Basic and Translational Neuroscience of Childhood-Onset Dystonia: A Control-Theory Perspective.

Dystonia is a collection of symptoms with involuntary muscle activation causing hypertonia, hyperkinetic movements, and overflow. In children, dystonia can have numerous etiologies with varying neuroanatomic distribution. The semiology of dystonia can be explained by gain-of-function failure of a feedback controller that is responsible for stabilizing posture and movement. Because postural control is maintained by a widely distributed network, many different anatomic regions may be responsible for symptoms of dystonia, although all features of dystonia can be explained by uncontrolled activation or hypersensitivity of motor cortical regions that can cause increased reflex gain, inserted postures, or sensitivity to irrelevant sensory variables. Effective treatment of dystonia in children requires an understanding of the relationship between etiology, anatomy, and the specific mechanism of failure of postural stabilization.

Improvement of speed-accuracy tradeoff during practice of a point-to-point task in children with acquired dystonia.

The tradeoff between speed and accuracy is a well-known constraint for human movement, but previous work has shown that this tradeoff can be modified by practice, and the quantitative relationship between speed and accuracy may be an indicator of skill in some tasks. We have previously shown that children with dystonia are able to adapt their movement strategy in a ballistic throwing game to compensate for increased variability of movement. Here, we test whether children with dystonia can adapt and improve skills learned on a trajectory task. We use a novel task in which children move a spoon with a marble between two targets. Difficulty is modified by changing the depth of the spoon. Our results show that both healthy children and children with acquired dystonia move more slowly with the more difficult spoons, and both groups improve the relationship between speed and spoon difficulty following 1 wk of practice. By tracking the marble position in the spoon, we show that children with dystonia use a larger fraction of the available variability, whereas healthy children adopt a much safer strategy and remain farther from the margins, as well as learning to adapt and have more control over the marble's utilized area by practice. Together, our results show that both healthy children and children with dystonia choose trajectories that compensate for risk and inherent variability, and that the increased variability in dystonia can be modified with continued practice.NEW & NOTEWORTHY This study provides insights into the adaptability of children with dystonia in learning a point-to-point task. We show that these children adjust their strategies to account for increased difficulty in the task. Our findings underscore the potential of task-specific practice in improving motor skills and show higher level of signal-dependent noise can be controlled through repetition and learned strategies, which provides an avenue for the quantitative evaluation of rehabilitation strategies in this challenging group.

The Effects of Prolonged Vibrotactile EMG-Based Biofeedback on Ankle Joint Range of Motion During Gait in Children with Spastic Cerebral Palsy: A Case Series.

AIMS: The objective of this case series was to examine the feasibility of vibrotactile EMG-based biofeedback (BF) as a home-based intervention tool to enhance sensory information during everyday motor activities and to explore its effectiveness to induce changes in active ankle range of motion during gait in children with spastic cerebral palsy (CP). METHODS: Ten children ages 6 to 13 years with spastic CP were recruited. Participants wore two EMG-based vibro-tactile BF devices for at least 4 hours per day for 1-month on the ankle and knee joints muscles. The device computed the amplitude of the EMG signal of the target muscle and actuated a silent vibration motor proportional to the magnitude of the EMG. RESULTS: Our results demonstrated the feasibility of the augmented sensory information of muscle activity to induce changes of the active ankle range of motion during gait for 6 children with an increase ranging from 8.9 to 51.6% compared to a one-month period without treatment. CONCLUSIONS: Preliminary findings of this case series demonstrate the feasibility of vibrotactile EMG-based BF and suggest potential effectiveness to increase active ankle range of motion, therefore serving as a promising therapeutic tool to improve gait in children with spastic CP.

Constraint-induced intervention as an emergent phenomenon from synaptic competition in biological systems.

