A kinematic analysis of visually-guided movement in Williams syndrome

Previous studies have reported that people with the neurodevelopmental disorder Williams syndrome exhibit difficulties with visuomotor control. In the current study, we examined the extent to which visuomotor deficits were associated with movement planning or feedback-based on-line control. We used a variant of the Fitts' reciprocal aiming task on a computerized touchscreen in adults with WS, IQ-matched individuals with Down syndrome (DS), and typically developing controls. By manipulating task difficulty both as a function of target size and amplitude, we were able to vary the requirements for accuracy to examine processes associated with dorsal visual stream and cerebellar functioning. Although a greater increase in movement time as a function of task difficulty was observed in the two clinical groups with WS and DS, greater magnitude in the late kinematic components of movement-specifically, time after peak velocity-was revealed in the WS group during increased demands for accuracy. In contrast, the DS group showed a greater speed-accuracy trade-off with significantly reduced and more variable endpoint accuracy, which may be associated with cerebellar deficits. In addition, the WS group spent more time stationary in the target when task-related features reflected a higher level of difficulty, suggestive of specific deficits in movement planning. Our results indicate that the visuomotor coordination deficits in WS may reflect known impairments of the dorsal stream, but may also indicate a role for the cerebellum in dynamic feed-forward motor control.     

Correlations between motor performance and cognitive functions in children born < 1250 g at school age

Very low birth weight born children manifest a higher prevalence of motor and cognitive impairments than term children. Seventy-four prospectively enrolled children born < 1250 g underwent testing of motor (Zurich neuromotor assessment ZNA: timed motor performances and associated movements) and cognitive functions (Kaufman-ABC) at age six years. Children with cerebral palsy or mental retardation were excluded. Adaptive motor tasks (pegboard and dynamic balance) and visuomotor cognitive functions were specifically impaired, and a distinct correlation pattern between motor and cognitive abilities was detected. The adaptive fine motor task (pegboard) correlated with visuomotor functions of the Kaufman-ABC ("triangles", r = 0.35; "matrix analogies", r = 0.39), while pure motor tasks of the ZNA (repetitive, alternating, and sequential movements) did not in spite of impaired motor performance. Timed motor performance below the 10th percentile correlated strongly with cognitive delay (IQ < 85: adaptive fine motor: OR 6.0 [95% CI] 4.7-7.3; adaptive gross motor: OR 7.0 [CI 5.6-8.4]; static balance: OR 9.6 [CI 8.2-11.0]). In conclusion, motor deficits in children born < 1250 g without severe disabilities correlate with specific cognitive impairments, in particular of the visuomotor domain. The correlation pattern may indicate specific dysfunction in visuomotor transformation, the intermediate process between visual-perceptual input and motor output. Early assessment of both motor and cognitive functions using standardized assessment tools is important to determine the extent and combination of specific developmental disturbances and to tailor therapeutic intervention.     

Gait profiles as indicators of domain-specific impairments in executive control across neurodevelopmental disorders

In neurodevelopmental disorders, unique profiles of executive control and attention appear to co-occur with poor motor coordination. However, less is known about how syndrome-specific cognitive profiles interact with motor control and impact behavioural outcomes in neurodevelopmental disorders such as Williams syndrome (WS) and Down syndrome (DS). Here we aimed to examine the extent to which specific components of executive function interact with gait control when performing cognitive dual-tasks (verbal fluency, digit span) in WS and DS. Spatiotemporal gait characteristics and intra-individual variability of gait were assessed in individuals with WS who were matched on spatial ability to individuals with DS, and chronologically age (CA) matched controls. During the concurrent verbal fluency task, the WS group had greater dual-task costs on spatiotemporal gait parameters and variability than CA controls. Conversely, individuals with DS had selective gait interference during the concurrent digit span task when compared to CA controls, but only under increased demands on cognitive control where there was greater variability in step timing in DS. The interrelationships between cognitive-motor interference and behavioural measures of executive functioning appeared to differentiate between WS and DS, and emphasise the importance of task modality in unpacking the executive control profile in these neurodevelopmental disorders. These findings support the notion that associated cerebellar-cortico abnormalities may produce quite distinct profiles of executive control across cognitive and motor domains that impact on behavioural outcomes in neurodevelopmental disorders.     

