Deep Brain Stimulation for Refractory Status Dystonicus in Children: Multicenter Case Series and Systematic Review.

OBJECTIVE: We sought to better understand the workflow, outcomes, and complications of deep brain stimulation (DBS) for pediatric status dystonicus (SD). We present a systematic review, alongside a multicenter case series of pediatric patients with SD treated with DBS. METHODS: We collected individual data regarding treatment, stimulation parameters, and dystonia severity for a multicenter case series (n = 8) and all previously published cases (n = 77). Data for case series were used to create probabilistic voxelwise maps of stimulated tissue associated with dystonia improvement. RESULTS: In our institutional series, DBS was implanted a mean of 25 days after SD onset. Programming began a mean of 1.6 days after surgery. All 8 patients in our case series and 73 of 74 reported patients in the systematic review had resolution of their SD with DBS, most within 2 to 4 weeks of surgery. Mean follow-up for patients in the case series was 16 months. DBS target for all patients in the case series and 68 of 77 in our systematic review was the globus pallidus pars interna (GPi). In our case series, stimulation of the posterior-ventrolateral GPi was associated with improved dystonia. Mean dystonia improvement was 32% and 51% in our institutional series and systematic review, respectively. Mortality was 4% in the review, which is lower than reported for treatment with pharmacotherapy alone (10-12.5%). INTERPRETATION: DBS is a feasible intervention with potential to reverse refractory pediatric SD and improve survival. More work is needed to increase awareness of DBS in this setting, so that it can be implemented in a timely manner. ANN NEUROL 2023.

Neurophysiological biomarkers to optimize deep brain stimulation in movement disorders.

Intraoperative neurophysiological information could increase accuracy of surgical deep brain stimulation (DBS) lead placement. Subsequently, DBS therapy could be optimized by specifically targeting pathological activity. In Parkinson's disease, local field potentials (LFPs) excessively synchronized in the beta band (13-35 Hz) correlate with akinetic-rigid symptoms and their response to DBS therapy, particularly low beta band suppression (13-20 Hz) and high frequency gamma facilitation (35-250 Hz). In dystonia, LFPs abnormally synchronize in the theta/alpha (4-13 Hz), beta and gamma (60-90 Hz) bands. Phasic dystonic symptoms and their response to DBS correlate with changes in theta/alpha synchronization. In essential tremor, LFPs excessively synchronize in the theta/alpha and beta bands. Adaptive DBS systems will individualize pathological characteristics of neurophysiological signals to automatically deliver therapeutic DBS pulses of specific spatial and temporal parameters.

Bilateral subdural hematomas and retinal hemorrhages mimicking nonaccidental trauma in a patient with D-2-hydroxyglutaric aciduria.

INTRODUCTION: Nonaccidental trauma (NAT) is considered when pediatric patients present with intracranial injuries and a negative history of an accidental injury or concomitant medical diagnosis. The evaluation of NAT should include the consideration of possible medical causes including coagulation, hematologic, metabolic and other genetic disorders, as well as witnessed and unwitnessed accidental injuries. CASE PRESENTATION: We present a 7-month-old male with spells and incidental findings of bilateral subdural hematomas, retinal hemorrhages, and secondary macrocephaly, leading to investigation for NAT. Biochemical analysis showed excretion of a large amount of D-2-hydroxyglutaric in urine consistent with a biochemical diagnosis of D-2-hydroxyglutaric aciduria, a rare neurometabolic disorder characterized by developmental delay, epilepsy, hypotonia, and psychomotor retardation. None of these symptoms were present in our patient at the time of diagnosis. Molecular genetic testing revealed a pathogenic splice site variant (c.685-2A>G) and a variant of uncertain significance (c.1256G>T) with evidence of pathogenicity in the D2HGDH gene, consistent with a molecular diagnosis of D-2-hydroxyglutaric aciduria type I (OMIM #600721). CONCLUSION: Since several metabolic disorders, including D-2-hydroxyglutaric aciduria type I, can present solely with symptoms suggestive of NAT (subdural and retinal hemorrhages), an early metabolic evaluation by urine organic acid analysis should be included in clinical protocols evaluating NAT. A methodical and nonjudgmental approach coordinated between pediatricians and metabolic specialists is also necessary to ensure that rare genetic conditions are not overlooked to prevent devastating social, legal, and financial consequences of suspected child abuse.

