Helen L. Carlson

Effectiveness of cognitive rehabilitation following epilepsy surgery: Current state of knowledge

Cognitive rehabilitation (CR) is a well‐researched therapeutic option for a variety of neurocognitive problems. Recently, CR has been proposed as an option for patients who experience cognitive difficulties following epilepsy surgery (ES). However, there is inconsistency in reporting the efficacy of CR in this population. We appraise existing evidence regarding CR approaches in patients undergoing resective ES and review effectiveness of specific CR strategies.

Transcranial direct current stimulation for children with perinatal stroke and hemiparesis

Objective: 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. Methods: This was a randomized, controlled, double-blind clinical trial. Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, age of 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention to treat. Results: Twenty-four participants were randomized (median age 11.8 ± 2.7 years, range 6.7–17.8). COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001). COPM scores increased more with tDCS compared to sham control (p = 0.004). AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well tolerated with no decrease in either arm function or serious adverse events. Conclusion: tDCS trials appear feasible and safe in hemiparetic children. Lack of change in objective motor function may reflect underdosing of therapy. Marked gains in subjective function with tDCS warrant further study. ClinicalTrials.gov identifier: NCT02170285. Classification of evidence: This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.

Cognition in the Emergency Department as a Predictor of Recovery after Pediatric Mild Traumatic Brain Injury

Cognitive abilities can be acutely disrupted in children and adolescents who sustain a mild traumatic brain injury (mTBI), with the potential that these disruptions may be predictive of recovery. The objective of this study was to determine if cognitive abilities in the emergency department (ED) can differentiate and predict poor symptom recovery following a pediatric mTBI. Participants included 77 male and female youth with a mTBI (mean age=13.6; SD=2.6). All participants completed computerized cognitive testing (four subtests from the CNS Vital Signs) when they presented to the ED. Symptom measurement occurred in the ED (for pre-injury), at 7-10 days, 1 month, 2 months, and 3 months post-mTBI using the post-concussion symptom inventory (PCSI). Recovery was determined using reliable change scores for symptom ratings from 28 orthopedic injury controls (mean age=13.9 years; SD=2.1). Significantly worse Reaction Time scores (i.e., rapid information processing) in the ED were found in those who remained symptomatic at 1 month. Performances on the Reaction Time and Cognitive Flexibility domain scores were predictive of symptom outcome at 1 month for youth (above and beyond sex and baseline symptom burden). Youth with low scores on Reaction Time and/or Cognitive Flexibility were nearly 15 times (95% CI=1.8-323.5) more likely to remain symptomatic at 1 month post-mTBI. No significant group differences were found at 7-10 days, 2 months, or 3 months post-injury. Rapid computerized cognitive testing in the ED following a mTBI may help clinicians predict which youth may or may not remain symptomatic at follow-up.

Reliability and variability of diffusion tensor imaging (DTI) tractography in pediatric epilepsy

BACKGROUND Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. METHODS Children diagnosed with epilepsy [N=43, mean age=11.7 years, standard deviation=3.7 years, 53% male] underwent a DTI sequence (6 directions, 2×2×3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). RESULTS Diffusion variables showed low variability (CV=2.7-8.8%) and very high reliability (ICC=.97-.99) except for limbic tracts [fornix (ICC=.75-.94); cingulum (ICC=.71-.98)]. Tract volume measurements showed high variability (CV=21.9-62.0%) and moderate reliability (ICC=.54-.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. CONCLUSIONS This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity.

Reconsidering “Inattention” in Attention-Deficit Hyperactivity Disorder: Implications for Neuropsychological Assessment and Intervention

Attention-deficit hyperactivity disorder (ADHD) does not exist. This explicit statement needs elucidation of course given ADHD is a common neurodevelopmental disorder, but it provides the reader with the impetus to reconsider long-held beliefs about this condition and its treatment. Surely, there is a disorder called ADHD from which this thesis is framed, but primary attention and hyperactivity-impulsivity problems are mediated by different albeit interrelated brain systems. Like many neurodevelopmental disorders (e.g., learning disabilities, autism spectrum disorder), the medical and psychological professions have used a single, large inclusive ADHD diagnostic category to represent children with different etiologies for their overt symptoms. Despite neurobiological differences among children diagnosed with ADHD, the clinical position that attention-deficit or primary attention problems are sufficient for ADHD identification undermines clinical practice. This commonly accepted dubious position not only undermines the diagnostic utility of our neuropsychological measures, but it attenuates treatment effects as well. Supported with evidence from our ongoing ADHD research program, this data-based review will support these contentions and provide implications for diagnosis and treatment of children with attention problems.

Treatment of dysphasia with rTMS and language therapy after childhood stroke: Multimodal imaging of plastic change.

Expressive dysphasia accompanies left inferior frontal gyrus (IFG/Broca) injury. Recovery may relate to interhemispheric balance with homologous, contralesional IFG but is unexplored in children. We evaluated effects of inhibitory rTMS to contralesional IFG combined with intensive speech therapy (SLT). A 15year-old, right-handed male incurred a left middle cerebral artery stroke. After 30months, severe non-fluent dysphasia impacted quality of life. Language networks, neuronal metabolism and white matter pathways were explored using MRI. Language function was measured longitudinally. An intensive SLT program was combined with contralesional inhibitory rTMS of right pars triangularis. Procedures were well tolerated. Language function improved persisting to four months. Post-treatment fMRI demonstrated increased left perilesional IFG activations and connectivity at rest. Bilateral changes in inositol and glutamate metabolism were observed. Contralesional, inhibitory rTMS appears safe in childhood stroke-induced dysphasia. We observed clinically significant improvements after SLT coupled with rTMS. Advanced neuroimaging can evaluate intervention-induced plasticity.