The principle of constraint-induced therapy is widely practiced in rehabilitation. In hemiplegic cerebral palsy (CP) with impaired contralateral corticospinal projection due to unilateral injury, function improves after imposing a temporary constraint on limbs from the less affected hemisphere. This type of partially-reversible impairment in motor control by early brain injury bears a resemblance to the experience-dependent plastic acquisition and modification of neuronal response selectivity in the visual cortex. Previously, such mechanism was modeled within the framework of BCM (Bienenstock-Cooper-Munro) theory, a rate-based synaptic modification theory. Here, we demonstrate a minimally complex yet sufficient neural network model which provides a fundamental explanation for inter-hemispheric competition using a simplified spike-based model of information transmission and plasticity. We emulate the restoration of function in hemiplegic CP by simulating the competition between cells of the ipsilateral and contralateral corticospinal tracts. We use a high-speed hardware neural simulation to provide realistic numbers of spikes and realistic magnitudes of synaptic modification. We demonstrate that the phenomenon of constraint-induced partial reversal of hemiplegia can be modeled by simplified neural descending tracts with 2 layers of spiking neurons and synapses with spike-timing-dependent plasticity (STDP). We further demonstrate that persistent hemiplegia following unilateral cortical inactivation or deprivation is predicted by the STDP-based model but is inconsistent with BCM model. Although our model is a highly simplified and limited representation of the corticospinal system, it offers an explanation of how constraint as an intervention can help the system to escape from a suboptimal solution. This is a display of an emergent phenomenon from the synaptic competition.

Expansion coding and computation in the cerebellum: 50 years after the Marr-Albus codon theory.

Fifty years ago, David Marr and James Albus proposed a computational model of cerebellar cortical function based on the pioneering circuit models described by John Eccles, Masao Ito and Janos Szentagothai. The Marr-Albus model remains one of the most enduring and influential models in computational neuroscience, despite apparent falsification of some of the original predictions. We re-examine the Marr-Albus model in the context of the modern theory of computational neural networks and in the context of expanded interpretations of the connectivity and function of cerebellar cortex within the full motor system. By doing so, we show that the original elements of the codon theory continue to make important predictions for cerebellar mechanism, and we show that evidence appearing to contradict the original model is based on an artificially narrow interpretation of cerebellar structure and motor function.

A Cerebellar Computational Mechanism for Delay Conditioning at Precise Time Intervals.

The cerebellum is known to have an important role in sensing and execution of precise time intervals, but the mechanism by which arbitrary time intervals can be recognized and replicated with high precision is unknown. We propose a computational model in which precise time intervals can be identified from the pattern of individual spike activity in a population of parallel fibers in the cerebellar cortex. The model depends on the presence of repeatable sequences of spikes in response to conditioned stimulus input. We emulate granule cells using a population of Izhikevich neuron approximations driven by random but repeatable mossy fiber input. We emulate long-term depression (LTD) and long-term potentiation (LTP) synaptic plasticity at the parallel fiber to Purkinje cell synapse. We simulate a delay conditioning paradigm with a conditioned stimulus (CS) presented to the mossy fibers and an unconditioned stimulus (US) some time later issued to the Purkinje cells as a teaching signal. We show that Purkinje cells rapidly adapt to decrease firing probability following onset of the CS only at the interval for which the US had occurred. We suggest that detection of replicable spike patterns provides an accurate and easily learned timing structure that could be an important mechanism for behaviors that require identification and production of precise time intervals.

Deep brain stimulation for cerebral palsy: where are we now?

Cerebral palsy (CP) is a complex disorder and children frequently have multiple impairments. Dystonia is a particularly frustrating impairment that interferes with rehabilitation and function and is difficult to treat. Of the available treatments, deep brain stimulation (DBS) has emerged as an option with the potential for large effect size in a subgroup of children. While brain stimulation has been used in CP for more than 40 years, modern devices and targeting methods are improving both the safety and efficacy of the procedure. Successful use of DBS depends on appropriate selection of patients, identification of effective neuroanatomical targets in each patient, careful neurosurgical procedure, and detailed follow-up evaluation and programming. The use of functional neurosurgery for neuromodulation in CP remains a technology in its infancy, but improving experience and knowledge are likely to make this one of the safest and most effective interventions for children with moderate-to-severe motor disorders. This review summarizes the current procedures for patient and target selection, and surgical implantation of DBS electrodes for CP. The history of DBS and future directions when used in secondary dystonia are also examined. WHAT THIS PAPER ADDS: Selection of candidates for deep brain stimulation (DBS) requires understanding of dystonia in cerebral palsy . DBS could become a first-line treatment option in some children.