Deep brain stimulation for orthostatic tremor: A single-center case series.

BACKGROUND: Orthostatic tremor (OT) is a high-frequency weight-bearing tremor of the legs and trunk associated with progressive disability and is often refractory to medications. Case reports suggest that thalamic deep brain stimulation (DBS) is effective. We report 5 female patients with medication-refractory OT who underwent bilateral thalamic DBS at the Mayo Clinic and assess factors associated with a successful DBS outcome. METHODS: Demographic, clinical, electrophysiology, and DBS data were abstracted. Outcomes were change in tremor-onset latency, standing time, standing ADLs, and patient and clinician global impression of change (PGIC; CGIC). RESULTS: All 5 patients had improved standing time (72 vs 408 seconds, p ≤ 0.001) and improved standing ADLs after surgery, without change in tremor-onset latency (16 vs 75 seconds, p = 0.14). Maximal benefit was reached up to 3 years after surgery and sustained for up to 6 years. CGIC was "much improved" in all; PGIC was "much improved" in 4 and "minimally improved" in 1. There were no major complications. Postoperative electrophysiology (n = 1) showed lower tremor amplitude and slower tremor ramp-up on vs off stimulation. CONCLUSIONS: Bilateral thalamic DBS improved OT symptoms with benefit lasting up to 6 years. A modest increase in standing time of several minutes was associated with meaningful improvement in standing ADLs. Microlesional effect and bilateral stimulation are likely favorable features, while baseline standing time of several minutes may be unfavorable. These findings may inform clinician and patient counseling and require confirmation in larger studies.

Rapidly Progressive Paraplegia in an 11-Year-Old Girl: A Case of Spinal Cord Infarction and Expected Imaging Findings.

Rapidly progressive non-traumatic paraplegia in a child is uncommonly encountered in clinical practice, but is an important presentation to consider given the potential for significant morbidity. We present the case of an 11-year-old girl who was found to have hyperacute paraplegia due to spinal cord infarction. We discuss the appropriate workup, differential diagnosis in children and how this relates to adults; and describe the prognosis and current state of management options for spinal cord infarction.

The Errors of Our Ways: Understanding Error Representations in Cerebellar-Dependent Motor Learning.

The cerebellum is essential for error-driven motor learning and is strongly implicated in detecting and correcting for motor errors. Therefore, elucidating how motor errors are represented in the cerebellum is essential in understanding cerebellar function, in general, and its role in motor learning, in particular. This review examines how motor errors are encoded in the cerebellar cortex in the context of a forward internal model that generates predictions about the upcoming movement and drives learning and adaptation. In this framework, sensory prediction errors, defined as the discrepancy between the predicted consequences of motor commands and the sensory feedback, are crucial for both on-line movement control and motor learning. While many studies support the dominant view that motor errors are encoded in the complex spike discharge of Purkinje cells, others have failed to relate complex spike activity with errors. Given these limitations, we review recent findings in the monkey showing that complex spike modulation is not necessarily required for motor learning or for simple spike adaptation. Also, new results demonstrate that the simple spike discharge provides continuous error signals that both lead and lag the actual movements in time, suggesting errors are encoded as both an internal prediction of motor commands and the actual sensory feedback. These dual error representations have opposing effects on simple spike discharge, consistent with the signals needed to generate sensory prediction errors used to update a forward internal model.

Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation.

