Automatic detection of significant areas for functional data with directional error control.

In this paper, we propose a large-scale multiple testing procedure to find the significant sub-areas between two samples of curves automatically. The procedure is optimal in that it controls the directional false discovery rate at any specified level on a continuum asymptotically. By introducing a nonparametric Gaussian process regression model for the two-sided multiple test, the procedure is computationally inexpensive. It can cope with problems with multidimensional covariates and accommodate different sampling designs across the samples. We further propose the significant curve/surface, giving an insight on dynamic significant differences between two curves. Simulation studies demonstrate that the proposed procedure enjoys superior performance with strong power and good directional error control. The procedure is also illustrated with the application to two executive function studies in hemiplegia.

The Tyneside Pegboard Test: development, validation, and observations in unilateral cerebral palsy.

AIM: The aims of this study were twofold: first, to develop and validate a timed test of unimanual and bimanual dexterity suitable for those with disability affecting hand function; second, to explore relationships between unimanual and bimanual completion times. METHOD: We developed the Tyneside Pegboard Test (TPT), an electronically timed test with three peg sizes, incorporating an asymmetrical bimanual task. Nine hundred and seventy-four participants (455 males, 519 females; age range 4-80y) provided normative data. Test-retest reliability and construct validity were assessed (50 adults: 14 males, 36 females; 15-73y) on two occasions 2 weeks apart. Bimanual and unimanual completion times were measured in 87 children (51 males, 36 females) with unilateral cerebral palsy (CP) and 498 individuals in a comparison group (238 males, 260 females; 5-15y). RESULTS: The comparison group showed an asymmetrical U-shaped relationship between completion times and age. Intraclass correlation coefficients ranged from 0.74 to 0.91, indicating moderate test-retest reliability. There was a negative relationship between average TPT bimanual times and Purdue pegboard bimanual scores (Spearman's rho -0.611, degrees of freedom 44, p<0.001). Children with unilateral CP had greater prolongation of bimanual than unimanual completion times compared with the comparison group (mean difference 20.31s, 95% confidence interval 18.13-22.49, p<0.001). INTERPRETATION: The TPT is accessible for those with impaired hand function. Children with unilateral CP demonstrated disproportionate bimanual deficits, even allowing for unimanual dexterity: this has implications for therapy. WHAT THIS PAPER ADDS: We developed an adapted, electronically timed 9-hole pegboard test. Our modifications facilitate use by those with disability affecting hand function. The test incorporates an asymmetrical bimanual task. Children with unilateral cerebral palsy showed disproportionate bimanual dexterity deficits even allowing for unimanual dexterity.

Developmental tuning and decay in senescence of oscillations linking the corticospinal system.

There is increasing evidence of the importance of synchronous activity within the corticospinal system for motor control. We compared oscillatory activity in the primary sensorimotor cortex [EEG of sensorimotor cortex (SMC-EEG)] and a motor neuronal pool [surface electromyogram of opponens pollicis (OP-EMG)], and their coherence in children (4-12 years of age), young adults (20-35 years of age), and elderly adults (>55 years of age). The ratio between lower (2-13 Hz) and higher (14-32 Hz) frequencies in both SMC-EEG and OP-EMG decreased with age, correlating inversely with motor performance. There was evidence for larger, more distributed cortical networks in the children and elderly compared with young adults. Corticomuscular coherence (CMC) was present in all age groups and shifted between frontal and parietal cortical areas. In children, CMC was smaller and less stationary in amplitude and frequency than in adults. Young adults had single peaks of CMC clustered near the modal frequency (23 Hz); multiple peaks with a broad spread of frequencies occurred in children and the elderly; the further the frequency of the maximum peak CMC was from 23 Hz, the poorer the performance. CMC amplitude was inversely related to performance in young adults but was not modulated in relation to performance in children and the elderly. We propose that progressive fine-tuning of the frequency coding and stabilization of the dynamic properties within and between corticospinal networks occurs during adolescence, refining the capacity for efficient dynamic communication in adulthood. In old age, blurring of the tuning between networks and breakdown in their integration occurs and is likely to contribute to a decrement in motor control.

Developmental plasticity connects visual cortex to motoneurons after stroke.

We report motor cortical function in the left occipital cortex of a subject who suffered a left middle cerebral artery stroke early in development. Transcranial magnetic stimulation of the left occipital cortex evoked contraction of right hand muscles. Electroencephalogram recorded over the left occipital cortex showed: 1) coherence with electromyogram from a right hand muscle; 2) a typical sensorimotor Mu rhythm at rest that was suppressed during contraction of right hand muscles. This is the first evidence that cortical plasticity extends beyond reshaping of primary sensory cortical fields to respecification of the cortical origin of subcortically projecting pathways.

Visual hallucinations in dementia with Lewy bodies: transcranial magnetic stimulation study.

