Publications
Robotics and Motor Control
Robot-Driven Locomotor Perturbations Reveal Synergy-Mediated, Context-Dependent Feedforward and Feedback Mechanisms of Adaptation
Humans respond to mechanical perturbations that affect their gait by changing their motor control strategy. Previous work indicates that adaptation during gait is context-dependent, and perturbations altering long-term stability are compensated for even at the cost of higher energy expenditure. However, it is unclear if gait adaptation is driven by unilateral or bilateral mechanisms, and what the roles of feedback and feedforward control are in the generation of compensatory responses. Here, we used a robot-based adaptation paradigm to investigate if feedback/feedforward and unilateral/bilateral contributions to locomotor adaptation are also context-dependent in healthy adults. A robot was used to induce two opposite unilateral mechanical perturbations affecting the step length over multiple gait cycles. Electromyographic signals were collected and analyzed to determine how muscle synergies change in response to perturbations. The results unraveled different unilateral modulation dynamics of the muscle-synergy activations during adaptation, characterized by the combination of a slow-progressive feedforward process and a fast-reactive feedback-driven process. The relative unilateral contributions of the two processes to motor-output adjustments, however, depended on which perturbation was delivered. Overall, these observations provide evidence that, in humans, both descending and afferent drives project onto the same spinal interneuronal networks that encode locomotor muscle synergies.
Robot-induced perturbations of human walking reveal a selective generation of motor adaptation
The processes underlying the generation of motor adaptation in response to mechanical perturbations during human walking have been subject to debate. We used a robotic system to apply mechanical perturbations to step length and step height over consecutive gait cycles. Specifically, we studied perturbations affecting only step length, only step height, and step length and height in combination. Both step-length and step-height perturbations disrupt normal walking patterns, but step-length perturbations have a far greater impact on locomotor stability. We found a selective process of motor adaptation in that participants failed to adapt to step-height perturbations but strongly adapted to step-length perturbations, even when these adaptations increased metabolic cost. These results indicate that motor adaptation during human walking is primarily driven by locomotor stability, and only secondarily by energy expenditure and walking pattern preservation. These findings have substantial implications for the design of protocols for robot-assisted gait rehabilitation.
Design of a gait training device for control of pelvic obliquity
This paper presents the design and testing of a novel device for the control of pelvic obliquity during gait. The device, called the Robotic Gait Rehabilitation (RGR) Trainer, consists of a single actuator system designed to target secondary gait deviations, such as hip-hiking, affecting the movement of the pelvis. Secondary gait deviations affecting the pelvis are generated in response to primary gait deviations (e.g. limited knee flexion during the swing phase) in stroke survivors and contribute to the overall asymmetrical gait pattern often observed in these patients. The proposed device generates a force field able to affect the obliquity of the pelvis (i.e. the rotation of the pelvis around the anteroposterior axis) by using an impedance-controlled single linear actuator acting on a hip orthosis. Tests showed that the RGR Trainer is able to induce changes in pelvic obliquity trajectories (hip-hiking) in healthy subjects. These results suggest that the RGR Trainer is suitable to test the hypothesis that has motivated our efforts toward developing the system, namely that addressing both primary and secondary gait deviations during robotic-assisted gait training may help promote a physiologically-sound gait behavior more effectively than when only primary deviations are addressed.
Subsensory stochastic electrical stimulation targeting muscle afferents alters gait control during locomotor adaptations to haptic perturbations
Subsensory noise stimulation targeting sensory receptors has been shown to improve balance control in healthy and impaired individuals. However, the potential for application of this technique in other contexts is still unknown. Gait control and adaptation rely heavily on the input from proprioceptive organs in the muscles and joints. Here we investigated the use of subsensory noise stimulation as a means to influence motor control by altering proprioception during locomotor adaptations to forces delivered by a robot. The forces increase step length unilaterally and trigger an adaptive response that restores the original symmetry. Healthy participants performed two adaptation experiments, one with stimulation applied to the hamstring muscles and one without. We found that participants adapted faster but to a lesser extent when undergoing stimulation.
Clinical Applications of Statistical Methods, Machine Learning, and Artificial Intelligence
Machine learning to predict passenger mortality and hospital length of stay following motor vehicle collision
Motor vehicle collisions (MVCs) account for 1.35 million deaths and cost $518 billion US dollars each year worldwide, disproportionately affecting young patients and low-income nations. The ability to successfully anticipate clinical outcomes will help physicians form effective management strategies and counsel families with greater accuracy. The authors aimed to train several classifiers, including a neural network model, to accurately predict MVC outcomes.
