Terence D. Sanger

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Stereo disparity computation using Gabor filters

A solution to the correspondence problem for stereopsis is proposed using the differences in the complex phase of local spatial frequency components. One-dimensional spatial Gabor filters (Gabor 1946; Marcelja 1980), at different positions and spatial frequencies are convolved with each member of a stereo pair. The difference between the complex phase at corresponding points in the two images is used to find the stereo disparity. Disparity values are combined across spatial frequencies for each image location. Three-dimensional depth maps have been computed from real images under standard lighting conditions, as well as from random-dot stereograms (Julesz 1971). The algorithm can discriminate disparities significantly smaller than the width of a pixel. It is possible that a similar mechanism might be used in the human visual system.

DEFINITION AND CLASSIFICATION OF HYPERKINETIC MOVEMENTS IN CHILDHOOD

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random‐appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock‐like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back‐and‐forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Abnormalities of spatial and temporal sensory discrimination in writer's cramp.

Clinical observations of patients with writers cramp suggest that abnormalities of the sensory system may be a frequent finding in this disorder. Neurophysiological data from an animal model of focal dystonia have revealed cells in somatosensory cortex with enlarged and overlapping tactile receptive fields. However, psychophysical studies so far have been unable to document a clinical correlate supporting a similar enlargement of receptive fields in humans. We compared the fingertip discrimination of the orientation of fine spatial gratings between writers cramp and control subjects and found a significant decrease in grating sensitivity in the patients, consistent with the possibility of enlarged tactile receptive fields. In addition, we duplicated previous experiments showing an abnormality of tactile temporal discrimination. The results provide psychophysical measures which may relate to the development of sensory cortical reorganization in patients with writers cramp. Mov. Disord. 16:94–99, 2001.

Sensory discrimination capabilities in patients with focal hand dystonia

To explore the concept that dystonia may result from dysfunction of the sensory system, 14 patients with focal hand dystonia were tested during two somatosensory discrimination tasks. Compared with controls, patients had a higher threshold in a task involving discrimination of two electric stimuli closely related temporally, an abnormality that correlated with the degree of severity of dystonia. There was no significant difference in a single‐touch, gross localization task. The possible relevance of these findings to the pathogenesis of dystonia is discussed. Ann Neurol 2000;47:377–380

Definition and Classification of Negative Motor Signs in Childhood

In this report we describe the outcome of a consensus meeting that occurred at the National Institutes of Health in Bethesda, Maryland, March 12 through 14, 2005. The meeting brought together 39 specialists from multiple clinical and research disciplines including developmental pediatrics, neurology, neurosurgery, orthopedic surgery, physical therapy, occupational therapy, physical medicine and rehabilitation, neurophysiology, muscle physiology, motor control, and biomechanics. The purpose of the meeting was to establish terminology and definitions for 4 aspects of motor disorders that occur in children: weakness, reduced selective motor control, ataxia, and deficits of praxis. The purpose of the definitions is to assist communication between clinicians, select homogeneous groups of children for clinical research trials, facilitate the development of rating scales to assess improvement or deterioration with time, and eventually to better match individual children with specific therapies. “Weakness” is defined as the inability to generate normal voluntary force in a muscle or normal voluntary torque about a joint. “Reduced selective motor control” is defined as the impaired ability to isolate the activation of muscles in a selected pattern in response to demands of a voluntary posture or movement. “Ataxia” is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity about the affected joints. “Apraxia” is defined as an impairment in the ability to accomplish previously learned and performed complex motor actions that is not explained by ataxia, reduced selective motor control, weakness, or involuntary motor activity. “Developmental dyspraxia” is defined as a failure to have ever acquired the ability to perform age-appropriate complex motor actions that is not explained by the presence of inadequate demonstration or practice, ataxia, reduced selective motor control, weakness, or involuntary motor activity.

A tree-structured adaptive network for function approximation in high-dimensional spaces

Nonlinear function approximation is often solved by finding a set of coefficients for a finite number of fixed nonlinear basis functions. However, if the input data are drawn from a high-dimensional space, the number of required basis functions grows exponentially with dimension, leading many to suggest the use of adaptive nonlinear basis functions whose parameters can be determined by iterative methods. The author proposes a technique based on the idea that for most of the data, only a few dimensions of the input may be necessary to compute the desired output function. Additional input dimensions are incorporated only where needed. The learning procedure grows a tree whose structure depends upon the input data and the function to be approximated. This technique has a fast learning algorithm with no local minima once the network shape is fixed, and it can be used to reduce the number of required measurements in situations where there is a cost associated with sensing. Three examples are given: controlling the dynamics of a simulated planar two-joint robot arm, predicting the dynamics of the chaotic Mackey-Glass equation, and predicting pixel values in real images from pixel values above and to the left.

Neural population codes.

In many regions of the brain, information is represented by patterns of activity occurring over populations of neurons. Understanding the encoding of information in neural population activity is important both for grasping the fundamental computations underlying brain function, and for interpreting signals that may be useful for the control of prosthetic devices. We concentrate on the representation of information in neurons with Poisson spike statistics, in which information is contained in the average spike firing rate. We analyze the properties of population codes in terms of the tuning functions that describe individual neuron behavior. The discussion centers on three computational questions: first, what information is encoded in a population; second, how does the brain compute using populations; and third, when is a population optimal? To answer these questions, we discuss several methods for decoding population activity in an experimental setting. We also discuss how computation can be performed within the brain in networks of interconnected populations. Finally, we examine questions of optimal design of population codes that may help to explain their particular form and the set of variables that are best represented. We show that for population codes based on neurons that have a Poisson distribution of spike probabilities, the behavior and computational properties of the code can be understood in terms of the tuning properties of individual cells.

Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study

Summary Background Dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms. Methods 11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding. Findings Children presented in infancy (median age 2·5 months, range 0·5–7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0–13·2 (normal range 1·3–4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei. Interpretation Dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development. Funding Birmingham Childrens Hospital Research Foundation, Birth Defects Foundation Newlife, Action Medical Research, US National Institutes of Health, Wellchild, and the Wellcome Trust.

Testing objective measures of motor impairment in early Parkinson's disease: Feasibility study of an at-home testing device.

We tested the feasibility of a computer based at‐home testing device (AHTD) in early‐stage, unmedicated Parkinsons disease (PD) patients over 6 months. We measured compliance, technical reliability, and patient satisfaction to weekly assessments of tremor, small and large muscle bradykinesia, speech, reaction/movement times, and complex motor control. relative to the UPDRS motor score. The AHTD is a 6.5″ × 10″ computerized assessment battery. Data are stored on a USB memory stick and sent by internet to a central data repository as encrypted data packets. Although not designed or powered to measure change, the study collected data to observe patterns relative to UPDRS motor scores. Fifty‐two PD patients enrolled, and 50 completed the 6 month trial, 48 remaining without medication. Patients complied with 90.6% of weekly 30‐minute assessments, and 98.5% of data packets were successfully transmitted and decrypted. On a 100‐point scale, patient satisfaction with the program at study end was 87.2 (range: 80–100). UPDRS motor scores significantly worsened over 6 months, and trends for worsening over time occurred for alternating finger taps (P = 0.08), tremor (P = 0.06) and speech (P = 0.11). Change in tremor was a significant predictor of change in UPDRS (P = 0.047) and was detected in the first month of the study. This new computer‐based technology offers a feasible format for assessing PD‐related impairment from home. The high patient compliance and satisfaction suggest the feasibility of its incorporation into larger clinical trials, especially when travel is difficult and early changes or frequent data collection are considered important to document.