BACKGROUND: The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism. AIMS: To determine visual cortical excitability in people with dementia with Lewy bodies compared with aged-matched controls and also the relationship between visual cortical excitability and visual hallucinations in dementia with Lewy bodies. METHOD: Visual cortical excitability was determined by using transcranial magnetic stimulation (TMS) applied to the occiput to elicit phosphenes (transient subjective visual responses) in 21 patients with dementia with Lewy bodies and 19 age-matched controls. RESULTS: Phosphene parameters were similar between both groups. However, in the patients with dementia with Lewy bodies, TMS measures of visual cortical excitability correlated strongly with the severity of visual hallucinations (P = 0.005). Six patients with dementia with Lewy bodies experienced visual hallucination-like phosphenes (for example, seeing people or figures on stimulation) compared with none of the controls (P = 0.02). CONCLUSIONS: Increased visual cortical excitability in dementia with Lewy bodies does not appear to explain visual hallucinations but it may be a marker for their severity.

Evaluating upper limb function after stroke using the free-living accelerometer data.

Accelerometer devices are becoming efficient tools in clinical studies for automatically measuring the activities of daily living. Such data provides a time series describing activity level at every second and displays a subject's activity pattern throughout a day. However, the analysis of such data is very challenging due to the large number of observations produced each second and the variability among subjects. The purpose of this study is to develop efficient statistical analysis techniques for predicting the recovery level of the upper limb function after stroke based on the free-living accelerometer data. We propose to use a Gaussian Mixture Model (GMM)-based method for clustering and extracting new features to capture the information contained in the raw data. A nonlinear mixed effects model with Gaussian Process prior for the random effects is developed as the predictive model for evaluating the recovery level of the upper limb function. Results of applying to the accelerometer data for patients after stroke are presented.

Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development.

The transcription factors Emx2 and Pax6 are expressed in the proliferating zones of the developing rodent neocortex, and gradients of expression interact in specifying caudal and rostral identities. Pax6 is also involved in corticoneurogenesis, being expressed by radial glial progenitors that give rise to cells that also sequentially express Tbr2, NeuroD and Tbr1, genes temporally downstream of Pax6. In this study, using in situ hybridization, we analysed the expression of EMX2, PAX6, TBR2, NEUROD and TBR1 mRNA in the developing human cortex between 8 and 12 postconceptional weeks (PCW). EMX2 mRNA was expressed in the ventricular (VZ) and subventricular zones (SVZ), but also in the cortical plate, unlike in the rodent. However, gradients of expression were similar to that of the rodent at all ages studied. PAX6 mRNA expression was limited to the VZ and SVZ. At 8 PCW, PAX6 was highly expressed rostrally but less so caudally, as has been seen in the rodent, however this gradient disappeared early in corticogenesis, by 9 PCW. There was less restricted compartment-specific expression of TBR2, NEUROD and TBR1 mRNA than in the rodent, where the gradients of expression were similar to that of PAX6 prior to 9 PCW. The gradient disappeared for TBR2 by 10 PCW, and for NEUROD and TBR1 by 12 PCW. These data support recent reports that EMX2 but not PAX6 is more directly involved in arealization, highlighting that analysis of human development allows better spatio-temporal resolution than studies in rodents.

Is hemiplegic cerebral palsy equivalent to amblyopia of the corticospinal system?

OBJECTIVE: Subjects with severe hemiplegic cerebral palsy have increased ipsilateral corticospinal projections from their noninfarcted cortex. We investigated whether their severe impairment might, in part, be caused by activity-dependent, competitive displacement of surviving contralateral corticospinal projections from the affected cortex by more active ipsilateral corticospinal projections from the nonaffected cortex, thereby compounding the impairment. METHODS: Transcranial magnetic stimulation (TMS) characterized corticospinal tract development from each hemisphere over the first 2 years in 32 healthy children, 14 children with unilateral stroke, and 25 with bilateral lesions. Magnetic resonance imaging and anatomic studies compared corticospinal tract growth in 13 patients with perinatal stroke with 46 healthy subjects. RESULTS: Infants with unilateral lesions initially had responses after TMS of the affected cortex, which became progressively more abnormal, and seven were eventually lost. There was associated hypertrophy of the ipsilateral corticospinal axons projecting from the noninfarcted cortex. Magnetic resonance imaging and anatomic studies demonstrated hypertrophy of the corticospinal tract from the noninfarcted hemisphere. TMS findings soon after the stroke did not predict impairment; subsequent loss of responses and hypertrophy of ipsilateral corticospinal axons from the noninfarcted cortex predicted severe impairment at 2 years. Infants with bilateral lesions maintained responses to TMS from both hemispheres with a normal pattern of development. INTERPRETATION: Rather than representing "reparative plasticity," increased ipsilateral projections from the noninfarcted cortex compound disability by competitively displacing surviving contralateral corticospinal projections from the infarcted cortex. This may provide a pathophysiological explanation for why signs of hemiplegic cerebral palsy appear late and progress over the first 2 years of life.

Robot Assisted Training for the Upper Limb after Stroke (RATULS): study protocol for a randomised controlled trial.

