Single-pulse transcranial magnetic stimulation for assessment of motor development in infants with early brain injury.

INTRODUCTION: Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a noninvasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy. AREAS COVERED: The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention. EXPERT OPINION: Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation toward clinical implementation. Future research may explore use of noninvasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes.

Single pulse transcranial magnetic stimulation (TMS) is a safe and noninvasive way to study brain activity in infants and children who have experienced brain injuries around the time of birth. Infants who have had an early brain injury may develop cerebral palsy, a developmental disability that affects movement. TMS uses a device that gives single pulses of energy to activate specific areas of the brain. This can be used to study how the brain connects to the muscles in the body through paths or 'tracts.' TMS helps researchers understand the development of the tracts and the potential need for therapy. This article reviews research studies that used TMS in infants and explains how TMS can be used to assess brain development. It also reviews safety considerations and challenges related to using TMS in infants. TMS could be a valuable tool for early diagnosis of cerebral palsy and could also help guide treatments for infants with brain injuries. However, more research is needed, using larger groups of infants, to potentially expand the use of TMS in clinical practice. Future directions include developing infant-specific research tools and using noninvasive brain stimulation to improve recovery for infants with brain injuries.

Safety and feasibility of transcranial direct current stimulation stratified by corticospinal organization in children with hemiparesis.

Children with hemiparesis (CWH) due to stroke early in life face lifelong impairments in motor function. Transcranial direct current stimulation (tDCS) may be a safe and feasible adjuvant therapy to augment rehabilitation. Given the variability in outcomes following tDCS, tailored protocols of tDCS are required. We evaluated the safety, feasibility, and preliminary effects of a single session of targeted anodal tDCS based on individual corticospinal tract organization on corticospinal excitability. Fourteen CWH (age = 13.8 ± 3.63) were stratified into two corticospinal organization subgroups based on transcranial magnetic stimulation (TMS)-confirmed motor evoked potentials (MEP): ipsilesional MEP presence (MEPIL+) or absence (MEPIL-). Subgroups were randomized to real anodal or sham tDCS (1.5 mA, 20 min) applied to the ipsilesional (MEPIL + group) or contralesional (MEPIL- group) hemisphere combined with hand training. Safety was assessed with questionnaires and motor function evaluation, and corticospinal excitability was assessed at baseline and every 15 min for 1 h after tDCS. No serious adverse events occurred and anticipated minor side effects were reported and were self-limiting. Six of 14 participants had consistent ipsilesional MEPs (MEPIL + group). Paretic hand MEP amplitude increased in 5/8 participants who received real anodal tDCS to either the ipsilesional or contralesional hemisphere (+80% change). Application of tDCS based on individual corticospinal organization was safe and feasible with expected effects on excitability, indicating the potential for tailored tDCS protocols for CWH. Additional research involving expanded experimental designs is needed to confirm these effects and to determine if this approach can be translated into a clinically relevant intervention.

Anodal Contralesional tDCS Enhances CST Excitability Bilaterally in an Adolescent with Hemiparetic Cerebral Palsy: A Brief Report.

Hemiparetic cerebral palsy (HCP), weakness on one side of the body typically caused by perinatal stroke, is characterized by lifelong motor impairments related to alterations in the corticospinal tract (CST). CST reorganization could be a useful biomarker to guide applications of neuromodulatory interventions, such as transcranial direct current stimulation (tDCS), to improve the effectiveness of rehabilitation therapies. We evaluated an adolescent with HCP and CST reorganization who demonstrated persistent heightened CST excitability in both upper limbs following anodal contralesional tDCS. The results support further investigation of targeted tDCS as an adjuvant therapy to traditional neurorehabilitation for upper limb function.

Remotely monitored transcranial direct current stimulation in pediatric cerebral palsy: open label trial protocol.

