Terence D Sanger

• MD, PhD
• Professor at University of California, Irvine

Objective Dystonia is a movement disorder causing involuntary muscle contractions and abnormal movements. Often, repeated practice does not lead to motor improvement in children with acquired dystonia, likely due to sensory deficits, which may contribute to their impairment. Therefore, improvement of sensory function might improve motor performance...

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 selec...

Introduction Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration (MEPAN) syndrome is a rare inherited metabolic condition caused by MECR gene mutations. This gene encodes a protein essential for fatty acid synthesis, and defects cause progressively worsening childhood-onset dystonia, optic atrophy, and basal ganglia abnormalities...

Introduction Deep brain stimulation (DBS) is a well-documented therapy for dystonia utilized in many adult and pediatric movement disorders. Pedunculopontine nucleus (PPN) has been investigated as a DBS target primarily in adult patients with dystonia or dyskinesias from Parkinson’s disease, showing improvement in postural instability and gait dysf...

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 movem...

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...

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. OB...

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 diff...

Deep brain stimulation (DBS) is a neuromodulation method for treatment of various neurological disorders. It is often assumed that the primary inhibition or excitation effect of DBS occurs at the site of stimulation. However, recent work has shown that DBS can lead to robust evoked potentials (EP) not only at the stimulation site, representing the...

Classical models of the physiology of dystonia suggest that involuntary muscle contractions are caused by inappropriately low activity in Globus Pallidus internus (GPi) that fails to adequately inhibit thalamic inputs to cortex. We test this prediction in three children with primary dystonia undergoing depth electrode recording in basal ganglia and...

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)...

The contribution of different brain regions to movement abnormalities in children with dystonia is unknown. Three awake subjects undergoing depth electrode implantation for assessments of potential deep brain recording targets performed a rhythmic figure-8 drawing task. Two subjects had dystonia, one was undergoing testing for treatment of Tourette...

Wearable robots are envisioned to amplify the independence of people with movement impairments by providing daily physical assistance. For portable, comfortable, and safe devices, soft pneumatic-based robots are emerging as a potential solution. However, due to the inherent complexities, including compliance and nonlinear mechanical behavior, feedb...

Treatment refractory Tourette syndrome has been shown to be improved with deep brain stimulation, but with multiple possible stimulation locations and variable and incomplete benefit. This study presents a single case of complete amelioration of motor and verbal tics in a patient with Tourette syndrome during placement of 12 stereo-EEG electrodes t...

Deep brain stimulation (DBS) is a common treatment of movement disorders, including dystonia and Parkinson’s disease. Despite the clinical success of DBS, its mechanisms of action remain largely unexplained; however, recent studies have detected high-frequency oscillations within the subthalamic nucleus (STN) and globus pallidus (GP) as a response...

Deep brain stimulation (DBS) is an effective symptomatic treatment in children with movement disorders such as dystonia. Stimulation of internal globus pallidus (GPi) in basal ganglia typically results in successful clinical outcomes, although the mechanism of effect is unknown. GPi stimulation elicits neurotransmitter release in ventralis oralis a...

Objective. Peripheral nerve stimulation has been proposed as a noninvasive treatment for patients with movement disorders such as essential tremor, Parkinson’s disease, and dystonia. While the outcomes have shown clinical effect, the mechanism behind the effect is not yet clear. The goal of this work was to study the brain’s responses to peripheral...

Children and adults with cerebral palsy (CP) can have involuntary upper limb movements as a consequence of the symptoms that characterize their motor disability, leading to difficulties in communicating with caretakers and peers. We describe how a socially assistive robot may help individuals with CP to practice non-verbal communicative gestures us...

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...

High-frequency peripheral nerve stimulation has recently emerged as a noninvasive alternative to thalamic deep brain stimulation (DBS) for treatment of essential tremor, but has not yet been investigated for use in childhood movement disorders, such as dystonia. Since stimulation in the thalamic ventralis intermediate nucleus (VIM) has been clinica...

High-frequency peripheral nerve stimulation has emerged as a noninvasive alternative to thalamic deep brain stimulation for some patients with essential tremor. It is not known whether such techniques might be effective for movement disorders in children, nor is the mechanism and transmission of the peripheral stimuli to central brain structures un...

The design of myocontrolled devices faces particular challenges in children with dyskinetic cerebral palsy because the electromyographic signal for control contains both voluntary and involuntary components. We hypothesized that voluntary and involuntary components of movements would be uncorrelated and thus detectable as different synergistic patt...

Deep brain stimulation (DBS) is one of the most important clinical therapies for neurological disorders. DBS also has great potential to become a great tool for clinical neuroscience research. Recently, the National Engineering Laboratory for Neuromodulation at Tsinghua University held an international Deep Brain Stimulation Initiative workshop to...

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...

Recently, respiratory aerosols with diameters smaller than 100 μm have been con- firmed as important vectors for the spread of SARS-CoV-2. While cloth masks afford some protection for larger ballistic droplets, they are typically inefficient at filtering these aerosols and require specialized fabrication devices to produce. We describe a fabricatio...

