination maze task. Participants performed a 'high difficulty' and 'low difficulty' maze training condition on separate visits. On an additional visit, no maze training was performed to serve as a control condition. Despite evidence of performance improvements during training, there were no significant changes in SAI or LAI following training in either condition. The total number of errors during maze training was significantly greater in the high-difficulty condition compared with the low-difficulty condition. These findings suggest that sensorimotor maze training for 30 min is insufficient to modify the magnitude of SAI and LAI.

Case report: The feasibility of rTMS with intrathecal baclofen pump for the treatment of unresolved neuropathic pain following spinal cord injury.

The main objective of this study was to assess the efficacy and safety of 10 Hz repetitive transcranial magnetic stimulation (rTMS) for the treatment of unresolved neuropathic pain in an individual with spinal cord injury and an intrathecal baclofen pump. A 62-year-old male presented with drug resistant neuropathic pain as a result of a complete spinal cord lesion at T8 level. Pain was classified into four types: pressure pain in the left foot, burning pain in buttocks, burning pain in sternum, and electrical attacks in the trunk. The treatment period involved 6 weeks of rTMS stimulation performed 5 days per week, a 6-week follow up period with no stimulation, and an 8-week top up session period which began 5-weeks after the end of the follow up period. 2004 pulses were delivered at 10Hz over the right-hand representation of the left primary motor cortex at 80% resting motor threshold during each session. Assessments were based on the numerical rating scale (NRS), neuropathic pain scale (NPS), Hamilton Depression and Anxiety rating scales. Following the treatment period there was a 30, 13, and 29% reduction in sternum, buttocks, and left foot pain respectively, as reported by the NRS. During this time, electrical attacks were abolished following the third week of treatment. These changes corresponded to a 38% decrease in NPS scores and a 65 and 25% reduction in anxiety and depressions scores respectively. The changes in sternum, buttocks, and left foot pain reported on the NRS persisted for 1 week following treatment. Top up sessions delivered 11 weeks after the end of the treatment period were unsuccessful in reducing pain to the level achieved during the treatment period. A 13% reduction in NPS was seen during these 8-weeks. Anxiety and depression scores decreased 78 and 67% respectively. The frequency of electrical attacks was zero during this time. rTMS stimulation delivered throughout this study did not cause any interference with the functioning of the intrathecal baclofen pump. This case study illustrates that rTMS may be effective at reducing drug resistant neuropathic pain with certain pain types exhibiting greater propensity for change.

Intensity matters: protocol for a randomized controlled trial exercise intervention for individuals with chronic stroke.

RATIONALE: Cardiovascular exercise is an effective method to improve cardiovascular health outcomes, but also promote neuroplasticity during stroke recovery. Moderate-intensity continuous cardiovascular training (MICT) is an integral part of stroke rehabilitation, yet it may remain a challenge to exercise at sufficiently high intensities to produce beneficial adaptations to neuroplasticity. High-intensity interval training (HIIT) could provide a viable alternative to achieve higher intensities of exercise by using shorter bouts of intense exercise interspersed with periods of recovery. METHODS AND DESIGN: This is a two-arm, parallel-group multi-site RCT conducted at the Jewish Rehabilitation Hospital (Laval, Québec, Canada) and McMaster University (Hamilton, Ontario, Canada). Eighty participants with chronic stroke will be recruited at both sites and will be randomly allocated into a HIIT or MICT individualized exercise program on a recumbent stepper, 3 days per week for 12 weeks. Outcomes will be assessed at baseline, at 12 weeks post-intervention, and at an 8-week follow-up. OUTCOMES: The primary outcome is corticospinal excitability, a neuroplasticity marker in brain motor networks, assessed with transcranial magnetic stimulation (TMS). We will also examine additional markers of neuroplasticity, measures of cardiovascular health, motor function, and psychosocial responses to training. DISCUSSION: This trial will contribute novel insights into the effectiveness of HIIT to promote neuroplasticity in individuals with chronic stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03614585 . Registered on 3 August 2018.

The Combined Influences of Exercise, Diet and Sleep on Neuroplasticity.