ESTIMULACIÓN CEREBRAL PROFUNDA PARA LA PARÁLISIS CEREBRAL: ¿DÓNDE ESTAMOS AHORA?: La parálisis cerebral (PC) es un trastorno complejo y los niños con frecuencia tienen discapacidades múltiples. La distonía es un deterioro particularmente frustrante que interfiere con la rehabilitación y la función y es difícil de tratar. De los tratamientos disponibles, la estimulación cerebral profunda (DBS, por sus siglas en inglés - deep brain stimulation) ha surgido como una opción con el potencial de un gran tamaño de efecto en un subgrupo de niños. Si bien la estimulación cerebral se ha utilizado en PC durante más de 40 años, los dispositivos modernos y los métodos de detección están mejorando tanto la seguridad como la eficacia del procedimiento. El uso exitoso de la DBS depende de la selección apropiada de los pacientes, la identificación de objetivos neuroanatómicos efectivos en cada paciente, el procedimiento neuroquirúrgico cuidadoso y la evaluación y programación de seguimiento detalladas. El uso de la neurocirugía funcional para la neuromodulación en la PC sigue siendo una tecnología en su infancia, pero es probable que la mejora de la experiencia y los conocimientos hagan de esta una de las intervenciones más seguras y efectivas para los niños con trastornos motores de moderados a graves. Esta revisión resume los procedimientos actuales para la selección de pacientes y objetivos, y la implantación quirúrgica de electrodos DBS para PC. La historia de DBS y las direcciones futuras cuando se utilizan en la distonía secundaria también se examinan.

ESTIMULAÇÃO CEREBRAL PROFUNDA PARA PARALISIA CEREBRAL: ONDE ESTAMOS AGORA?: Paralisia cerebral (PC) é uma desordem complexa e crianças frequentemente apresentam múltiplas deficiências. A distonia é uma deficiência particularmente frustrante que interfere com a reabilitação e função, e é difícil de tratar. Dentre dos tratamentos disponíveis, a estimulação cerebral profunda (ECP) emergiu como uma opção com potencial de grande tamanho de efeito em um subgrupo de crianças. Embora a estimulação cerebral seja usada em PC há mais de 40 anos, dispositivos modernos e métodos de identificação de áreas alvo tem melhorado tanto a segurança quanto a eficácia do procedimento. O uso bem sucedido da ECP depende da seleção apropriada dos pacientes, identificação dos alvos neuroanatômicos efetivos para cada paciente, procedimento neurocirúrgico cuidadoso, e avaliação e programação detalhadas no acompanhamento. O uso de neurocirurgia funcional para neuromodulação em PC ainda é uma tecnologia iniciante, mas a crescente experiência e conhecimento provavelmente farão dela uma das mais seguras e efetivas intervenções para crianças com transtornos motores de moderados a severos. Esta revisão sintetiza os procedimentos atuais para seleção de pacientes e alvos, e a implantação cirúrgica de eletrodos de ECP para PC. A história da ECP e direções futuras, quando usados em distonia secundária, também são examinados.

EMG-based vibro-tactile biofeedback training: effective learning accelerator for children and adolescents with dystonia? A pilot crossover trial.