Behavioural abnormalities contribute to functional decline in Huntington's disease

The independent and relative contributions of motor, cognitive, and behavioural deficits to functional decline in patients with Huntington's disease are examined. Twenty two patients with Huntington's disease were assessed with rating scales for motor dysfunction, cognitive measures of executive functions, and behavioural measures of apathy, executive dysfunction, and disinhibition. Their functional status was assessed with informant based and clinician based ratings of activities of daily living (ADL). A composite apathy/executive dysfunction behavioural index was strongly related to decline in ADL independently and after controlling for motor and cognitive deficits. These results suggest that behavioural dysfunction contributes to functional decline in patients with Huntington's disease and may impede their ability to utilise motor or cognitive skills that remain available in the early stages of the disease.     

Executive neuropsychological functioning in individuals with Williams syndrome

The present study investigated executive neuropsychological functioning in individuals with the neuro-developmental disorder Williams syndrome (WS) using a set of validated standardized neuropsychological tasks. Relatively few studies have examined frontal lobe related executive functions within the cognitive phenotype associated with the disorder. The present study compared participants with WS to typically developing participants who were individually matched for (1) chronological age and (2) verbal mental age (N = 19 each group) on tasks of attention-set shifting, planning and working memory from the Cambridge Neuropsychological Test Automated Battery (CANTAB). To address the specificity of executive function impairment, non-executive tasks of delayed short-term memory and short-term memory span were also administered. Individuals with WS (mean age 18 years) showed impaired executive functioning on tasks of attention set-shifting, working memory, and planning. Non-executive deficits were also observed in short-term delayed memory and memory span. Neuropsychological impairments were correlated with a range of behavioural problems assessed using parent-rated Questionnaires. Overall, these findings point to the role of a range of executive function impairments in WS but further suggest that cognitive impairments extend beyond executive dysfunction.     

Age differences in spatial working memory contributions to visuomotor adaptation and transfer

Throughout our life span we encounter challenges that require us to adapt to the demands of our changing environment; this entails learning new skills. Two primary components of motor skill learning are motor acquisition, the initial process of learning the skill, and motor transfer, when learning a new skill is benefitted by the overlap with a previously learned one. Older adults typically exhibit declines in motor acquisition compared to young adults, but remarkably, do not demonstrate deficits in motor transfer [10]. Our recent work demonstrates that a failure to engage spatial working memory (SWM) is associated with skill learning deficits in older adults [16]. Here, we investigate the role that SWM plays in both motor learning and transfer in young and older adults. Both age groups exhibited performance savings, or positive transfer, at transfer of learning for some performance variables. Measures of spatial working memory performance and reaction time correlated with both motor learning and transfer for young adults. Young adults recruited overlapping brain regions in prefrontal, premotor, parietal and occipital cortex for performance of a SWM and a visuomotor adaptation task, most notably during motor learning, replicating our prior findings [12]. Neural overlap between the SWM task and visuomotor adaptation for the older adults was limited to parietal cortex, with minimal changes from motor learning to transfer. Combined, these results suggest that age differences in engagement of cognitive strategies have a differential impact on motor learning and transfer.     

Short-term learning of a visually guided power-grip task is associated with dynamic changes in EEG oscillatory activity.

OBJECTIVE: Performing a motor task after a period of training has been associated with reduced cortical activity and changes in oscillatory brain activity. Little is known about whether learning also affects the neural network associated with motor preparation and post movement processes. Here we investigate how short-term motor learning affects oscillatory brain activity during the preparation, execution, and post-movement stage of a force-feedback task. METHODS: Participants performed a visually guided power-grip tracking task. EEG was recorded from 64 scalp electrodes. Power and coherence data for the early and late stages of the task were compared. RESULTS: Performance improved with practice. During the preparation for the task alpha power was reduced for late experimental blocks. A movement execution-related decrease in beta power was attenuated with increasing task practice. A post-movement increase in alpha and lower beta activity was observed that decreased with learning. Coherence analysis revealed changes in cortico-cortical coupling with regard to the stage of the visuomotor task and with regard to learning. Learning was variably associated with increased coherence between contralateral and/or ipsilateral frontal and parietal, fronto-central, and occipital brain regions. CONCLUSIONS: Practice of a visuomotor power-grip task is associated with various changes in the activity of a widespread cortical network. These changes might promote visuomotor learning. SIGNIFICANCE: This study provides important new evidence for and sheds new light on the complex nature of the brain processes underlying visuomotor integration and short-term learning.     