Neuroplasticity refers to the brain's ability to undergo structural and functional adaptations in response to experience, and this process is associated with learning, memory and improvements in cognitive function. The brain's propensity for neuroplasticity is influenced by lifestyle factors including exercise, diet and sleep. This review gathers evidence from molecular, systems and behavioral neuroscience to explain how these three key lifestyle factors influence neuroplasticity alone and in combination with one another. This review collected results from human studies as well as animal models. This information will have implications for research, educational, fitness and neurorehabilitation settings.

The distribution and reliability of TMS-evoked short- and long-latency afferent interactions.

Short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) occur when the motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS) is reduced by the delivery of a preceding peripheral nerve stimulus. The intra-individual variability in SAI and LAI is considerable, and the influence of sample demographics (e.g., age and biological sex) and testing context (e.g., time of day) is not clear. There are also no established normative values for these measures, and their reliability varies from study-to-study. To address these issues and facilitate the interpretation of SAI and LAI research, we pooled data from studies published by our lab between 2014 and 2020 and performed several retrospective analyses. Patterns in the depth of inhibition with respect to age, biological sex and time of testing were investigated, and the relative reliability of measurements from studies with repeated baseline SAI and LAI assessments was examined. Normative SAI and LAI values with respect to the mean and standard deviation were also calculated. Our data show no relationship between the depth of inhibition for SAI and LAI with either time of day or age. Further, there was no significant difference in SAI or LAI between males and females. Intra-class correlation coefficients (ICC) for repeated measurements of SAI and LAI ranged from moderate (ICC = 0.526) to strong (ICC = 0.881). The mean value of SAI was 0.71 ± 0.27 and the mean value of LAI was 0.61 ± 0.34. This retrospective study provides normative values, reliability estimates, and an exploration of demographic and testing influences on these measures as assessed in our lab. To further facilitate the interpretation of SAI and LAI data, similar studies should be performed by other labs that use these measures.

Biological sex differences in afferent-mediated inhibition of motor responses evoked by TMS.

Sensorimotor integration can be assessed by pairing electrical peripheral nerve stimulation with transcranial magnetic stimulation (TMS). The resulting afferent inhibition is observed when TMS precedes nerve stimulation by âˆ¼ 20-25 ms, termed short-latency afferent inhibition (SAI), or by 200 ms, termed long-latency afferent inhibition (LAI). The purpose of this study was to determine whether biological sex influences the magnitude of SAI or LAI. SAI and LAI were assessed in fifteen males (21.5 ± 2.7 years) and fifteen females (20.2 ± 2.3 years). TMS was delivered to the primary motor cortex (M1) following stimulation of the contralateral median nerve at the wrist or digital nerve of the index finger, and motor-evoked potentials (MEPs) were obtained from the right first dorsal interosseous (FDI) muscle. SAI evoked by median and digital nerve stimulation, and LAI evoked by median nerve stimulation, were not different between males and females. LAI evoked by digital nerve stimulation was increased in females compared to males, but this difference between sexes was no longer present following the removal of datapoints where inhibition was not observed. This study is the first to investigate biological sex differences in afferent inhibition.

Data Processing in Functional Near-Infrared Spectroscopy (fNIRS) Motor Control Research.

FNIRS pre-processing and processing methodologies are very important-how a researcher chooses to process their data can change the outcome of an experiment. The purpose of this review is to provide a guide on fNIRS pre-processing and processing techniques pertinent to the field of human motor control research. One hundred and twenty-three articles were selected from the motor control field and were examined on the basis of their fNIRS pre-processing and processing methodologies. Information was gathered about the most frequently used techniques in the field, which included frequency cutoff filters, wavelet filters, smoothing filters, and the general linear model (GLM). We discuss the methodologies of and considerations for these frequently used techniques, as well as those for some alternative techniques. Additionally, general considerations for processing are discussed.

Association of short- and long-latency afferent inhibition with human behavior.