BACKGROUND: This study is aimed at better understanding the role of a wearable and silent ElectroMyoGraphy-based biofeedback on motor learning in children and adolescents with primary and secondary dystonia. METHODS: A crossover study with a wash-out period of at least 1 week was designed; the device provides the patient with a vibration proportional to the activation of an impaired target muscle. The protocol consisted of two 5-day blocks during which subjects were trained and tested on a figure-8 writing task: their performances (at different levels of difficulty) were evaluated in terms of both kinematics and muscular activations on day 1 and day 5, while the other 3 days were purely used as training sessions. The training was performed with and without using the biofeedback device: the week of use was randomized. Data were collected on 14 subjects with primary and secondary (acquired) dystonia (age: 6-19 years). RESULTS: Results comparing kinematic-based and EMG-based outcome measures pre- and post-training showed learning due to practice for both subjects with primary and secondary dystonia. On top of said learning, an improvement in terms of inter-joint coordination and muscular pattern functionality was recorded only for secondary dystonia subjects, when trained with the aid of the EMG-based biofeedback device. CONCLUSIONS: Our results support the hypothesis that children and adolescents with primary dystonia in which there is intact sensory processing do not benefit from feedback augmentation, whereas children with secondary dystonia, in which sensory deficits are often present, exhibit a higher learning capacity when augmented movement-related sensory information is provided. This study represents a fundamental investigation to address the scarcity of noninvasive therapeutic interventions for young subjects with dystonia.

Comparison of speed-accuracy tradeoff between linear and nonlinear filtering algorithms for myocontrol.

Nonlinear Bayesian filtering of surface electromyography (EMG) can provide a stable output signal with little delay and the ability to change rapidly, making it a potential control input for prosthetic or communication devices. We hypothesized that myocontrol follows Fitts' Law, and that Bayesian filtered EMG would improve movement times and success rates when compared with linearly filtered EMG. We tested the two filters using a Fitts' Law speed-accuracy paradigm in a one-muscle myocontrol task with EMG captured from the dominant first dorsal interosseous muscle. Cursor position in one dimension was proportional to EMG. Six indices of difficulty were tested, varying the target size and distance. We examined two performance measures: movement time (MT) and success rate. The filter had a significant effect on both MT and success. MT followed Fitts' Law and the speed-accuracy relationship exhibited a significantly higher channel capacity when using the Bayesian filter. Subjects seemed to be less cautious using the Bayesian filter due to its lower error rate and smoother control. These findings suggest that Bayesian filtering may be a useful component for myoelectrically controlled prosthetics or communication devices. NEW & NOTEWORTHY Whereas previous work has focused on assessing the Bayesian algorithm as a signal processing algorithm for EMG, this study assesses the use of the Bayesian algorithm for online EMG control. In other words, the subjects see the output of the filter and can adapt their own behavior to use the filter optimally as a tool. This study compares how subjects adapt EMG behavior using the Bayesian algorithm vs. a linear algorithm.

Increased task-uncorrelated muscle activity in childhood dystonia.

BACKGROUND: Even if movement abnormalities in dystonia are obvious on observation-based examinations, objective measures to characterize dystonia and to gain insights into its pathophysiology are still strongly needed. We hypothesize that motor abnormalities in childhood dystonia are partially due to the inability to suppress involuntary variable muscle activity irrelevant to the achievement of the desired motor task, resulting in the superposition of unwanted motion components on the desired movement. However, it is difficult to separate and quantify appropriate and inappropriate motor signals combined in the same muscle, especially during movement. METHODS: We devise an innovative and practical method to objectively measure movement abnormalities during the performance of a continuous figure-eight writing task in 7 children with dystonia and 9 age-matched healthy controls. During the execution of a continuous writing task, muscle contractions should occur at frequencies that match the frequencies of the writing outcome. We compare the power spectra of kinematic trajectories and electromyographic signals of 8 upper limb muscles to separate muscle activity with the same frequency content of the figure-eight movement (task-correlated) from activity occurring at frequencies extraneous to the task (task-uncorrelated). RESULTS: Children with dystonia present a greater magnitude of task-uncorrelated muscle components. The motor performance achieved by children with dystonia is characterized by an overall lower quality, with high spatial and temporal variability and an altered trade-off between speed and accuracy. CONCLUSIONS: Findings are consistent with the hypothesis that, in childhood dystonia, the ability to appropriately suppress variable and uncorrelated elements of movement is impaired. Here we present a proof-of-concept of a promising tool to characterize the phenomenology of movement disorders and to inform the design of neurorehabilitation therapies.

