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Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries ...

University of Calgary

Mild traumatic brain injury (mTBI) outcomes are variable, and 10-15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes.

Cortical excitability after pediatric mild traumatic brain injury.

To determine whether the addition of transcranial direct current stimulation (tDCS) to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy.

Transcranial direct current stimulation for children with perinatal stroke and hemiparesis.

Transcallosal fibers facilitate interhemispheric networks involved in motor tasks. Despite their clinical relevance, interhemispheric motor control systems have not been completely defined in the developing brain. The objective of this study was to examine the developmental profile of transcallosal inhibition in healthy children and adolescents. Nineteen typically developing right-handed participants were recruited. Two transcranial magnetic stimulation (TMS) paradigms assessed transcallosal inhibition: ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). TMS was applied to the motor hotspot of the first dorsal interosseous muscle. Resting motor threshold (RMT), iSP latency, duration and suppression strength, and paired-pulse IHI were measured from both hemispheres. The Purdue Pegboard Test assessed unimanual motor function. Hemispheric differences were evident for RMT and iSP latency and suppression strength, where the left hemisphere had a lower RMT, prolonged latency, and greater suppression strength. iSP duration showed hemispheric symmetry. RMT and iSP latency decreased with age, whereas iSP suppression strength increased. Girls showed shorter iSP latency. Children typically displayed IHI, although hemispheric differences were observed. iSP suppression strength was uniquely associated with IHI within individuals. iSP duration correlated with motor performance. TMS can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, sex, and motor performance. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy. Here we demonstrate that transcranial magnetic stimulation can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, handedness, and motor performance. Interestingly, we also demonstrated sex effects, possibly related to the differing developmental profiles of boys and girls. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.

Developmental profile of motor cortex transcallosal inhibition in children and adolescents.

Development of motor pathways is modulated by activity in these pathways, when they are maturing (ie, critical period). Perinatal stroke injures motor pathways, including the corticospinal tracts, reducing their activity and impairing motor function. Current intervention for the lower limb emphasizes passive approaches (stretching, braces, botulinum toxin injections). The study hypothesis was that intensive, early, child-initiated activity during the critical period will enhance connectivity of motor pathways to the legs and improve motor function.

Early Intensive Leg Training to Enhance Walking in Children With Perinatal Stroke: Protocol for a Randomized Controlled Trial.

Brain stimulation and constraint therapy may enhance function after perinatal stroke but mechanisms are unknown. We characterized interhemispheric interactions (IHI) in hemiparetic children and explored their relationship to motor function and neuromodulation.

Interhemispheric motor interactions in hemiparetic children with perinatal stroke: Clinical correlates and effects of neuromodulation therapy.

 Transcranial direct current stimulation (tDCS) can improve motor learning in children. High-definition approaches (HD-tDCS) have not been examined in children.  We hypothesized that primary motor cortex HD-tDCS would enhance motor learning but be inferior to tDCS in children.  Twenty-four children were recruited for a randomized, sham-controlled, double-blinded interventional trial (NCT03193580, clinicaltrials.gov/ct2/show/NCT03193580) to receive (1) right hemisphere (contralateral) primary motor cortex (M1) 1 mA anodal conventional 1 × 1 tDCS (tDCS), (2) right M1 1 mA anodal 4 × 1 HD-tDCS (HD-tDCS), or (3) sham. Over five consecutive days, participants trained their left hand using the Purdue Pegboard Test (PPT). The Jebsen-Taylor Test, Serial Reaction Time Task, and right hand and bimanual PPT were also tested at baseline, post-training, and 6-week retention time (RT).  Both the tDCS and HD-tDCS groups demonstrated enhanced motor learning compared to sham with effects maintained at 6 weeks. Effect sizes were moderate-to-large for tDCS and HD-tDCS groups at the end of day 4 (Cohen's  tDCS = 0.960, HD-tDCS = 0.766) and day 5 (tDCS = 0.655, HD-tDCS = 0.851). Enhanced motor learning effects were also seen in the untrained hand. HD-tDCS was well tolerated and safe with no adverse effects.  HD-tDCS and tDCS can enhance motor learning in children. Further exploration is indicated to advance rehabilitation therapies for children with motor disabilities such as cerebral palsy.  clinicaltrials.gov, identifier NCT03193580.