Deep brain stimulation is an elective surgical intervention that improves the function and quality of life in children with dystonia and other movement disorders. Both basal ganglia and thalamic nuclei have been found to be relevant targets for treatment of dystonia in children, including the ventral intermediate nucleus of the thalamus, in which s...

Fifty years have passed since David Marr, Masao Ito, and James Albus proposed seminal models of cerebellar functions. These models share the essential concept that parallel-fiber-Purkinje-cell synapses undergo plastic changes, guided by climbing-fiber activities during sensorimotor learning. However, they differ in several important respects, inclu...

Myocontrol holds great promise because it has the potential to provide flexible and accurate prosthetic control that approaches the quality of normal movement. Speed and accuracy are important factors to consider when applying myoelectric signals to external devices. Fitts's law can be used to assess the speed-accuracy trade-off. We hypothesized th...

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New d...

Fifty years have passed since David Marr, Masao Ito, and James Albus proposed seminal models of cerebellar functions. These models share the essential concept that parallel-fiber-Purkinje-cell synapses undergo plastic changes, guided by climbing-fiber activities during sensorimotor learning. However, they differ in several important respects, inclu...

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 so...

Whole-body movements are performed daily, and humans must constantly take into account the inherent instability of a standing posture. At times these movements may be performed in risky environments and when facing different costs of failure. The aim of the study was to test the hypothesis that in upright stance participants continuously estimate b...

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 proport...

This study presents the design and feasibility testing of an interactive portable motion-analysis device for the assessment of upper-limb motor functions in clinical and home settings. The device engages subjects to perform tasks that imitate activities of daily living, e.g. drinking from a cup and moving other complex objects. Sitting at a magneti...

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 su...

The mechanism by which deep brain stimulation (DBS) improves dystonia is not understood, partly heterogeneity of the underlying disorders leads to differing effects of stimulation in different locations. Similarity between the effects of DBS and the effects of lesions has led to biophysical models of blockade or reduced transmission of involuntary...

Background: Deep brain stimulation for secondary dystonia has been limited by unknown optimal targets for individual children. Objectives: We report the first case of a 7-year-old girl with severe generalized dystonia due to acquired striatal necrosis in whom we used a new method for identifying targets for deep brain stimulation. Methods: We...

Deep brain stimulation (DBS) for secondary (acquired, combined) dystonia does not reach the high degree of efficacy achieved in primary (genetic, isolated) dystonia. We hypothesize that this may be due to variability in the underlying injury, so that different children may require placement of electrodes in different regions of basal ganglia and th...

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 stabiliz...

Table S1. Patient Demographics & Therapy Information

Excess involuntary movements and slowness of movement in children with dyskinetic cerebral palsy often result in the inability to properly interact with Augmentative and Alternative Communication (AAC) devices. This significantly limits communication. It is, therefore, essential to know how to adjust the device layout in order to maximize each chil...

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 succes...

Computational neuroscience is a field that traces its origins to the efforts of Hodgkin and Huxley, who pioneered quantitative analysis of electrical activity in the nervous system. While also continuing as an independent field, computational neuroscience has combined with computational systems biology, and neural multiscale modeling arose as one o...

We tested the ability of a synergy-based myocontrol scheme to achieve simultaneous, continuous control of two degrees of freedom (DOFs) of a robotic arm that reproduces the child’s movement (or intention of movement), using muscle synergies extracted from muscles recorded during both isometric contractions and unconstrained flexion-extension moveme...

INTRODUCTION The optimal target for deep brain stimulation (DBS) treatment in children with secondary dystonia is not known, and the target may vary depending on the etiology and anatomic distribution of injury in each child. We present a new technique for determining optimal neuro-anatomical targets in these patients. METHODS Up to ten depth elec...

View Supplementary Video1 View Supplementary Video2 View Supplementary Video3 View Supplementary Video4 View Supplementary Video5 View Supplementary Video6 View Supplementary Video7 Background Abnormal involuntary postures are characteristic of dystonia, but the specific postures observed clinically have not previously been categorized or enumerat...

Introduction Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%–80% of patients. Thus, comprehen...

Childhood dystonia is a movement disorder characterized by muscle overflow and variability. This is the first study that investigates upper limb muscle synergies in childhood dystonia with the twofold aim of deepening the understanding of neuromotor dysfunctions and paving the way to possible synergy-based myocontrol interfaces suitable for this ne...

Objective: One goal of neuromorphic engineering is to create ‘realistic’ robotic systems that interact with the physical world by adopting neuromechanical principles from biology. Critical to this is the methodology to implement the spinal circuitry responsible for the behavior of afferented muscles. At its core, muscle afferentation is the closed-...

Objective. We studied the fundamentals of muscle afferentation by building a Neuro–mechano–morphic system actuating a cadaveric finger. This system is a faithful implementation of the stretch reflex circuitry. It allowed the systematic exploration of the effects of different fusimotor drives to the muscle spindle on the closed-loop stretch reflex r...