A Nonlinear Stochastic Filter for Continuous-Time State Estimation.

Nonlinear filters produce a nonparametric estimate of the probability density of state at each point in time. Currently-known nonlinear filters include Particle Filters and the Kushner equation (and its un-normalized version: the Zakai equation). However, these filters have limited measurement models: Particle Filters require measurement at discrete times, and the Kushner and Zakai equations only apply when the measurement can be represented as a function of the state. We present a new nonlinear filter for continuous-time measurements with a much more general stochastic measurement model. It integrates to Bayes' rule over short time intervals and provides Bayes-optimal estimates from quantized, intermittent, or ambiguous sensor measurements. The filter has a close link to Information Theory, and we show that the rate of change of entropy of the density estimate is equal to the mutual information between the measurement and the state and thus the maximum achievable. This is a fundamentally new class of filter that is widely applicable to nonlinear estimation for continuous-time control.

Current and emerging strategies for treatment of childhood dystonia.

Childhood dystonia is a movement disorder characterized by involuntary sustained or intermittent muscle contractions causing twisting and repetitive movements, abnormal postures, or both (Sanger et al, 2003). Dystonia is a devastating neurological condition that prevents the acquisition of normal motor skills during critical periods of development in children. Moreover, it is particularly debilitating in children when dystonia affects the upper extremities such that learning and consolidation of common daily motor actions are impeded. Thus, the treatment and rehabilitation of dystonia is a challenge that continuously requires exploration of novel interventions. This review will initially describe the underlying neurophysiological mechanisms of the motor impairments found in childhood dystonia followed by the clinical measurement tools that are available to document the presence and severity of symptoms. Finally, we will discuss the state-of-the-art of therapeutic options for childhood dystonia, with particular emphasis on emergent and innovative strategies.

Risk-aware control.

Human movement differs from robot control because of its flexibility in unknown environments, robustness to perturbation, and tolerance of unknown parameters and unpredictable variability. We propose a new theory, risk-aware control, in which movement is governed by estimates of risk based on uncertainty about the current state and knowledge of the cost of errors. We demonstrate the existence of a feedback control law that implements risk-aware control and show that this control law can be directly implemented by populations of spiking neurons. Simulated examples of risk-aware control for time-varying cost functions as well as learning of unknown dynamics in a stochastic risky environment are provided.

Stereotactic Awake Basal Ganglia Electrophysiological Recording and Stimulation (SABERS): A Novel Staged Procedure for Personalized Targeting of Deep Brain Stimulation in Pediatric Movement and Neuropsychiatric Disorders.

Selection of targets for deep brain stimulation (DBS) has been based on clinical experience, but inconsistent and unpredictable outcomes have limited its use in patients with heterogeneous or rare disorders. In this large case series, a novel staged procedure for neurophysiological assessment from 8 to 12 temporary depth electrodes is used to select targets for neuromodulation that are tailored to each patient's functional needs. Thirty children and young adults underwent deep brain stimulation target evaluation with the new procedure: Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation (SABERS). Testing is performed in an inpatient neuromodulation monitoring unit over 5-7 days, and results guide the decision to proceed and the choice of targets for permanent deep brain stimulation implantation. Results were evaluated 3-6 months postoperatively with the Burke-Fahn-Marsden Dystonia Rating Scale and the Barry-Albright Dystonia Scale. Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation testing allowed modulation to be tailored to specific neurologic deficits in a heterogeneous population, including subjects with primary dystonia, secondary dystonia, and Tourette syndrome. All but one subject were implanted with 4 permanent deep brain stimulation leads. Results showed significant improvement on both scales at postoperative follow-up. No significant adverse events occurred. Use of the Stereotactic Awake Basal ganglia Electrophysiological Recording and Stimulation protocol with evaluation in the neuromodulation monitoring unit is feasible and results in significant patient benefit compared with previously published results in these populations. This new technique supports a significant expansion of functional neurosurgery to predict effective stimulation targets in a wide range of disorders of brain function, including those for which the optimal target is not yet known.