The cerebellum is essential in motor learning. At the cellular level, changes occur in both the simple spike and complex spike firing of Purkinje cells. Because simple spike discharge reflects the main output of the cerebellar cortex, changes in simple spike firing likely reflect the contribution of the cerebellum to the adapted behavior. Therefore, we investigated in Rhesus monkeys how the representation of arm kinematics in Purkinje cell simple spike discharge changed during adaptation to mechanical perturbations of reach movements. Monkeys rapidly adapted to a novel assistive or resistive perturbation along the direction of the reach. Adaptation consisted of matching the amplitude and timing of the perturbation to minimize its effect on the reach. In a majority of Purkinje cells, simple spike firing recorded before and during adaptation demonstrated significant changes in position, velocity, and acceleration sensitivity. The timing of the simple spike representations change within individual cells, including shifts in predictive versus feedback signals. At the population level, feedback-based encoding of position increases early in learning and velocity decreases. Both timing changes reverse later in learning. The complex spike discharge was only weakly modulated by the perturbations, demonstrating that the changes in simple spike firing can be independent of climbing fiber input. In summary, we observed extensive alterations in individual Purkinje cell encoding of reach kinematics, although the movements were nearly identical in the baseline and adapted states. Therefore, adaption to mechanical perturbation of a reaching movement is accompanied by widespread modifications in the simple spike encoding.

The cerebellum for jocks and nerds alike.

Historically the cerebellum has been implicated in the control of movement. However, the cerebellum's role in non-motor functions, including cognitive and emotional processes, has also received increasing attention. Starting from the premise that the uniform architecture of the cerebellum underlies a common mode of information processing, this review examines recent electrophysiological findings on the motor signals encoded in the cerebellar cortex and then relates these signals to observations in the non-motor domain. Simple spike firing of individual Purkinje cells encodes performance errors, both predicting upcoming errors as well as providing feedback about those errors. Further, this dual temporal encoding of prediction and feedback involves a change in the sign of the simple spike modulation. Therefore, Purkinje cell simple spike firing both predicts and responds to feedback about a specific parameter, consistent with computing sensory prediction errors in which the predictions about the consequences of a motor command are compared with the feedback resulting from the motor command execution. These new findings are in contrast with the historical view that complex spikes encode errors. Evaluation of the kinematic coding in the simple spike discharge shows the same dual temporal encoding, suggesting this is a common mode of signal processing in the cerebellar cortex. Decoding analyses show the considerable accuracy of the predictions provided by Purkinje cells across a range of times. Further, individual Purkinje cells encode linearly and independently a multitude of signals, both kinematic and performance errors. Therefore, the cerebellar cortex's capacity to make associations across different sensory, motor and non-motor signals is large. The results from studying how Purkinje cells encode movement signals suggest that the cerebellar cortex circuitry can support associative learning, sequencing, working memory, and forward internal models in non-motor domains.

Purkinje cell simple spike discharge encodes error signals consistent with a forward internal model.

Processing motor errors is essential for online control of goal-directed movements and motor learning. Evidence from psychophysical and imaging studies supports the long-standing view that error processing is central to cerebellar function. The dominant view is that error-related signals are encoded in the complex spike discharge of Purkinje cells. However, the findings are inconsistent on whether complex spike activity correlates with motor errors. Recently, we examined if simple spike firing carries error signals in monkeys trained to manually track a randomly moving target. The task requires continuous processing of motor errors characterized by the relative movements between the hand-driven cursor and the target center. Linear regression models show that error parameters are robustly represented in the simple spike activity of most Purkinje cells. At the single cell level, the error signals are encoded independently and integrated with kinematic signals. In a large majority of Purkinje cells, correlation strengths between the simple spike discharge and an error parameter have bimodal profiles with respect to time, exhibiting a local maxima corresponding to firing leading the behavior and another one corresponding to firing lagging behavior. The bimodal temporal profiles suggest that individual error parameters are dually encoded as both an internal prediction used for feedback-independent, compensatory movements and the actual sensory feedback used to monitor performance. Approximately 75 % of the dual representations have opposing modulations of the simple spike activity, one increasing firing and the other depressing firing, as reflected by the reversed signs of the regression coefficients corresponding to the local maxima of the R (2) profile. These dual representations of individual parameters with opposing modulation of the simple spike firing are consistent with the signals needed to generate sensory prediction errors used to update an internal model.