BACKGROUND: Pediatric applications of non-invasive brain stimulation using transcranial direct current stimulation (tDCS) have demonstrated its safety with few adverse events reported. Remotely monitored tDCS, as an adjuvant intervention to rehabilitation, may improve quality of life for children with cerebral palsy (CP) through motor function improvements, reduced treatment costs, and increased access to tDCS therapies. Our group previously evaluated the feasibility of a remotely monitored mock tDCS setup in which families and children successfully demonstrated the ability to follow tDCS instructional guidance. METHODS AND DESIGN: Here, we designed a protocol to investigate the feasibility, safety, and tolerability of at-home active transcranial direct current stimulation in children with CP with synchronous supervision from laboratory investigators. Ten participants will be recruited to participate in the study for 5 consecutive days with the following sessions: tDCS setup practice on day 1, sham tDCS on day 2, and active tDCS on days 3-5. Sham stimulation will consist of an initial 30-second ramp up to 1.5 mA stimulation followed by a 30-second ramp down. Active stimulation will be delivered at 1.0 - 1.5 mA for 20 minutes and adjusted based on child tolerance. Feasibility will be evaluated via photographs of montage setup and the quality of stimulation delivery. Safety and tolerability will be assessed through an adverse events survey, the Box and Blocks Test (BBT) motor assessment, and a setup ease/comfort survey. DISCUSSION: We expect synchronous supervision of at-home teleneuromodulation to be tolerable and safe with increasing stimulation quality over repeated sessions when following a tDCS setup previously determined to be feasible. The findings will provide opportunity for larger clinical trials exploring efficacy and illuminate the potential of remotely monitored tDCS in combination with rehabilitation interventions as a means of pediatric neurorehabilitation. This will demonstrate the value of greater accessibility of non-invasive brain stimulation interventions and ultimately offer the potential to improve care and quality of life for children and families with CP. TRIAL REGISTRATION: October 8, 2021( https://clinicaltrials.gov/ct2/show/NCT05071586 ).

Study Protocol: Multimodal Longitudinal Assessment of Infant Brain Organization and Recovery in Perinatal Brain Injury.

PURPOSE: Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in lifelong motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. METHODS: Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to noninvasively measure CST functional and structural integrity across multiple time points in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. DISCUSSION: This protocol will identify bioindicators of motor outcome and neuroplasticity and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds, and related diagnoses.

Disrupted Access to Therapies and Impact on Well-Being During the COVID-19 Pandemic for Children With Motor Impairment and Their Caregivers.

OBJECTIVES: The aim of this study was to determine the impact of the COVID-19 pandemic on access to rehabilitation therapies and the impact of changes in therapy access on the physical and mental well-being of children with motor impairment and their caregivers. DESIGN: Caregivers of children younger than 18 yrs with childhood-onset motor impairment (primarily cerebral palsy) completed an anonymous survey through the online platform REDCap between May 5 and July 13, 2020. RESULTS: The survey was completed by 102 participants. Before the pandemic, 92 of 102 children (90%) were receiving one or more therapies; at the time surveyed, 55 children (54%) were receiving any therapies (P < 0.001). More than 40% of the sample reported increased child stress, decreased physical activity, and/or decline in mobility/movement. Participants who reported a decrease in number of therapies at the time surveyed more frequently reported lower satisfaction with treatment delivery (P < 0.001), a decline in child's mobility (P = 0.001), and increased caregiver stress (P = 0.004). Five qualitative themes were identified from open-ended question responses related to therapies and well-being. CONCLUSIONS: Access to pediatric rehabilitation therapies was disrupted during COVID-19. Disrupted access may be related to impact on physical and mental health. With the expansion of telehealth, caregiver and child feedback should be incorporated to optimize benefit.

Evaluating transcranial magnetic stimulation (TMS) induced electric fields in pediatric stroke.

Transcranial magnetic stimulation (TMS) is an increasingly popular tool for stroke rehabilitation. Consequently, researchers have started to explore the use of TMS in pediatric stroke. However, the application of TMS in a developing brain with pathologies comes with a unique set of challenges. The effect of TMS-induced electric fields has not been explored in children with stroke lesions. Here, we used finite element method (FEM) modeling to study how the electric field strength is affected by the presence of a lesion. We created individual realistic head models from MRIs (n = 6) of children with unilateral cerebral palsy due to perinatal stroke. We conducted TMS electric field simulations for coil locations over lesioned and non-lesioned hemispheres. We found that the presence of a lesion can strongly affect the electric field distribution. On the group level, the mean electric field strength did not differ between lesioned and non-lesioned hemispheres but exhibited a greater variability in the lesioned hemisphere. Other factors such as coil-to-cortex distance have a strong influence on the TMS electric field even in the presence of lesions. Our study has important implications for the delivery of TMS in children with brain lesions with respect to TMS dosing and coil placement.