Deep brain stimulation in children and young adults with secondary dystonia: the Children's Hospital Los Angeles experience.

BACKGROUND: Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. It can be classified as primary or secondary. There is no cure for dystonia and the goal of treatment is to provide a better quality of life for the patient. Surgical intervention is considered for patients in whom an adequate trial of medical treatment has failed. Deep brain stimulation (DBS), specifically of the globus pallidus interna (GPi), has been shown to be extremely effective in primary generalized dystonia. There is much less evidence for the use of DBS in patients with secondary dystonia. However, given the large number of patients with secondary dystonia, the significant burden on the patients and their families, and the potential for DBS to improve their functional status and comfort level, it is important to continue to investigate the use of DBS in the realm of secondary dystonia. OBJECT: The objective of this study is to review a series of cases involving patients with secondary dystonia who have been treated with pallidal DBS. METHODS: A retrospective review of 9 patients with secondary dystonia who received treatment with DBS between February 2011 and February 2013 was performed. Preoperative and postoperative videos were scored using the Barry-Albright Dystonia Scale (BADS) and Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) by a neurologist specializing in movement disorders. In addition, the patients' families completed a subjective questionnaire to assess the perceived benefit of DBS. RESULTS: The average age at DBS unit implantation was 15.1 years (range 6-20 years). The average time to follow-up for the BADS evaluation from battery implantation was 3.8 months (median 3 months). The average time to follow-up for the subjective benefit evaluation was 10.6 months (median 9.5 months). The mean BADS scores improved by 9% from 26.5 to 24 (p = 0.04), and the mean BFMDRS scores improved by 9.3% (p = 0.055). Of note, even in patients with minimal functional improvement, there seemed to be decreased contractures and spasms leading to improved comfort. There were no complications such as infections or hematoma in this case series. In the subjective benefit evaluation, 3 patients' families reported "good" benefit, 4 reported "minimal" benefit, and 1 reported no benefit. CONCLUSIONS: These early results of GPi stimulation in a series of 9 patients suggest that DBS is useful in the treatment of secondary generalized dystonia in children and young adults. Objective improvements in BADS and BFMDRS scores are demonstrated in some patients with generalized secondary dystonia but not in others. Larger follow-up studies of DBS for secondary dystonia, focusing on patient age, history, etiology, and patterns of dystonia, are needed to learn which patients will respond best to DBS.

Improvement of speed-accuracy tradeoff during practice of a point to point task in children with secondary dystonia.

The tradeoff between speed and accuracy is a well-known constraint for human movement, but previous work has shown that this tradeoff can be modified by practice, and the quantitative relationship between speed and accuracy may be an indicator of skill in some tasks. We have previously shown that children with dystonia are able to adapt their movement strategy in a ballistic throwing game to compensate for increased variability of movement. Here we test whether children with dystonia can adapt and improve skill learnt on a trajectory task. We use a novel task in which children move a spoon with a marble between two targets. Difficulty is modified by changing the depth of the spoon. Our results show that both healthy children and children with secondary dystonia move more slowly with the more difficult spoons, and both groups improve the relationship between speed and spoon difficulty following one week of practice. By tracking the marble position in the spoon, we show that children with dystonia use a larger fraction of the available variability, whereas healthy children adopt a much safer strategy and remain farther from the margins, as well as learning to adopt and have more control over the marble's utilized area by practice. Together, our results show that both healthy children and children with dystonia choose trajectories that compensate for risk and inherent variability, and that the increased variability in dystonia can be modified with continued practice.

What is the effect of benzodiazepines on deep brain activity? A study in pediatric patients with dystonia.

