Fatigue in children using motor imagery and P300 brain-computer interfaces.

BACKGROUND: Brain-computer interface (BCI) technology offers children with quadriplegic cerebral palsy unique opportunities for communication, environmental exploration, learning, and game play. Research in adults demonstrates a negative impact of fatigue on BCI enjoyment, while effects on BCI performance are variable. To date, there have been no pediatric studies of BCI fatigue. The purpose of this study was to assess the effects of two different BCI paradigms, motor imagery and visual P300, on the development of self-reported fatigue and an electroencephalography (EEG) biomarker of fatigue in typically developing children. METHODS: Thirty-seven typically-developing school-aged children were recruited to a prospective, crossover study. Participants attended three sessions: (A) motor imagery-BCI, (B) visual P300-BCI, and (C) video viewing (control). The motor imagery task involved an imagined left- or right-hand squeeze. The P300 task involved attending to one square on a 3 × 3 grid during a random single flash sequence. Each paradigm had respective calibration periods and a similar visual counting game. Primary outcomes were self-reported fatigue and the power of the EEG alpha band both collected during resting-state periods pre- and post-task. Self-reported fatigue was measured using a 10-point visual analog scale. EEG alpha band power was calculated as the integrated power spectral density from 8 to 12 Hz of the EEG spectrum. RESULTS: Thirty-two children completed the protocol (age range 7-16, 63% female). Self-reported fatigue and EEG alpha band power increased across all sessions (F(1,155) = 33.9, p < 0.001; F = 5.0(1,149), p = 0.027 respectively). No differences in fatigue development were observed between session types. There was no correlation between self-reported fatigue and EEG alpha band power change. BCI performance varied between participants and paradigms as expected but was not associated with self-reported fatigue or EEG alpha band power. CONCLUSION: Short periods (30-mintues) of BCI use can increase self-reported fatigue and EEG alpha band power to a similar degree in children performing motor imagery and P300 BCI paradigms. Performance was not associated with our measures of fatigue; the impact of fatigue on useability and enjoyment is unclear. Our results reflect the variability of fatigue and the BCI experience more broadly in children and warrant further investigation.

Differences in neurometabolites and transcranial magnetic stimulation motor maps in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. METHODS: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory (γ-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. RESULTS: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036).Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal-to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. CONCLUSION: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD.

Can Children With Perinatal Stroke Use a Simple Brain Computer Interface?

Background and Purpose: Perinatal stroke is the leading cause of hemiparetic cerebral palsy resulting in lifelong disability for millions of people worldwide. Options for motor rehabilitation are limited, especially for the most severely affected children. Brain computer interfaces (BCIs) sample brain activity to allow users to control external devices. Functional electrical stimulation enhances motor recovery after stroke, and BCI-activated functional electrical stimulation was recently shown to improve upper extremity function in adult stroke. We aimed to determine the ability of children with perinatal stroke to operate a simple BCI. Methods: Twenty-one children with magnetic resonance imaging­confirmed perinatal stroke (57% male, mean [SD] 13.5 [2.6] years, range 9­18) were compared with 24 typically developing controls (71% male, mean age [SD] 13.7 [3.7] years, range 6­18). Participants trained on a simple EEG-based BCI over 2 sessions (10 trials each) utilizing 2 different mental imagery strategies: (1) motor imagery (imagine opening and closing of hands) and (2) goal oriented (imagine effector object moving toward target) to complete 2 tasks: (1) drive a remote controlled car to a target and (2) move a computer cursor to a target. Primary outcome was Cohen Kappa with a score >0.40 suggesting BCI competence. Results: BCI performance was comparable between stroke and control participants. Mean scores were 0.39 (0.18) for stroke versus 0.42 (0.18) for controls (t[42]=0.478, P=0.94). No difference in performance between venous (M=0.45, SD=0.29) and arterial (M=0.34, SD=0.22) stroke (t[82]=1.89, P=0.090) was observed. No effect of task or strategy was observed in the stroke participants. Over 90% of stroke participants demonstrated competency on at least one of the 4 task-strategy combinations. Conclusions: Children with perinatal stroke can achieve proficiency in basic tasks using simple BCI systems. Future directions include exploration of BCI-functional electrical stimulation systems for rehabilitation for children with hemiparesis and other forms of cerebral palsy.

Complementary and Alternative Therapy Use in Children with Cerebral Palsy.