Cross-Sectional Analysis of Backward, Forward, and Dual Task Gait Kinematics in People With Parkinson Disease With and Without Freezing of Gait.

People with Parkinson disease demonstrate increased gait variability, but the primary variability sources are poorly understood. People with Parkinson disease and freezing of gait (freezers) have greater gait impairments than people with Parkinson disease without freezing of gait (nonfreezers), which may relate to cerebellar dysfunction. Thirteen freezers and 31 nonfreezers completed backward, forward, and forward with dual task gait trials. Sagittal joint angle waveforms were extracted for the hip, knee, and ankle using 3D motion capture. Decomposition indices were calculated for the 3 joint combinations. Principal component analysis extracted variance sources from the joint waveforms. Freezers had significantly greater decomposition between hip-ankle (F1,42 = 5.1, P = .03) and hip-knee (F1,42 = 5.3, P = .03) movements. The principal component analysis did not differentiate freezers and nonfreezers; however, primary variance sources differed between conditions. Primary variance during forward and forward with dual task gait came from joint angle magnitude and peak angle timing. Backward gait showed primary variance from joint angle magnitude and range of motion. The results show that freezers decompose movement more than nonfreezers, implicating cerebellar involvement in freezing of gait. Primary variance differs between gait conditions, and tailoring gait interventions to address variability sources may improve intervention efficacy.

Ipsilateral Corticospinal Tract Excitability Contributes to the Severity of Mirror Movements in Unilateral Cerebral Palsy: A Case Series.

Mirror movements (MM) can be a clinical manifestation of unilateral cerebral palsy (UCP) causing involuntary movements when attempting to use either hand for functional activities. Atypical development of the corticospinal tract (CST) contributes to impairments in observed motor movements and functional activities. However, little is known about the underlying neurophysiology and contribution of the CST to MM. The current case study characterizes MM in 13 children and young adults with UCP ranging in age from 7 to 19 years and includes clinical and neurophysiologic variables. Clinical profiles included MM of each hand (ie, Woods and Teuber), bimanual coordination and hand use (Assisting Hand Assessment [AHA]), and perception of performance (Canadian Occupational Performance Measure [COPM]). We measured the strength of motor-evoked potentials (MEP) elicited from single-pulse transcranial magnetic stimulation (TMS) of each hemisphere to create a ratio of hemispheric responses. Our sample included three types of CST circuitry: ipsilateral (n = 5), bilateral (n = 3), and contralateral (n = 4). The MEP ratio ranged from 0 to 1.45 (median 0.11) with greater MM observed in participants with ratios greater than 0.5. We observed a positive relationship between the MEP ratio and the more-affected MM score, meaning participants with larger ipsilateral responses from contralesional stimulation (eg, the contralesional hemisphere was stimulated with TMS resulting in an ipsilateral MEP response), as compared with contralateral responses, displayed greater MM than those that did not. There was no relationship between MM and function as measured by the AHA or COPM. These findings suggest a role of the contralesional hemisphere to MM, which could serve as a therapeutic target for interventions.

A crossed-disciplinary evaluation of parental perceptions surrounding pediatric non-invasive brain stimulation research.