Effects of High-Definition and Conventional Transcranial Direct-Current Stimulation on Motor Learning in Children.

We aimed to determine if the mirror movements that often result in children with unilateral cerebral palsy (CP) after perinatal stroke represent a clinical biomarker of developmental plasticity.

Mirror movements in children with unilateral cerebral palsy due to perinatal stroke: clinical correlates of plasticity reorganization.

 The options for severely disabled children with intact cognition to interact with their environment are extremely limited. A brain computer interface (BCI) has the potential to allow such persons to gain meaningful function, communication, and independence. While the pediatric population might benefit most from BCI technology, research to date has been predominantly in adults.  In this prospective, cross-over study, we quantified the ability of healthy school-aged children to perform simple tasks using a basic, commercially available, EEG-based BCI. Typically developing children aged 6-18 years were recruited from the community. BCI training consisted of a brief set-up and EEG recording while performing specific tasks using an inexpensive, commercially available BCI system (EMOTIV EPOC). Two tasks were trained (driving a remote-control car and moving a computer cursor) each using two strategies (sensorimotor and visual imagery). Primary outcome was the kappa coefficient between requested and achieved performance. Effects of task, strategy, age, and learning were also explored.  Twenty-six of thirty children completed the study (mean age 13.2 ± 3.6 years, 27% female). Tolerability was excellent with >90% reporting the experience as neutral or pleasant. Older children achieved performance comparable to adult studies, but younger age was associated with lesser though still good performance. The car task demonstrated higher performance compared to the cursor task ( = 0.027). Thought strategy was also associated with performance with visual imagery strategies outperforming sensorimotor approaches ( = 0.031).  Children can quickly achieve control and execute multiple tasks using simple EEG-based BCI systems. Performance depends on strategy, task and age. Such success in the developing brain mandates exploration of such practical systems in severely disabled children.

Evaluating If Children Can Use Simple Brain Computer Interfaces.

 Major depressive disorder (MDD) is common in youth and treatment options are limited. We evaluated the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in adolescents and transitional aged youth with treatment resistant MDD.  Thirty-two outpatients with moderate to severe, treatment-resistant MDD, aged 13-21 years underwent a three-week, open-label, single center trial of rTMS (ClinicalTrials.gov identifier NCT01731678). rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) using neuronavigation and administered for 15 consecutive week days (120% rest motor threshold; 40 pulses over 4 s [10 Hz]; inter-train interval, 26 s; 75 trains; 3,000 pulses). The primary outcome measure was change in the Hamilton Depression Rating Scale (Ham-D). Treatment response was defined as a >50% reduction in Ham-D scores. Safety and tolerability were also examined.  rTMS was effective in reducing MDD symptom severity ( = 8.94,  = 31,  < 0.00001). We observed 18 (56%) responders (≥ 50% reduction in Ham-D score) and 14 non-responders to rTMS. Fourteen subjects (44%) achieved remission (Ham-D score ≤ 7 post-rTMS). There were no serious adverse events (i.e., seizures). Mild to moderate, self-limiting headaches (19%) and mild neck pain (16%) were reported. Participants ranked rTMS as highly tolerable. The retention rate was 91% and compliance rate (completing all study events) was 99%.  Our single center, open trial suggests that rTMS is a safe and effective treatment for youth with treatment resistant MDD. Larger randomized controlled trials are needed.  www.ClinicalTrials.gov, identifier: NCT01731678.

Repetitive Transcranial Magnetic Stimulation in Youth With Treatment Resistant Major Depression.

 Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown.  To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time.  This was a prospective, longitudinal, controlled cohort study comparing children (8-18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters.  One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events.  TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved.

Longitudinal Assessment of Cortical Excitability in Children and Adolescents With Mild Traumatic Brain Injury and Persistent Post-concussive Symptoms.

To characterize fatigue in children with hemiparesis with perinatal stroke and explore associations with measures of motor performance and corticospinal excitability.

Ephrem Zewdie

Cumming School of Medicine,
Department of Pediatrics,
Alberta Children's Hospital Research Institute

University of Calgary

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Ephrem Zewdie

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Cumming School of Medicine,Department of Pediatrics,Alberta Children's Hospital Research Institute

University of Calgary

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Cumming School of Medicine,
Department of Pediatrics,
Alberta Children's Hospital Research Institute