Deep learning for robust detection of interictal epileptiform discharges
Automatic detection of interictal epileptiform discharges (IEDs, short as 'spikes') from an epileptic brain can help predict seizure recurrence and support the diagnosis of epilepsy. Developing fast, reliable, and robust detection methods for IEDs based on scalp or intracranial electroencephalogram (iEEG) may facilitate online seizure monitoring and closed-loop neurostimulation.
Return of intracranial beta oscillations and traveling waves with recovery from traumatic brain injury
Beta oscillations (13-30 Hz) are a prominent feature of neural activity in the healthy human brain and are central to theories of motor and cognitive function. However, little is known about how these oscillations are affected by traumatic brain injury (TBI) and how they relate to recovery of consciousness. We report the case of a patient undergoing electrocorticographic (ECoG) monitoring for epilepsy surgery following severe TBI. We investigated the spatial and temporal properties of intracranial beta oscillations and their relationship to motor and cognitive recovery.
Brain-Computer Interfaces
Brain-Computer Interface, Neuromodulation, and Neurorehabilitation Strategies for Spinal Cord Injury
As neural bypass interfacing, neuromodulation, and neurorehabilitation continue to evolve, there is growing recognition that combination therapies may achieve superior results. This article briefly introduces these broad areas of active research and lays out some of the current evidence for their use for patients with spinal cord injury.
Implantable brain-computer interface for neuroprosthetic-enabled volitional hand grasp restoration in spinal cord injury
Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in one 21-year-old male subject with complete cervical quadriplegia (C5 American Spinal Injury Association Impairment Scale A) using a portable fully implanted brain-computer interface within the home environment. The brain-computer interface consists of subdural surface electrodes placed over the dominant-hand motor cortex and connects to a transmitter implanted subcutaneously below the clavicle, which allows continuous reading of the electrocorticographic activity. Movement-intent was used to trigger functional electrical stimulation of the dominant hand during an initial 29-weeks laboratory study and subsequently via a mechanical hand orthosis during in-home use. Movement-intent information could be decoded consistently throughout the 29-week in-laboratory study with a mean accuracy of 89.0% (range 78-93.3%). Improvements were observed in both the speed and accuracy of various upper extremity tasks, including lifting small objects and transferring objects to specific targets. At-home decoding accuracy during open-loop trials reached an accuracy of 91.3% (range 80-98.95%) and an accuracy of 88.3% (range 77.6-95.5%) during closed-loop trials. Importantly, the temporal stability of both the functional outcomes and decoder metrics were not explored in this study. A fully implanted brain-computer interface can be safely used to reliably decode movement-intent from the motor cortex, allowing for accurate volitional control of hand grasp.
Design-development of an at-home modular brain-computer interface (BCI) platform in a case study of cervical spinal cord injury
The objective of this study was to develop a portable and modular brain-computer interface (BCI) software platform independent of input and output devices. We implemented this platform in a case study of a subject with cervical spinal cord injury (C5 ASIA A).
5-year follow-up of a fully implanted brain-computer interface in a spinal cord injury patient
Spinal cord injury (SCI) affects over 250 000 individuals in the US. Brain-computer interfaces (BCIs) may improve quality of life by controlling external devices. Invasive intracortical BCIs have shown promise in clinical trials but degrade in the chronic period and tether patients to acquisition hardware. Alternatively, electrocorticography (ECoG) records data from electrodes on the cortex. This study presents the long-term feasibility and viability of an ECoG-based BCI system that persists in the home environment in a case of SCI. The study analyzed data from the patient's home environment over 54 months, revealing stable event-related desynchronization and a decoder average AUROC of 0.959. Importantly, 40 months of the data collected was gathered from the subject's home or community environment.
Brain-Computer interface control of stepping from invasive electrocorticography upper-limb motor imagery in a patient with quadriplegia
Most spinal cord injuries (SCI) result in lower extremities paralysis, thus diminishing ambulation. Using brain-computer interfaces (BCI), patients may regain leg control using neural signals that actuate assistive devices. Here, we present a case of a subject with cervical SCI with an implanted electrocorticography (ECoG) BCI to restore stepping movements. The subject was able to use upper-limb motor imagery decoded from the ECoG signals to control a functional electrical stimulation system for lower-limb stepping, demonstrating the feasibility of cross-limb BCI control for locomotion restoration.