Cognitive and psychiatric phenotypes of movement disorders in children: a systematic review

Aim The cognitive and psychiatric aspects of adult movement disorders are well established, but specific behavioural profiles for paediatric movement disorders have not been delineated. Knowledge of non‐motor phenotypes may guide treatment and determine which symptoms are suggestive of a specific movement disorder and which indicate medication effects. Method The goal of this review is to outline the known cognitive and psychiatric symptoms associated with paediatric movement disorders. We used a systematic approach, via PubMed, and reviewed over 400 abstracts of studies of selected disorders, of which 88 papers reporting paediatric non‐motor symptoms are summarized. Results Obsessive–compulsive disorder was manifest in children with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and Sydenham chorea. Children with opsoclonus–myoclonus syndrome had, for the most part, cognitive and behavioural problems, and attention‐deficit–hyperactivity disorder was reported as a major comorbidity in Tourette syndrome, stereotypies, and restless legs syndrome. Symptoms of depression and anxiety were more frequent in individuals with idiopathic dystonia. Affective disorders were suggestive of Wilson disease. Cognitive decline was common in children with juvenile Huntington disease. A limitation of this review was the lack of systematic assessment in paediatric movement disorders for evaluation and uniform definitions. Interpretation Although the literature in non‐motor phenomena is still emerging, recognition of salient cognitive and psychiatric phenomena may facilitate management of paediatric movement disorders.     

Visual Inattention in West Syndrome: A Neuropsychological and Neurofunctional Imaging Study

Summary: Visual behavior is frequently impaired at onset of West syndrome (WS). We studied the neuropsy- chological outcome of eight children who had cryptogenic WS and moderate to severe visual impairment at the onset of epilepsy. At the last examination, a regional cerebral blood flow study using SPECT (single photon emission computed tomography) was performed. The behavior abnormalities observed initially evolved to various defects of cognitive function. Three patients had severe mental retardation with autistic features. Two had marked speech disorders but one had global cognitive impairment. Three patients had specific visual-spatial deficits. SPECT showed perfusion defects involving the parieto-occipital areas in 6 of 8 patients. These abnormalities were restricted to parieto-occipital regions in the three patients with selective visual-spatial deficits, whereas they were associated with other perfusion defects in the three remaining patients. This study demonstrates that the visual inattention observed at the onset of WS is frequently associated with long-term cognitive and/ or perfusion defects involving the parieto-occipital regions.     

Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp2 1lox mice

Rett syndrome (RTT) is an autistic spectrum developmental disorder associated with mutations in the X-linked Mecp2 gene, and severe behavioural and neuropathological deficits. In a mouse model of RTT (Mecp2(1lox)), we examined whether environmental enrichment (EE) alters behavioural performance and regional brain volume. At weaning, Mecp2(1lox) and control mice were assigned to enriched or standard housing. From postnatal day 29 to 43, mice were subjected to behavioural tasks measuring motor and cognitive performance. At postnatal day 44, volumes of whole brain, cerebellum, ventricles, and motor cortex were measured using magnetic resonance imaging. EE provided subtle improvements to locomotor activity and contextual fear conditioning in Mecp2(1lox) mice. Additionally, EE reduced ventricular volumes, which correlated with improved locomotor activity, suggesting that neuroanatomical changes contribute to improved behaviour. Our results suggest that post-weaning EE may provide a non-invasive palliative treatment for RTT.     

In-depth analysis of spatial cognition in Williams syndrome: A critical assessment of the role of the LIMK1 gene

The LIM kinase1 protein (LIMK1) is thought to be involved in neuronal development and brain function. However, its role in spatial cognition in individuals with Williams syndrome (WS) is currently ambiguous, with conflicting reports on the cognitive phenotypes of individuals who do not have classic WS but harbour partial deletions including LIMK1. Two families with partial WS deletions have been described with deficits in visuospatial cognition (Frangiskakis, J. M., Ewart, A. K., Morris, C. A., Mervis, C. B., Bertrand, & J., Robinson, et al. (1996). LIM-kinase 1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 59-69), in contrast to others with similar partial deletions who did not display spatial impairments (Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. J., Grant, J., & Dennis, N., et al. (1999). Williams syndrome: Use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. American Journal of Human Genetics, 64, 118-125). To determine the role of LIMK1 in the highly penetrant visuospatial deficits associated with classic WS, it is essential to investigate the discrepancies between the two studies. Previous research used a standardised task to measure spatial cognition, which may not pick up subtle impairments. We therefore undertook more extensive testing of the spatial cognition of two adults with partial genetic deletions in the WS critical region (LIMK1 and ELN only), who had not displayed spatial impairments in the previous study, and compared them to two high-functioning adults with WS matched on verbal ability. All participants completed a broad battery of 16 perceptual and constructive spatial tests, and the clear-cut spatial difficulties observed in the WS group were not found in the partial deletion group. These findings rule out the claim that the deletion of one copy of LIMK1 is alone sufficient to result in spatial impairment, but leave open the possibility that LIMK1 contributes to the WS cognitive deficits if deleted in combination with other genes within the WS deletion. We conclude that a deeper assessment of WS at the genetic level is required before the contribution of specific genes to phenotypic outcomes can be fully understood.     