PURPOSE ­: Recruitment for pediatric non-invasive brain stimulation (NIBS) studies is often challenged by low enrollment. Understanding parental perceptions regarding NIBS is crucial to develop new communication strategies to increase enrollment. DESIGN/METHODOLOGY/APPROACH ­: Integrating a crossed-disciplinary approach, the authors conducted a survey at the 2018 Minnesota State Fair querying the perception of risk and preferences of current and future parents associated with pediatric NIBS research. The survey consisted of 28 closed-text questions including demographics, photographs portraying NIBS, terminologies and factors related to NIBS studies. FINDINGS ­: Complete surveys were analyzed from 622 parent participants. A significant number of participants (42.8%) perceived the photographs of NIBS as "risky." Additionally, 65.43% perceived the term "Non-invasive brain therapy" as not risky, a word combination not currently being used when recruiting potential participants. Over 90% (561/622) of participants chose the photograph of child-friendly MRI suite. RESEARCH LIMITATIONS/IMPLICATIONS ­: Although this survey identified aspects crucial in recruitment for pediatric NIBS research, there were limitations. For example, the authors did not record the sex or demographic distribution (e.g. rural versus urban setting) of the participants. These factors may also influence recruitment messaging. ORIGINALITY/VALUE ­: For important medical research to impact and improve the lives of the potential remedies, participation by the public in clinical trials is necessary. Often the general public perceives the trials as risky as a result of poor marketing communication recruitment material. This study sought to be understood if how the message is encoded has an impact on the decoding by the receiver.

Yoga Improves Balance and Low-Back Pain, but Not Anxiety, in People with Parkinson's Disease.

Individuals with Parkinson's disease (PD) experience postural instability, low-back pain (LBP), and anxiety. These symptoms increase the risk of falls and decrease quality of life. Research shows yoga improves balance and decreases LBP and anxiety in healthy adults, but its effects in PD are poorly understood. All participants were part of a larger intervention study. Participants received pretest and posttest evaluations, including the Balance Evaluation Systems Test (BESTest), Beck Anxiety Inventory (BAI), and Revised Oswestry Disability Index (ROSW). Total scores for each measure, as well as individual balance system section scores from the BESTest (biomechanical constraints, stability limits/verticality, transitions/anticipatory, reactive, sensory orientation, and stability in gait) were compared within groups pre- to posttest. Participants in the yoga group (n = 13) completed a twice-weekly 12-week yoga interve n t i o n , whereas controls (n = 13) continued their usual routines for 12 weeks. Both the yoga (Z = -3.20, p = 0.001) and control (Z = -2.10, p = 0.040) groups improved on the BESTest total score. The control group showed no changes in individual balance systems, whereas the yoga group improved in stability limits/verticality (Z = -2.3, p = 0.020), transitions/ anticipatory (Z = -2.50, p = 0.010), reactive (Z = -2.70, p = 0.008), and sensory orientation (Z = -2.30, p = 0.020). ROSW decreased in the yoga group only (Z = -2.10, p = 0.030). BAI did not change in either group. Yoga is a nonpharmacological intervention that can improve balance and LBP in people with PD. This study demonstrated that yoga is feasible for people with PD, and participants reported high levels of enjoyment and intent to practice yoga after the study.

Usability of a daily mHealth application designed to address mobility, speech and dexterity in Parkinson's disease.

Aim: This study investigated the usability of a mobile health (mHealth) smartphone application to treat gait, speech and dexterity in people with Parkinson's disease. Methods: Participants either used an mHealth application (intervention) or maintained their normal routine (control) for 12 weeks and were evaluated at baseline and post-test time points for primary outcome measures of adherence, gait, speech and dexterity. mHealth application adherence was compared with percent change scores on gait, speech and dexterity measures. Results: Adherence was moderate and there were no significant group, time or interaction effects for any outcome measures. Correlations between adherence and outcomes were weak and negative. Conclusion: These data suggest that usability of this mHealth application was limited as indicated by low adherence. The application alone in its present form was not adequate to treat symptoms of gait, speech or dexterity in people with Parkinson's disease.

Dose of remote limb ischemic conditioning for enhancing learning in healthy young adults.