Epilepsy
Ablation dynamics during laser interstitial thermal therapy for mesiotemporal epilepsy
The recent emergence of laser interstitial thermal therapy (LITT) as a frontline surgical tool in the management of brain tumors and epilepsy is a result of advances in MRI thermal imaging. A limitation to further improving LITT is the diversity of brain tissue thermoablative properties, which hinders our ability to predict LITT treatment-related effects. Utilizing the mesiotemporal lobe as a consistent anatomic model system, the goal of this study was to use intraoperative thermal damage estimate (TDE) maps to study short- and long-term effects of LITT and to identify preoperative variables that could be helpful in predicting tissue responses to thermal energy.
Neural fragility as an EEG marker of the seizure onset zone
Over 15 million patients with epilepsy worldwide do not respond to drugs. Successful surgical treatment requires complete removal or disconnection of the seizure onset zone (SOZ), brain region(s) where seizures originate. Unfortunately, surgical success rates vary between 30 and 70% because no clinically validated biological marker of the SOZ exists. We develop and retrospectively validate a new electroencephalogram (EEG) marker-neural fragility-in a retrospective analysis of 91 patients by using neural fragility of the annotated SOZ as a metric to predict surgical outcomes. Fragility predicts 43 out of 47 surgical failures, with an overall prediction accuracy of 76% compared with the accuracy of clinicians at 48% (successful outcomes). In failed outcomes, we identify fragile regions that were untreated. When compared to 20 EEG features proposed as SOZ markers, fragility outperformed in predictive power and interpretability, which suggests neural fragility as an EEG biomarker of the SOZ.
Long-term seizure and psychiatric outcomes following laser ablation of mesial temporal structures
Postsurgical seizure outcome following laser interstitial thermal therapy (LiTT) for the management of drug-resistant mesial temporal lobe epilepsy (MTLE) has been limited to 2 years. Furthermore, its impact on presurgical mood and anxiety disorders has not been investigated. The objectives of this study were (1) to identify seizure outcome changes over a period ranging from 18 to 81 months; (2) to investigate the seizure-free rate in the last follow-up year; (3) to identify the variables associated with seizure freedom; and (4) to identify the impact of LiTT on presurgical mood and anxiety disorders.
The sixth sense: how much does interictal intracranial EEG add to determining the focality of epileptic networks?
Intracranial EEG is used for two main purposes: to determine (i) if epileptic networks are amenable to focal treatment and (ii) where to intervene. Currently, these questions are answered qualitatively and differently across centres. There is a need to quantify the focality of epileptic networks systematically, which may guide surgical decision-making, enable large-scale data analysis and facilitate multi-centre prospective clinical trials. We analysed interictal data from 101 patients with drug-resistant epilepsy who underwent pre-surgical evaluation with intracranial EEG at a single centre.
Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study
Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported.
Thalamic stereo-EEG in epilepsy surgery: where do we stand?
This review examines the current role and future potential of thalamic stereo-electroencephalography (SEEG) in the surgical evaluation of epilepsy, exploring how thalamic recordings can inform our understanding of seizure networks and improve surgical outcomes.
Modern intracranial electroencephalography for epilepsy localization with combined subdural grid and depth electrodes with low and improved hemorrhagic complication rates
Recent trends have moved from subdural grid electrocorticography (ECoG) recordings toward stereo-electroencephalography (SEEG) depth electrodes for intracranial localization of seizures, in part because of perceived morbidity from subdural grid and strip electrodes. For invasive epilepsy monitoring, the authors describe the outcomes of a hybrid approach, whereby patients receive a combination of subdural grids, strips, and frameless stereotactic depth electrode implantations through a craniotomy. Evolution of surgical techniques was employed to reduce complications.
Movement Disorders
Freezing of Gait in Parkinson's Disease: Invasive and Noninvasive Neuromodulation
Freezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with the perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life.
Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation
There is a pressing and unmet need for effective therapies for freezing of gait (FOG) and other neurological gait disorders. Deep brain stimulation (DBS) of a midbrain target known as the pedunculopontine nucleus (PPN) was proposed as a potential treatment based on its postulated involvement in locomotor control as part of the mesencephalic locomotor region (MLR). However, DBS trials fell short of expectations, leading many clinicians to abandon this strategy. Here, we discuss the potential reasons for this failure and review recent clinical data along with preclinical optogenetics evidence to argue that another nearby nucleus, the cuneiform nucleus (CnF), may be a superior target.
MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson's Disease Patient With Levodopa-Resistant Freezing of Gait
Freezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson's Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.
Effect of Motor Imagery on Tremor in a Patient With Parkinson Disease Undergoing Intraoperative Testing
This study reports the effect of motor imagery on tremor in a patient with Parkinson disease undergoing intraoperative testing during deep brain stimulation surgery, providing insights into the neural mechanisms of tremor modulation.