Vibratory feedback can be a useful tool for rehabilitation. We examined its use in children with dystonia to understand how it affects muscle activity in a population that does not respond well to standard rehabilitation. We predicted scaled vibration (ie, vibration that was directly or inversely proportional to muscle activity) would increase use...

Risk-aware control is a new type of robust nonlinear stochastic controller in which state variables are represented by time-varying probability densities and the desired trajectory is replaced by a cost function that specifies both the goals of movement and the potential risks associated with deviations. Efficient implementation is possible using t...

Objective. Motor overflow is a common and frustrating symptom of dystonia, manifested as unintentional muscle contraction that occurs during an intended voluntary movement. Although it is suspected that motor overflow is due to cortical disorganization in some types of dystonia (e.g. focal hand dystonia), it remains elusive which mechanisms could i...

Children with dystonia are characterized by highly variable and seemingly uncontrolled movements. An important question for any rehabilitative effort is whether these children can learn and improve their performance. This study compared children with dystonia due to cerebral palsy, typically developing children, and healthy adults in their ability...

Presentation on "25th Annual Computational Neuroscience Meeting: CNS-2016 " BMC Neuroscience 17, 112-113 (2016).

A large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas inc...

Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to invasive neuromodulation and experimental gene and stem cell therapies. The clinical effects of these therapies are variable and often poorly sustained, and only a...

ICGenealogy: towards a common topology of neuronal ion channel function and genealogy in model and experiment Ion channels are fundamental constituents determining the function of single neurons and neuronal circuits. To understand their complex interactions, the field of computational modeling has proven essential: since its emergence, thousands...

To tackle the limits of the literature investigating biofeedback training in children with secondary dystonia, the current study employs a wearable and silent EMG-based biofeedback device that aims at improving control over the impaired muscle by providing the patient with a vibration proportional to muscle activation. The device is tested on two c...

Medical students are attracted by the prospect of a meaningful addition to their clinical work. Engineering students are excited by a unique opportunity to learn directly alongside their medical student peers. For both, as well as the scientific community at large, the boutique program at the University of Southern California (USC) linking engineer...

Fitts' Law describes the speed-accuracy trade-off of human movements, and it is an elegant strategy that compensates for random and uncontrollable noise in the motor system. The control strategy during targeted movements may also take into account the rewards or costs of any outcomes that may occur. The aim of this study was to test the hypothesis...

Children with cerebral palsy often have a mixture of multiple disorders of movement that interact with each other and with the developmental process. While this complicates the process of symptomatic diagnosis, there is nevertheless a close link between clinical impairments and the underlying etiology and distribution of injury. I describe the majo...

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 discret...

Muscle synergies are hypothesized to represent motor modules recruited by the nervous system to flexibly perform subtasks necessary to achieve movement. Muscle synergy analysis may offer a better view of the neural structure underlying motor behaviors and how they change in motor deficits and rehabilitation. The aim of this study is to investigate...

Date Presented 4/16/2015 To inform the refinement and development of occupational therapy interventions addressing sensory integration deficits, the researchers document brain connectivity between known sensory and motor neural structures within typically developing children and those with autism using advanced neuroimaging techniques.

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 mu...

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patient...

Objective. Childhood dystonia is a movement disorder that interferes with daily movements and can have a devastating effect on quality of life for children and their families. Although injury to basal ganglia is associated with dystonia, the neurophysiological mechanisms leading to the clinical manifestations of dystonia are not understood. Previou...

The role of motor uncertainty in discrete or static space tasks, such as pointing tasks, has been investigated in many experiments. These studies have shown that humans hold an internal representation of intrinsic and extrinsic motor uncertainty and compensate for this variability when planning movement. The aim of this study was to investigate how...

Motor speed and accuracy are both affected in childhood dystonia. Thus, deriving a speed-accuracy function is an important metric for assessing motor impairments in dystonia. Previous work in dystonia studied the speed-accuracy trade-off during point-to-point tasks. To achieve a more relevant measurement of functional abilities in dystonia, the pre...

Abnormal motor cortex activity is common in dystonia. Cathodal transcranial direct current stimulation may alter cortical activity by decreasing excitability while anodal stimulation may increase motor learning. Previous results showed that a single session of cathodal transcranial direct current stimulation can improve symptoms in childhood dyston...

For children with severe cerebral palsy (CP), social and emotional interactions can be significantly limited due to impaired speech motor function. However, if it is possible to extract continuous voluntary control signals from the electromyograph (EMG) of limb muscles, then EMG may be used to drive the synthesis of intelligible speech with control...

In this study, we test the feasibility of the synergy-based approach for application in the realistic and clinically-oriented framework of multi-DOF robotic control. We developed and tested online, on ten able-bodied subjects, a semi-supervised method to achieve simultaneous, continuous control of two DOFs of a robotic arm, using muscle synergies e...

The lack of multi-scale empirical measurements (e.g., recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a syntheti...

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...