Introduction: Benzodiazepines (BDZs) are commonly used to treat the symptoms of movement disorders; however, deep brain stimulation (DBS) has become a popular treatment for these disorders. Previous studies have investigated the effects of BDZ on cortical activity, no data are currently available on their effects on deep brain regions, nor on these regions' responses to DBS. How the BDZ affects the thalamus and basal ganglia in dystonia patients remains unknown. Methods: DBS recordings were performed in ventral oralis anterior/posterior (VoaVop), ventral intermediate (VIM) and ventral anterior (VA) thalamic subnuclei, as well as globus pallidus interna (GPi) and subthalamic nucleus (STN). Evoked potentials (EP) and frequency domain analysis were performed to determine the BDZ effect on neural activities compared to the control condition (off-BDZ). Three male pediatric patients with dystonia treated with BDZ and undergoing depth electrode evaluation for clinical targeting were recruited for the study. Stimulation was administered at 25 and 55 Hz frequencies and recordings were simultaneously gathered through pairs of externalized stereoelectroencephalography (sEEG) electrodes. EP amplitude and the effect of stimulation on the frequency spectrum of activity were compared at baseline and following clinical administration of BDZ. Results: Frequency analysis showed consistent reductions in activity during BDZ treatment in all studied brain regions for all patients. Evoked potential (EP) analysis showed increased subthalamic nucleus (STN) EP amplitude and decreased ventral intermediate (VIM) and STN EP amplitude during BDZ treatment. Interpretation: BDZs reduce thalamic and basal ganglia activity in multiple regions and alter the efficacy of transmission between these regions. While the mechanism is unknown our results confirm the known widespread effects of this class of medications and identify specific areas within the motor system that are directly affected.

Deep brain stimulation in an adolescent with hypomyelination with atrophy of the basal ganglia and cerebellum due to a TUBB4A mutation: illustrative case.

BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare genetic disease due to a TUBB4A mutation, with motor features including dystonia. Deep brain stimulation (DBS) can be used to treat dystonia in pediatric populations, although the response is highly variable and preferential toward specific etiologies. OBSERVATIONS: A single pediatric subject with H-ABC received DBS using a staged procedure involving temporary depth electrode placement, identification of optimal stimulation targets, and permanent electrode implantation. After surgery, the patient significantly improved on both the Burke-Fahn-Marsden Dystonia Rating Scale and the Barry-Albright Dystonia Scale. The patient's response suggests that DBS can have potential benefit in H-ABC. LESSONS: TUBB4A mutations are associated with a variety of clinical phenotypes, and there is a lack of clearly identified targets for DBS, with this case being the second reported instance of DBS in this condition. The staged procedure with temporary depth electrode testing is recommended to identify optimal stimulation targets. The response seen in this patient implies that such a staged procedure may provide benefit in other conditions where DBS targets are currently unknown, including rare genetic or metabolic conditions associated with movement disorders.

Globus pallidus internus activity increases during voluntary movement in children with dystonia.

The rate model of basal ganglia function predicts that muscle activity in dystonia is due to disinhibition of thalamus resulting from decreased inhibitory input from pallidum. We seek to test this hypothesis in children with dyskinetic cerebral palsy undergoing evaluation for deep brain stimulation (DBS) to analyze movement-related activity in different brain regions. The results revealed prominent beta-band frequency peaks in the globus pallidus interna (GPi), ventral oralis anterior/posterior (VoaVop) subnuclei of the thalamus, and subthalamic nucleus (STN) during movement but not at rest. Connectivity analysis indicated stronger coupling between STN-VoaVop and STN-GPi compared to GPi-STN. These findings contradict the hypothesis of decreased thalamic inhibition in dystonia, suggesting that abnormal patterns of inhibition and disinhibition, rather than reduced GPi activity, contribute to the disorder. Additionally, the study implies that correcting abnormalities in GPi function may explain the effectiveness of DBS targeting the STN and GPi in treating dystonia.