Transcranial magnetic stimulation (TMS) paired with nerve stimulation evokes short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI), which are non-invasive assessments of the excitability of the sensorimotor system. SAI and LAI are abnormally reduced in various special populations in comparison to healthy controls. However, the relationship between afferent inhibition and human behavior remains unclear. The purpose of this review is to survey the current literature and synthesize observations and patterns that affect the interpretation of SAI and LAI in the context of human behavior. We discuss human behaviour across the motor and cognitive domains, and in special and control populations. Further, we discuss future considerations for research in this field and the potential for clinical applications. By understanding how human behavior is mediated by changes in SAI and LAI, this can allow us to better understand the neurophysiological underpinnings of human motor control.

Understanding the Neurophysiological and Molecular Mechanisms of Exercise-Induced Neuroplasticity in Cortical and Descending Motor Pathways: Where Do We Stand?

Exercise is a promising, cost-effective intervention to augment successful aging and neurorehabilitation. Decline of gray and white matter accompanies physiological aging and contributes to motor deficits in older adults. Exercise is believed to reduce atrophy within the motor system and induce neuroplasticity which, in turn, helps preserve motor function during aging and promote re-learning of motor skills, for example after stroke. To fully exploit the benefits of exercise, it is crucial to gain a greater understanding of the neurophysiological and molecular mechanisms underlying exercise-induced brain changes that prime neuroplasticity and thus contribute to postponing, slowing, and ameliorating age- and disease-related impairments in motor function. This knowledge will allow us to develop more effective, personalized exercise protocols that meet individual needs, thereby increasing the utility of exercise strategies in clinical and non-clinical settings. Here, we review findings from studies that investigated neurophysiological and molecular changes associated with acute or long-term exercise in healthy, young adults and in healthy, postmenopausal women.

Current Methodological Pitfalls and Caveats in the Assessment of Exercise-Induced Changes in Peripheral Brain-Derived Neurotrophic Factor: How Result Reproducibility Can Be Improved.

Neural mechanisms, such as enhanced neuroplasticity within the motor system, underpin exercise-induced motor improvements. Being a key mediator of motor plasticity, brain-derived neurotrophic factor (BDNF) is likely to play an important role in mediating exercise positive effects on motor function. Difficulties in assessing brain BDNF levels in humans have drawn attention to quantification of blood BDNF and raise the question of whether peripheral BDNF contributes to exercise-related motor improvements. Methodological and non-methodological factors influence measurements of blood BDNF introducing a substantial variability that complicates result interpretation and leads to inconsistencies among studies. Here, we discuss methodology-related issues and approaches emerging from current findings to reduce variability and increase result reproducibility.

Transcranial Magnetic Stimulation to Assess Exercise-Induced Neuroplasticity.

Aerobic exercise facilitates neuroplasticity and has been linked to improvements in cognitive and motor function. Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to quantify changes in neurophysiology induced by exercise. The present review summarizes the single- and paired-pulse TMS paradigms that can be used to probe exercise-induced neuroplasticity, the optimal stimulation parameters and the current understanding of the neurophysiology underlying each paradigm. Further, this review amalgamates previous research exploring the modulation of these paradigms with exercise-induced neuroplasticity in healthy and clinical populations and highlights important considerations for future TMS-exercise research.

The Influence of Recreational Substance Use in TMS Research.

(1) Background: Transcranial magnetic stimulation (TMS) approaches are widely used to study cortical and corticospinal function. However, responses to TMS are subject to significant intra-and inter-individual variability. Acute and chronic exposure to recreational substances alters the excitability of the sensorimotor system and may contribute to the variability in TMS outcome measures. The increasing prevalence of recreational substance use poses a significant challenge for executing TMS studies, but there is a lack of clarity regarding the influence of these substances on sensorimotor function. (2) Methods: The literature investigating the influence of alcohol, nicotine, caffeine and cannabis on TMS outcome measures of corticospinal, intracortical and interhemispheric excitability was reviewed. (3) Results: Both acute and chronic use of recreational substances modulates TMS measures of excitability. Despite the abundance of research in this field, we identify knowledge gaps that should be addressed in future studies to better understand the influence of these substances on TMS outcomes. (4) Conclusions: This review highlights the need for TMS studies to take into consideration the history of participant substance use and to control for acute substance use prior to testing.

Altered motor system function in post-concussion syndrome as assessed via transcranial magnetic stimulation.