OBJECTIVE: To describe complementary and alternative medicine (CAM) use amongst children with cerebral palsy (CP) in Canada and to identify factors associated with CAM use. METHODS: We conducted a cross-sectional study, utilising data from the Canadian CP Registry. We explored the association between CAM use and regional, socioeconomic and CP phenotypic variables, and parental perception of the family-centredness of clinical care using the Measures of Process of Care-56 (MPOC-56). Chi-square analyses were performed, and odds ratios (OR) and 95% confidence intervals (CI) were obtained. Mann-Whitney U tests were used to compare MPOC-56 scores between CAM users and non-CAM users. RESULTS: The study sample consisted of 313 families of which 27% reported CAM use in the past year. Children with CP using CAM were more likely to reside in Western Canada (OR 3.3, 95% CI 1.6-6.7), live in a two-parent household (OR 3.5, 95% CI 1.5-8.4), have an ataxic/hypotonic or dyskinetic CP subtype (OR 3.0, 95% CI 1.5-6.1) and have a greater motor impairment (OR 2.8, 95% CI 1.7-4.9). MPOC-56 subscale scores were not significantly associated with CAM use. CONCLUSION: Physicians need to be aware of existing CAM therapies, the level of evidence supporting their efficacy (beneficence), their associated risks of adverse events (non-maleficence) and enable fair access to care that may be of benefit to each child.

Goals of children with unilateral cerebral palsy in a brain stimulation arm rehabilitation trial.

AIM: To explore relationships between category classifications for children's rehabilitation goals, outcomes, and participant characteristics. METHOD: Children with hemiparetic cerebral palsy due to perinatal stroke rated self-selected goals with the Canadian Occupational Performance Measure (COPM) and completed the Assisting Hand Assessment (AHA) and Box and Block Test (BBT), at baseline and 6 months, in a randomized, controlled 10-day neuromodulation rehabilitation trial using repetitive transcranial magnetic stimulation. Goals were classified with the Canadian Model of Occupational Performance and Engagement and the International Classification of Functioning, Disability and Health. Analysis included standard linear regression. RESULTS: Data for 45 participants (mean age 11y 7mo, SD 3y 10mo, range 6-19y, 29 males, 16 females) on 186 goals were included. Self-care goal percentage corresponded with baseline BBT by age (standardized ß=-0.561, p=0.004). Leisure goal percentage corresponded with baseline BBT (standardized ß=0.419, p=0.010). AHA change corresponded with productivity goals (standardized ß=0.327, p=0.029) and age (standardized ß=0.481, p=0.002). COPM change corresponded with baseline COPM and age by AHA change (p<0.05). INTERPRETATION: Younger children with lower motor function were more likely to select self-care goals while those with better function tended to select leisure goals. Functional improvement corresponded with older age and productivity goals. COPM change scores reflected functional improvement among older children. Children chose functionally and developmentally appropriate goals. Consequently, children should be free to set goals that matter to them. WHAT THIS PAPER ADDS: Children in a brain stimulation trial chose divergent upper extremity functional goals. Younger children with lower ability chose more self-care goals. Children with higher ability chose more leisure goals. Older children's goal ratings reflected objective functional motor gains. Children chose goals appropriate to their function and level of development.

A Case of Neuromuscular Electrical Stimulation for Childhood Stroke Hyperkinesis: A Brief Report.

AIM: Some conditions within specific populations are so rare rigorous evidence is unavailable. Childhood hyperkinesis is one example, yet presents an opportunity to examine sensation's contribution to motor function. METHODS: The patient experienced functional difficulty from hyperkinesis as a result of childhood stroke. Home-based passive neuromuscular electrical stimulation (NMES) was implemented an hour/day, six days/week, over 6 weeks (36 hours). Clinical and robotic measures (Assisting Hand Assessment, Box and Block Test, Jebsen Taylor Test of Hand Function, Kinarm) were administered before and after the intervention and at 9 months. RESULTS: NMES was feasible and well tolerated. Clinically important gains of arm function were maintained at 9 months. Robotic measures showed improved hyperkinesis, namely reduced movement segmentation and improved target approximation, in addition to improved proprioceptive function after NMES. CONCLUSION: This case study illustrates the use of NMES within a previously unexplored population and highlights the potential importance of sensory systems to motor gains.

Enhancing Stroke Recovery Across the Life Span With Noninvasive Neurostimulation.