The social deprivation index and deep brain stimulation: A cohort study
Deep brain stimulation (DBS) is an important treatment option for patients with movement disorders; however, prior studies have demonstrated inequitable access to this important treatment. We used the Social Deprivation Index (SDI), an index of neighborhood affluence, to examine the distribution of DBS cases and to determine the association between the SDI and outcomes. This was a retrospective cohort study of all patients who have undergone DBS implantation within the University of Pennsylvania Health System from January 2013 to April 2024.
Correlation of the clinical rating scale for tremor with a global assessment
The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (CRST) includes three parts (tremor severity, motor task performance, functional disability) and a separate global assessment of impairment completed by both the patient and examiner. Although the CRST is used to determine tremor severity and the efficacy of treatments for tremor, the instrument may not sufficiently capture the patient's perspective. The objective of this study was to determine the association of the CRST subpart and total scores with the global assessment.
Intraprocedural Three-Dimensional Imaging Registration Optimizes Magnetic Resonance Imaging-Guided Focused Ultrasound and Facilitates Novel Applications
Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has revolutionized ablative treatment of essential tremor in recent years. However, limitations in precision targeting may account for suboptimal efficacy and significant side effects. We describe a simple intraprocedural three-dimensional image-guided lesion shaping technique that can improve overall outcomes of MRgFUS for essential tremor and facilitate expansion to novel indications.
Reasons for Hospitalizations and Emergency Department Visits Among Patients with Essential Tremor
Prior studies suggest that patients with essential tremor (ET) have increased rates of healthcare utilization, but the reason for this increased use is unknown. This was a retrospective cross-sectional study of ET patients with an admission or emergency department (ED) visit at a tertiary health system from 2018-2023. Patients were matched on an encounter level with control patients based on propensity scores incorporating age, sex, race, and co-morbid conditions.
Validation of the International Classification of Diseases, Tenth Revision-Clinical Modification Diagnostic Code for Essential Tremor
The positive predictive value (PPV) of the ICD-9-CM code for essential and other specified forms of tremor in identifying essential tremor (ET) cases was found to be less than 50%. The ability of the ICD-10-CM G25.0 code for essential tremor to identify ET has not been determined. Patients in a tertiary health system with a primary care encounter associated with ICD-10-CM code G25.0 in 2022 underwent medical record review to determine if the consensus criteria from the International Parkinson and Movement Disorder Society were met.
Cerebellar deep brain stimulation for the treatment of movement disorders in cerebral palsy
Cerebral palsy (CP) represents the most common childhood physical disability that encompasses disorders of movement and posture attributed to nonprogressive disturbances that occurred in the developmental fetal or infant brain. Dyskinetic CP (DCP), the second most common type of CP after spastic forms, refers to a subset of patients in whom dystonia and choreoathetosis are the predominant motor manifestations. This study examines cerebellar deep brain stimulation as a treatment option for movement disorders in cerebral palsy.
Cerebellar Deep Brain Stimulation in Cerebral Palsy: Promising Early Results and a Look Forward to a Larger Clinical Trial
This report presents promising early results of cerebellar deep brain stimulation in cerebral palsy patients and outlines the path forward toward a larger clinical trial to further evaluate the safety and efficacy of this novel approach.
Neuromodulation
Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide
Obesity and related conditions are associated with distressing food preoccupation that often culminates in dysregulated eating behaviors. Incretin-based therapies can reduce excessive weight in obesity, but their impact on dysregulated eating behaviors remains largely unexamined. Understanding how these pharmacologics engage the brain's mesolimbic circuitry may inform the expansion of their therapeutic potential. We report a rare, first-in-human exploration of the physiological action of these therapies by examining the electrophysiology directly within the human nucleus accumbens.
Stereoelectroencephalography Electrode Implantation for Inpatient Workup of Treatment-Resistant Depression
Treatment-resistant depression is a leading cause of disability. Our center's trial for neurosurgical intervention for treatment-resistant depression involves a staged workup for implantation of a personalized, closed-loop neuromodulation device for refractory depression. The first stage of workup involves implantation of 10 stereoelectroencephalography (SEEG) electrodes bilaterally into 5 anatomically defined brain regions and involves a specialized preoperative imaging and planning workup and a frame-based operating protocol.
Pain
A surgical decision aid for occipital neuralgia with literature review and single center case series
Occipital neuralgia (ON) is a debilitating headache disorder. Due to the rarity of this disorder and lack of high-level evidence, a clear framework for choosing the optimal surgical approach for medically refractory ON incorporating shared decision making with patients does not exist. A literature review of studies reporting pain outcomes of patients who underwent surgical treatment for ON was performed, as well as a retrospective chart review of patients who underwent surgery for ON within our institution.