Uncovering a context-specific connectional fingerprint of human dorsal premotor cortex

Primate electrophysiological and lesion studies indicate a prominent role of the left dorsal premotor cortex (PMd) in action selection based on learned sensorimotor associations. Here we applied transcranial magnetic stimulation (TMS) to human left PMd at low or high intensity while right-handed individuals performed externally paced sequential key presses with their left hand. Movements were cued by abstract visual stimuli, and subjects either freely selected a key press or responded according to a prelearned visuomotor mapping rule. Continuous arterial spin labeling was interleaved with TMS to directly assess how stimulation of left PMd modulates task-related brain activity depending on the mode of movement selection. Relative to passive viewing, both tasks activated a frontoparietal motor network. Compared with low-intensity TMS, high-intensity TMS of left PMd was associated with an increase in activity in medial and right premotor areas without affecting task performance. Critically, this increase in task-related activity was only present when movement selection relied on arbitrary visuomotor associations but not during freely selected movements. Psychophysiological interaction analysis revealed a context-specific increase in functional coupling between the stimulated left PMd and remote right-hemispheric and mesial motor regions that was only present during arbitrary visuomotor mapping. Our TMS perturbation approach yielded causal evidence that the left PMd is implicated in mapping external cues onto the appropriate movement in humans. Furthermore, the data suggest that the left PMd may transiently form a functional network together with right-hemispheric and mesial motor regions to sustain visuomotor mapping performed with the left nondominant hand.     

Cognitive deficits precede motor deficits in a slowly progressing model of parkinsonism in the monkey

Five adult Macaca fascicularis monkeys were trained to perform tests of cognitive and motor functioning that included a complex visual pattern discrimination task, an object retrieval task, a test of task persistence, and a timed motor task. Once stable baseline performance was achieved, monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at doses of 0.05 to 0.075 mg/kg, 2 to 3 times per week for a total of 24 weeks. Animals were assessed weekly for performance on the previously learned tasks. All monkeys developed performance deficits in a predictable pattern with behavioural and cognitive deficits (i.e. deficits in task persistence and the cognitive component of object retrieval) appearing in advance of measurable motor deficits. Deficits in visual pattern discrimination never appeared. These results show that specific cognitive dysfunction pre-dates motor dysfunction in a chronic, slowly progressing parkinson model in monkeys and support the contention that cognitive deficits in Parkinson's disease may precede the motor signs of the disorder and may not be caused by them.     

Long-term neurological complications after hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy accompanying cardiac arrest is a common cause of long-term neurological dysfunction. With the improvement in prehospital emergency systems, larger numbers of people are resuscitated from cardiac arrests, although with the increased prospect of neurological sequelae. Neurological impairment after cardiac arrest is dependent on the degree of brain damage suffered during the arrest. Although the duration and severity of brain ischemia is often difficult to determine, clinicians are often faced with difficult issues related to predicting outcome related to awakening and long-term neurological deficits after the arrest. Neurological impairments range from mild cognitive deficits to severe motor and cognitive deficits that preclude independence in many activities of daily living. Several neurological syndromes have been described in patients who awaken from hypoxic-ischemic coma with lasting motor and cognitive deficits. This review will address many of the common syndromes after hypoxic-ischemic encephalopathy, including persistent vegetative states, seizures, myoclonus, movement disorders, cognitive dysfunction, and other neurological abnormalities.     