BACKGROUND: Loss of arm function is a common and distressing consequence of stroke. We describe the protocol for a pragmatic, multicentre randomised controlled trial to determine whether robot-assisted training improves upper limb function following stroke. METHODS/DESIGN: Study design: a pragmatic, three-arm, multicentre randomised controlled trial, economic analysis and process evaluation. SETTING: NHS stroke services. PARTICIPANTS: adults with acute or chronic first-ever stroke (1 week to 5 years post stroke) causing moderate to severe upper limb functional limitation. Randomisation groups: 1. Robot-assisted training using the InMotion robotic gym system for 45 min, three times/week for 12 weeks 2. Enhanced upper limb therapy for 45 min, three times/week for 12 weeks 3. Usual NHS care in accordance with local clinical practice Randomisation: individual participant randomisation stratified by centre, time since stroke, and severity of upper limb impairment. PRIMARY OUTCOME: upper limb function measured by the Action Research Arm Test (ARAT) at 3 months post randomisation. SECONDARY OUTCOMES: upper limb impairment (Fugl-Meyer Test), activities of daily living (Barthel ADL Index), quality of life (Stroke Impact Scale, EQ-5D-5L), resource use, cost per quality-adjusted life year and adverse events, at 3 and 6 months. Blinding: outcomes are undertaken by blinded assessors. Economic analysis: micro-costing and economic evaluation of interventions compared to usual NHS care. A within-trial analysis, with an economic model will be used to extrapolate longer-term costs and outcomes. Process evaluation: semi-structured interviews with participants and professionals to seek their views and experiences of the rehabilitation that they have received or provided, and factors affecting the implementation of the trial. SAMPLE SIZE: allowing for 10% attrition, 720 participants provide 80% power to detect a 15% difference in successful outcome between each of the treatment pairs. Successful outcome definition: baseline ARAT 0-7 must improve by 3 or more points; baseline ARAT 8-13 improve by 4 or more points; baseline ARAT 14-19 improve by 5 or more points; baseline ARAT 20-39 improve by 6 or more points. DISCUSSION: The results from this trial will determine whether robot-assisted training improves upper limb function post stroke. TRIAL REGISTRATION: ISRCTN, identifier: ISRCTN69371850 . Registered 4 October 2013.

Greater intermanual transfer in the elderly suggests age-related bilateral motor cortex activation is compensatory.

Hemispheric lateralization of movement control diminishes with age; whether this is compensatory or maladaptive is debated. The authors hypothesized that if compensatory, bilateral activation would lead to greater intermanual transfer in older subjects learning tasks that activate the cortex unilaterally in young adults. They studied 10 young and 14 older subjects, learning a unimanual visuomotor task comprising a feedforward phase, where there is unilateral cortical activation in young adults, and a feedback phase, which activates the cortex bilaterally in both age groups. Increased intermanual transfer was demonstrated in older subjects during feedforward learning, with no difference between groups during feedback learning. This finding is consistent with bilateral cortical activation being compensatory to maintain performance despite declining computational efficiency in neural networks.

Henoch-Schönlein purpura with posterior reversible encephalopathy syndrome.

We describe atypical Henoch-Schönlein purpura with posterior reversible encephalopathy syndrome in a normotensive 11-year-old girl. Her Henoch-Schönlein purpura was atypical because she initially presented with abdominal pain and vomiting and neurologic complications, rather than with the classic rash of Henoch-Schönlein Purpura. This previously healthy child was also unusual because she manifested the radiologic and clinical features of posterior reversible encephalopathy syndrome in the absence of hypertension induced by Henoch-Schönlein purpura. Her abnormal findings resolved with supportive therapy. We discuss the association of posterior reversible encephalopathy syndrome with Henoch-Schönlein purpura in three previously reported cases.

High-energy and -protein diet increases brain and corticospinal tract growth in term and preterm infants after perinatal brain injury.

OBJECTIVE: Our hypothesis was that infants with perinatal brain injury fail to thrive in the first postnatal year because of increased energy and protein requirements from deficits that accumulated during neonatal intensive care. Our aim was to assess whether dietary energy and protein input was a rate-limiting factor in brain and body growth in the first year after birth. METHODS: We conducted a prospective, double-blind and randomized, 2-stage group sequential study and controlled for gestation, gender, and brain lesion. Neonates with perinatal brain damage were randomly allocated to receive either a high- (120% recommended average intake) or average (100% recommended average intake) energy and protein diet. The study began at term and continued for 12 months. Three-day dietary diaries estimated energy and protein intake. The primary outcome measure was growth of occipitofrontal circumference. Other measures were growth of axonal diameters in the corticospinal tract, which were estimated by using transcranial magnetic stimulation, weight gain, and length. RESULTS: The study was terminated at the first analysis when the 16 subjects had completed the protocol, because the predetermined stopping criterion of >1 SD difference in occipitofrontal circumference at 12 months' corrected age in those receiving the higher-energy and -protein diet had been demonstrated. Axonal diameters in the corticospinal tract, length, and weight were also significantly increased. CONCLUSIONS: These data support our hypothesis that infants with significant perinatal brain damage have increased nutritional requirements in the first postnatal year and suggest that decreased postnatal brain growth may exacerbate their impairment. There are no measures of cognitive ability at 12 months of age, and whether there will be any improvement in the status of these children, therefore, remains to be shown.