Segmental Diffusion Properties of the Corticospinal Tract and Motor Outcome in Hemiparetic Children With Perinatal Stroke

Perinatal stroke injures developing motor systems, resulting in hemiparetic cerebral palsy. Diffusion tensor imaging can explore structural connectivity. We used diffusion tensor imaging to assess corticospinal tract diffusion in hemiparetic children with perinatal stroke. Twenty-eight children (6-18 years) with unilateral stroke underwent diffusion tensor imaging. Four corticospinal tract assessments included full tract, partial tract, minitract and region of interest. Diffusion characteristics (fractional anisotropy, mean, axial, and radial diffusivity) were calculated. Ratios (lesioned/nonlesioned) were compared across segments and to validated long-term motor outcomes (Pediatric Stroke Outcome Measure, Assisting Hand Assessment, Melbourne Assessment). Fractional anisotropy and radial diffusivity ratios decreased as tract size decreased, while mean diffusivity showed consistent symmetry. Poor motor outcomes were associated with lower fractional anisotropy in all segments and radial diffusivity correlated with both Assisting Hand Assessment and Melbourne Assessment. Diffusion imaging of segmented corticospinal tracts is feasible in hemiparetic children with perinatal stroke. Correlations with disability support clinical relevance and utility in model development for personalized rehabilitation.

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.

Diffusion imaging of cerebral diaschisis in childhood arterial ischemic stroke

Background Diffusion-weighted imaging magnetic resonance imaging may detect changes in brain structures remote but connected to stroke consistent with neuropathological descriptions of diaschisis. Early diffusion-weighted imaging demonstrates restriction in corticospinal pathways after arterial ischemic stroke of all ages that correlates with motor outcome. Aim/hypothesis We hypothesized that cerebral diaschisis is measurable in childhood arterial ischemic stroke and explored associations with outcome. Methods This sub-study of the validation of the Pediatric NIH Stroke Scale study prospectively enrolled children with acute arterial ischemic stroke and both acute and early follow-up (5–14 days) diffusion-weighted imaging. Inclusion criteria were (1) unilateral middle cerebral artery arterial ischemic stroke, (2) acute and subacute diffusion-weighted imaging (b = 1000), and (3) 12 month neurological follow-up (Pediatric Stroke Outcome Measure). A validated method using ImageJ software quantified diffusion-weighted imaging diaschisis in anatomically connected structures. Diaschisis measures were corrected for infarct volume, compared to age, imaging timing, and outcomes (Chi square/Fisher, Mann–Whitney test). Results Nineteen children (53% male, median 8.1 years) had magnetic resonance imaging at medians of 21 and 168 h post-stroke onset. Diaschisis was common and evolved over time, observed in one (5%) on acute but eight (42%) by follow-up diffusion-weighted imaging. Thalamic and callosal diaschisis were most common (5, 26%). Estimates of perilesional diaschisis varied (54 ± 18% of infarct volume). Children with diaschisis tended to be younger (7.02 ± 5.4 vs. 11.82 ± 4.3 years, p = 0.08). Total diaschisis score was associated with poor cognitive outcomes (p = 0.03). Corticospinal tract diaschisis was associated with motor outcome (p = 0.004). Method reliability was excellent. Conclusions Diffusion-weighted imaging diaschisis occurs in childhood arterial ischemic stroke. Mistaking diaschisis for new areas of infarction carries important clinical implications. Improved recognition and study are required to establish clinical relevance.

Sensory tractography and robot‐quantified proprioception in hemiparetic children with perinatal stroke

Perinatal stroke causes most hemiparetic cerebral palsy, resulting in lifelong disability. We have demonstrated the ability of robots to quantify sensory dysfunction in hemiparetic children but the relationship between such deficits and sensory tract structural connectivity has not been explored. It was aimed to characterize the relationship between the dorsal column medial lemniscus (DCML) pathway connectivity and proprioceptive dysfunction in children with perinatal stroke. Twenty‐nine participants (6–19 years old) with MRI‐classified, unilateral perinatal ischemic stroke (14 arterial, 15 venous), and upper extremity deficits were recruited from a population‐based cohort and compared with 21 healthy controls. Diffusion tensor imaging (DTI) defined DCML tracts and five diffusion properties were quantified: fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, AD), and fiber count. A robotic exoskeleton (KINARM) tested upper limb proprioception in an augmented reality environment. Correlations between robotic measures and sensory tract diffusion parameters were evaluated. Lesioned hemisphere sensory tracts demonstrated lower FA and higher MD, RD, and AD compared with the non‐dominant hemisphere of controls. Dominant (contralesional) hemisphere tracts were not different from controls. Both arterial and venous stroke groups demonstrated impairments in proprioception that correlated with lesioned hemisphere DCML tract diffusion properties. Sensory tract connectivity is altered in the lesioned hemisphere of hemiparetic children with perinatal stroke. A correlation between lesioned DCML tract diffusion properties and robotic proprioceptive measures suggests clinical relevance and a possible target for therapeutic intervention. Hum Brain Mapp 38:2424–2440, 2017.