Remote limb ischemic conditioning (RLIC) is a technique in which tissues distant from the target organ are exposed to brief, sub-lethal bouts of ischemia. The effects of remotely applied ischemic conditioning are systemically transferred to the target organ, and typically manifested as protection from subsequent ischemic injury. Previous studies in our lab have found and confirmed that RLIC enhances learning and retention during motor training on a balance task. The current study tested the effect of RLIC dose (number of cycles) on learning enhancement in young, healthy adults. Forty healthy participants age 18-40 years were randomized to receive 5 cycles of sham conditioning (n = 9), 3 cycles of RLIC (n = 11), 4 cycles of RLIC (n = 10), or 5 cycles of RLIC (n = 10) using a blood pressure cuff around the upper arm once a day for 7 consecutive weekdays (Days 1-7). Participants concurrently trained on a balance task, bimanual cup stacking task, and a discrete sequence production task on Days 3-7. Change in performance on each of the three tasks was compared across groups. Participants in all four groups improved their performance on each of the three tasks over time. However, RLIC at any dose did not enhance learning on any of the three tasks. While RLIC is safe, inexpensive, and clinically feasible, reproducibility may be challenged by unidentified factors, raising critical challenges to the straightforward translation of RLIC for improving rehabilitation outcomes in individuals recovering from neurological injury.

Remote Limb Ischemic Conditioning and Motor Learning: Evaluation of Factors Influencing Response in Older Adults.

Remote limb ischemic conditioning (RLIC) is a clinically feasible method of promoting tissue protection against subsequent ischemic insult. Recent findings from our lab demonstrated that RLIC robustly enhances motor learning in young, healthy humans. The next step is to determine which individuals would receive maximum benefit from RLIC before applying these findings to clinical rehabilitation populations such as stroke. Numerous factors, such as age, sex, body mass index (BMI), and cardiovascular comorbidities may influence the response. Sixty-nine participants aged 40-80 were randomized to receive either RLIC (n = 33) or sham (n = 36) conditioning. Participants underwent seven consecutive sessions consisting of RLIC or sham conditioning with a blood pressure cuff on the upper extremity and motor training on a stability platform balance task, with two follow-up sessions. Balance change (post-test-pre-test) was compared across participants, groups, and the factors of age, sex, BMI, and comorbidities. Participants in both groups improved their performance on the balance task from pre- to post-test. Overall balance change was independently associated with age and BMI. There was no difference in balance change between RLIC and Sham groups. However, RLIC significantly enhanced balance performance in participants with no comorbidities. Compared with our previous study in young adults, middle-aged and older adults demonstrated smaller improvements on the balance task. RLIC enhanced learning in middle-aged and older adults only in the absence of pre-defined comorbidities. RLIC may be a promising tool for enhancing motor recovery, but the accumulation of comorbidity with age may decrease its effectiveness.

Low to moderate relationships between gait and postural responses in Parkinson disease.

OBJECTIVE: To evaluate the relationship between spatiotemporal parameters of forward and backward gait and quality of compensatory stepping responses in forward and backward directions in people with Parkinson's disease with and without freezing of gait. DESIGN: Cross-sectional analysis. SUBJECTS: A total of 111 individuals with mild to moderate Parkinson's disease. METHODS: Forward and backward gait velocity and step length were evaluated using a GAITRite walkway. Forward and backward postural responses were evaluated using items from the Mini Balance Evaluation Systems Test and the Movement Disorders Society Unified Parkinson Disease Rating Scale motor subsection. Relationships between gait and postural responses were examined for the full sample and for sub-groups with and without freezing of gait. RESULTS: There were significant (p < 0.05) low to moderate correlations between postural responses and gait overall. Correlations were similar in the freezer and non-freezer sub-groups. Freezers performed worse than non-freezers on all gait parameters and backward postural response items (p < 0.05). CONCLUSION: Low to moderate relationships between gait and postural responses indicate the complexity of postural control and the potential involvement of different neural circuitry across these tasks. Better understanding of the relationships between gait and postural deficits in Parkinson's disease may inform the future development of targeted interventions to address these impairments.

Pencil-and-Paper Neural Networks: An Undergraduate Laboratory Exercise in Computational Neuroscience.

Although it has been more than 70 years since McCulloch and Pitts published their seminal work on artificial neural networks, such models remain primarily in the domain of computer science departments in undergraduate education. This is unfortunate, as simple network models offer undergraduate students a much-needed bridge between cellular neurobiology and processes governing thought and behavior. Here, we present a very simple laboratory exercise in which students constructed, trained and tested artificial neural networks by hand on paper. They explored a variety of concepts, including pattern recognition, pattern completion, noise elimination and stimulus ambiguity. Learning gains were evident in changes in the use of language when writing about information processing in the brain.