Neurodevelopmental and behavioral issues in Williams syndrome

Much existing research on Williams syndrome (WS) has focused on the individuals' unusual cognitive profile, with less emphasis placed on the developmental and neural underpinnings of the disorder. We review recent findings from brain imaging and begin to discuss links from these data to the behavioral phenotype. Overall brain size is significantly reduced in individuals with WS, as it is in many mental retardation syndromes. However, the specific profile of deficits in WS, particularly the visuospatial deficits, appears to be linked to parietal lobe abnormalities. Results from both genetic and brain imaging studies have provided useful insights into WS neurobiology. However, future work needs to remediate the lack of studies investigating developmental processes.     

Benign rolandic epilepsy -- perhaps not so benign: use of magnetic source imaging as a predictor of outcome

The purpose of this study was to evaluate children with benign rolandic epilepsy, a childhood epilepsy characterized by centrotemporal/rolandic spike-wave discharges with infrequent partial seizures that may secondarily generalize. Recently, some investigators have questioned whether benign rolandic epilepsy is indeed "benign" or whether long-term cognitive outcome may be adversely affected. We initiated an ongoing study to identify children with benign rolandic epilepsy. The children were evaluated in the Texas Comprehensive Epilepsy Program using outpatient or continuous video-electroencephalographic monitoring, brain magnetic resonance imaging, magnetoencephalography, and neuropsychological testing. Neuropsychological testing revealed fine motor dysfunction, visuomotor integration deficits, dyscalculia, and/or expressive language deficits in all of the 9 patients evaluated, reaffirming that benign rolandic epilepsy is not necessarily a benign disorder. Our study shows a high concordance of motor and cognitive deficits in benign rolandic epilepsy, as others have previously suggested. Furthermore, magnetic source imaging shows a higher resolution of dipole localization compared with conventional electroencephalography, which may ultimately improve prediction of deficits. This reaffirms that magnetoencephalography is a valuable diagnostic tool in the evaluation of children with benign rolandic epilepsy.     

White matter alterations in Williams syndrome related to behavioral and motor impairments

Myelin is the electrical insulator surrounding the neuronal axon that makes up the white matter (WM) of the brain. It helps increase axonal conduction velocity (CV) by inducing saltatory conduction. Damage to the myelin sheath and WM is associated with many neurological and psychiatric disorders. Decreasing myelin deficits, and thus improving axonal conduction, has the potential to serve as a therapeutic mechanism for reducing the severity of some of these disorders. Myelin deficits have been previously linked to abnormalities in social behavior, suggesting an interplay between brain connectivity and sociability. This review focuses on Williams syndrome (WS), a genetic disorder characterized by neurocognitive characteristics and motor abnormalities, mainly known for its hypersociability characteristic. We discuss fundamental aspects of WM in WS and how its alterations can affect motor abilities and social behavior. Overall, findings regarding changes in myelin genes and alterations in WM structure in WS suggest new targets for drug therapy aimed at improving conduction properties and altering brain‐activity synchronization in this disorder.     

Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients

BackgroundWhereas the motor dysfunction in Parkinson's disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.MethodsHigh-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.ResultsPD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.ConclusionsNon-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure–function relationships is needed to understand the neural bases of symptom progression in PD.     

Specific impairments in visuospatial working and short-term memory following low-dose scopolamine challenge in healthy older adults

Scopolamine-induced deficits in cognitive and motor processes have been widely demonstrated in animals and humans, although the role of acetylcholine in working memory is not as well understood. This study examined the role of acetylcholine neurotransmission in visuospatial short term and working memory using the Groton Maze Learning Test (GMLT). The GMLT is a computerized hidden maze learning test that yields measures of component cognitive processes such as spatial memory, working memory, and visuomotor function, as well as their integration in trial-and-error problem solving. Healthy older adults were administered scopolamine (0.3 mg subcutaneous), the acetlycholinesterase inhibitor donepezil (5 mg oral), scopolamine with donepezil, or placebo. Compared to placebo, low-dose scopolamine led to performance deficits on all measures of the GMLT. The greatest scopolamine-induced deficits were observed in errors reflecting working memory processes (e.g., perseverative errors d=-2.98, and rule-break errors d=-2.49) and these impairments remained robust when statistical models accounted for scopolamine-related slowing in visuomotor speed. Co-administration of donepezil partially ameliorated scopolamine-related impairments and this effect was greatest for measures of working memory than short-term memory. By itself, donepezil was associated with a small improvement in visuomotor function. These results suggest that scopolamine disrupts processes required for rule maintenance and performance monitoring, in combination with visuomotor slowing and sequential location learning.