OBJECTIVE: It is unclear why specific individuals incur chronic symptoms following a concussion. This exploratory research aims to identify and characterize any neurophysiological differences that may exist in motor cortex function in post-concussion syndrome (PCS). METHODS: Fifteen adults with PCS and 13 healthy, non-injured adults were tested. All participants completed symptom questionnaires, and transcranial magnetic stimulation (TMS) was used to measure intracortical and transcallosal excitability and inhibition in the dominant motor cortex. RESULTS: Cortical silent period (p = 0.02, g = 0.96) and ipsilateral silent period (p = 0.04, g = 0.78) were shorter in the PCS group compared to the control group which may reflect reduced GABA-mediated inhibition in PCS. Furthermore, increased corticomotor excitability was observed in the left hemisphere but not the right hemisphere. CONCLUSIONS: These data suggest that persistent neurophysiological differences are present in those with PCS. The exact contributing factors to such changes remain to be investigated by future studies. SIGNIFICANCE: This study provides novel evidence of lasting neurophysiological changes in PCS.

A Single Bout of High-intensity Interval Exercise Increases Corticospinal Excitability, Brain-derived Neurotrophic Factor, and Uncarboxylated Osteolcalcin in Sedentary, Healthy Males.

Exercise induces neuroplasticity in descending motor pathways facilitating motor learning, and as such it could be utilized as an intervention in neurorehabilitation, for example when re-learning motor skills after stroke. To date, however, the neurophysiological and molecular mechanisms underlying exercise-induced neuroplasticity remain largely unknown impeding the potential utilization of exercise protocols as 'motor learning boosters' in clinical and non-clinical settings. Here, we assessed corticospinal excitability, intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI) using transcranial magnetic stimulation (TMS) and serum biochemical markers including brain-derived neurotrophic factor (BDNF), total and precursor cathepsin B (tCTSB, proCTSB), uncarboxylated and carboxylated osteocalcin (unOCN, cOCN) and irisin using ELISA. Measurements were carried out in sedentary, healthy males before and after a single session of high-intensity interval exercise (HIIE) or in individuals who rested and did not perform exercise (No Exercise). We found that HIIE increased corticospinal excitability, BDNF and unOCN, and decreased cOCN. We also determined that greater increases in BDNF were associated with increases in unOCN and irisin and decreases in cOCN only in participants who underwent HIIE, suggesting that unOCN and irisin may contribute to exercise-induced BDNF increases. Conversely, no changes other than a decrease in serum unOCN/tOCN were found in No Exercise participants. The present findings show that a single session of HIIE is sufficient to modulate corticospinal excitability and to increase BDNF and unOCN in sedentary, healthy males.

Fitness Level Influences White Matter Microstructure in Postmenopausal Women.

Aerobic exercise has both neuroprotective and neurorehabilitative benefits. However, the underlying mechanisms are not fully understood and need to be investigated, especially in postmenopausal women, who are at increased risk of age-related disorders such as Alzheimer's disease and stroke. To advance our understanding of the potential neurological benefits of aerobic exercise in aging women, we examined anatomical and functional responses that may differentiate women of varying cardiorespiratory fitness using neuroimaging and neurophysiology. A total of 35 healthy postmenopausal women were recruited (59 ± 3 years) and cardiorespiratory fitness estimated (22-70 mL/kg/min). Transcranial magnetic stimulation was used to assess -aminobutyric acid (GABA) and glutamate (Glu) receptor function in the primary motor cortex (M1), and magnetic resonance spectroscopy (MRS) was used to quantify GABA and Glu concentrations in M1. Magnetic resonance imaging was used to assess mean cortical thickness (MCT) of sensorimotor and frontal regions, while the microstructure of sensorimotor and other white matter tracts was evaluated through diffusion tensor imaging. Regression analysis revealed that higher fitness levels were associated with improved microstructure in pre-motor and sensory tracts, and the hippocampal cingulum. Fitness level was not associated with MCT, MRS, or neurophysiology measures. These data indicate that, in postmenopausal women, higher cardiorespiratory fitness is linked with preserved selective white matter microstructure, particularly in areas that influence sensorimotor control and memory.