Stroke is the leading cause of neurologic disability not only in adults but perinatal and childhood stroke affect millions of children as well worldwide with deficits that last a lifetime. The rapidly increasing evidence base for how noninvasive neuromodulation may enhance stroke recovery in adults may be applicable to the youngest stroke survivors. In return, how the plasticity of the developing brain contributes to stroke recovery and its modulation may provide equally valuable insight toward mechanisms and opportunities for enhancing recovery in all stroke patients. Despite this synergistic relationship, examinations of stroke recovery and neuromodulation across the life span have rarely been considered. Here, we attempt to amalgamate the worlds of adult, childhood, and perinatal stroke to explore the differences and commonalities between the models and approaches that are driving advances in noninvasive neuromodulation toward better outcomes for stroke patients of all ages.

Effects of Transcranial Direct Current Stimulation on GABA and Glx in Children: A pilot study.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults.

Diffusion Imaging of Cerebral Diaschisis in Neonatal Arterial Ischemic Stroke.

BACKGROUND: Neonatal arterial ischemic stroke is a leading cause of cerebral palsy and lifelong disability. Diffusion-weighted imaging has revolutionized diagnosis and facilitated outcome prognostication in acute neonatal arterial ischemic stroke. Diaschisis refers to changes in brain areas functionally connected but structurally remote from primary injury. We hypothesized that acute diffusion-weighted imaging can quantify cerebral diaschisis and is associated with outcome from neonatal arterial ischemic stroke. METHODS: Subjects were identified from a prospective, population-based research cohort (Alberta Perinatal Stroke Project). Inclusion criteria were unilateral middle cerebral artery neonatal arterial ischemic stroke, diffusion-weighted magnetic resonance imaging within 10 days of birth, and more than 12-months follow-up (pediatric stroke outcome measure). Diaschisis was characterized and quantified using a validated software method (ImageJ). Volumetric analysis assessed atrophy of affected structures. Diaschisis scores were corrected for infarct size and compared with outcomes (Mann-Whitney). RESULTS: From 20 eligible neonatal arterial ischemic strokes, two were excluded for poor image quality. Of 18 remaining (61% male, median age 3.2 days), 16 (89%) demonstrated diaschisis. Thalamus (88%) was the most common location in addition to corpus callosum (50%). Age at imaging was not associated with diaschisis. Affected structures demonstrated atrophy on imaging. Long-term outcomes available in 81% (median age 7.5 years) were not associated with diaschisis scores. CONCLUSIONS: Cerebral diaschisis occurs in neonatal arterial ischemic stroke and can be quantified with diffusion-weighted imaging. Occurrence is common and should not be mistaken for additional infarction. Determining clinical significance will require larger samples with well-characterized long-term outcomes.

Thalamic diaschisis following perinatal stroke is associated with clinical disability.

BACKGROUND: Perinatal stroke causes most hemiparetic cerebral palsy and leads to lifelong disability. Understanding developmental neuroplasticity following early stroke is increasingly translated into novel therapies. Diaschisis refers to alterations brain structures remote from, but connected to, stroke lesions. Ipsilesional thalamic diaschisis has been described following adult stroke but has not been investigated in perinatal stroke. We hypothesized that thalamic diaschisis occurs in perinatal stroke and its degree would be inversely correlated with clinical motor function. METHODS: Population-based, controlled cohort study. Participants were children (<19 years) with unilateral perinatal stroke (arterial ischemic stroke [AIS] or periventricular venous infarction [PVI]), anatomical magnetic resonance imaging (MRI) >6 months of age, symptomatic hemiparetic cerebral palsy, and no additional neurologic disorders. Typically developing controls had comparable age and gender proportions. T1-weighted anatomical scans were parcellated into 99 regions of interest followed by generation of regional volumes. The primary outcome was thalamic volume expressed as ipsilesional (ILTV), contralesional (CLTV) and thalamic ratio (CLTV/ILTV). Standardized clinical motor assessments were correlated with thalamic volume metrics. RESULTS: Fifty-nine participants (12.9 years old ±4.0 years, 46% female) included 20 AIS, 11 PVI, and 28 controls. ILTV was reduced in both AIS and PVI compared to controls (p < .001, p = .029, respectively). Ipsilesional thalamic diaschisis was not associated with clinical motor function. However, CLTV was significantly larger in AIS compared to both controls and PVI (p = .005, p < .001, respectively). CLTV was inversely correlated with all four clinical motor assessments (all p < .003). CONCLUSION: Bilateral thalamic volume changes occur after perinatal stroke. Ipsilesional volume loss is not associated with clinical motor function. Contralesional volume is inversely correlated with clinical motor function, suggesting the thalamus is involved in the known developmental plasticity that occurs in the contralesional hemisphere after early unilateral injury.

Changes in spectroscopic biomarkers after transcranial direct current stimulation in children with perinatal stroke.

BACKGROUND: Perinatal stroke causes lifelong motor disability, affecting independence and quality of life. Non-invasive neuromodulation interventions such as transcranial direct current stimulation (tDCS) combined with intensive therapy may improve motor function in adult stroke hemiparesis but is under-explored in children. Measuring cortical metabolites with proton magnetic resonance spectroscopy (MRS) can inform cortical neurobiology in perinatal stroke but how these change with neuromodulation is yet to be explored. METHODS: A double-blind, sham-controlled, randomized clinical trial tested whether tDCS could enhance intensive motor learning therapy in hemiparetic children. Ten days of customized, goal-directed therapy was paired with cathodal tDCS over contralesional primary motor cortex (M1, 20 min, 1.0 mA, 0.04 mA/cm2) or sham. Motor outcomes were assessed using validated measures. Neuronal metabolites in both M1s were measured before and after intervention using fMRI-guided short-echo 3T MRS. RESULTS: Fifteen children [age(range) = 12.1(6.6-18.3) years] were studied. Motor performance improved in both groups and tDCS was associated with greater goal achievement. After cathodal tDCS, the non-lesioned M1 showed decreases in glutamate/glutamine and creatine while no metabolite changes occurred with sham tDCS. Lesioned M1 metabolite concentrations did not change post-intervention. Baseline function was highly correlated with lesioned M1 metabolite concentrations (N-acetyl-aspartate, choline, creatine, glutamate/glutamine). These correlations consistently increased in strength following intervention. Metabolite changes were not correlated with motor function change. Baseline lesioned M1 creatine and choline levels were associated with clinical response. CONCLUSIONS: MRS metabolite levels and changes may reflect mechanisms of tDCS-related M1 plasticity and response biomarkers in hemiparetic children with perinatal stroke undergoing intensive neurorehabilitation.

Advancing non-invasive neuromodulation clinical trials in children: Lessons from perinatal stroke.

Applications of non-invasive brain stimulation including therapeutic neuromodulation are expanding at an alarming rate. Increasingly established scientific principles, including directional modulation of well-informed cortical targets, are advancing clinical trial development. However, high levels of disease burden coupled with zealous enthusiasm may be getting ahead of rational research and evidence. Experience is limited in the developing brain where additional issues must be considered. Properly designed and meticulously executed clinical trials are essential and required to advance and optimize the potential of non-invasive neuromodulation without risking the well-being of children and families. Perinatal stroke causes most hemiplegic cerebral palsy and, as a focal injury of defined timing in an otherwise healthy brain, is an ideal human model of developmental plasticity. Advanced models of how the motor systems of young brains develop following early stroke are affording novel windows of opportunity for neuromodulation clinical trials, possibly directing neuroplasticity toward better outcomes. Reviewing the principles of clinical trial design relevant to neuromodulation and using perinatal stroke as a model, this article reviews the current and future issues of advancing such trials in children.

Spectroscopic biomarkers of motor cortex developmental plasticity in hemiparetic children after perinatal stroke.

Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P < 0.01], creatine [Cre 8.0 ± 0.9 vs. 7.4 ± 0.9, P < 0.05] and myo-Inositol [Ins 6.5 ± 0.84 vs. 5.8 ± 1.1, P < 0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc.

Can noninvasive brain stimulation measure and modulate developmental plasticity to improve function in stroke-induced cerebral palsy?

The permanent nature of motor deficits is a consistent cornerstone of cerebral palsy definitions. Such pessimism is disheartening to children, families, and researchers alike and may no longer be appropriate for it ignores the fantastic plastic potential of the developing brain. Perinatal stroke is presented as the ideal human model of developmental neuroplasticity following distinct, well-defined, focal perinatal brain injury. Elegant animal models are merging with human applied technology methods, including noninvasive brain stimulation for increasingly sophisticated models of plastic motor development following perinatal stroke. In this article, how potential central therapeutic targets are identified and potentially modulated to enhance motor function within these models is discussed. Also, future directions and emerging clinical trials are reviewed.