Predictive and feedback performance errors are signaled in the simple spike discharge of individual Purkinje cells.

The cerebellum has been implicated in processing motor errors required for on-line control of movement and motor learning. The dominant view is that Purkinje cell complex spike discharge signals motor errors. This study investigated whether errors are encoded in the simple spike discharge of Purkinje cells in monkeys trained to manually track a pseudorandomly moving target. Four task error signals were evaluated based on cursor movement relative to target movement. Linear regression analyses based on firing residuals ensured that the modulation with a specific error parameter was independent of the other error parameters and kinematics. The results demonstrate that simple spike firing in lobules IV-VI is significantly correlated with position, distance, and directional errors. Independent of the error signals, the same Purkinje cells encode kinematics. The strongest error modulation occurs at feedback timing. However, in 72% of cells at least one of the R(2) temporal profiles resulting from regressing firing with individual errors exhibit two peak R(2) values. For these bimodal profiles, the first peak is at a negative τ (lead) and a second peak at a positive τ (lag), implying that Purkinje cells encode both prediction and feedback about an error. For the majority of the bimodal profiles, the signs of the regression coefficients or preferred directions reverse at the times of the peaks. The sign reversal results in opposing simple spike modulation for the predictive and feedback components. Dual error representations may provide the signals needed to generate sensory prediction errors used to update a forward internal model.

Representation of limb kinematics in Purkinje cell simple spike discharge is conserved across multiple tasks.

Encoding of movement kinematics in Purkinje cell simple spike discharge has important implications for hypotheses of cerebellar cortical function. Several outstanding questions remain regarding representation of these kinematic signals. It is uncertain whether kinematic encoding occurs in unpredictable, feedback-dependent tasks or kinematic signals are conserved across tasks. Additionally, there is a need to understand the signals encoded in the instantaneous discharge of single cells without averaging across trials or time. To address these questions, this study recorded Purkinje cell firing in monkeys trained to perform a manual random tracking task in addition to circular tracking and center-out reach. Random tracking provides for extensive coverage of kinematic workspaces. Direction and speed errors are significantly greater during random than circular tracking. Cross-correlation analyses comparing hand and target velocity profiles show that hand velocity lags target velocity during random tracking. Correlations between simple spike firing from 120 Purkinje cells and hand position, velocity, and speed were evaluated with linear regression models including a time constant, τ, as a measure of the firing lead/lag relative to the kinematic parameters. Across the population, velocity accounts for the majority of simple spike firing variability (63 ± 30% of R(adj)(2)), followed by position (28 ± 24% of R(adj)(2)) and speed (11 ± 19% of R(adj)(2)). Simple spike firing often leads hand kinematics. Comparison of regression models based on averaged vs. nonaveraged firing and kinematics reveals lower R(adj)(2) values for nonaveraged data; however, regression coefficients and τ values are highly similar. Finally, for most cells, model coefficients generated from random tracking accurately estimate simple spike firing in either circular tracking or center-out reach. These findings imply that the cerebellum controls movement kinematics, consistent with a forward internal model that predicts upcoming limb kinematics.

What features of limb movements are encoded in the discharge of cerebellar neurons?

This review examines the signals encoded in the discharge of cerebellar neurons during voluntary arm and hand movements, assessing the state of our knowledge and the implications for hypotheses of cerebellar function. The evidence for the representation of forces, joint torques, or muscle activity in the discharge of cerebellar neurons is limited, questioning the validity of theories that the cerebellum directly encodes the motor command. In contrast, kinematic parameters such as position, direction, and velocity are widely and robustly encoded in the activity of cerebellar neurons. These findings favor hypotheses that the cerebellum plans or controls movements in a kinematic framework, such as the proposal that the cerebellum provides a forward internal model. Error signals are needed for on-line correction and motor learning, and several hypotheses postulate the need for their representations in the cerebellum. Error signals have been described mostly in the complex spike discharge of Purkinje cells, but no consensus has emerged on the exact information signaled by complex spikes during limb movements. Newer studies suggest that simple spike firing may also encode error signals. Finally, Purkinje cells located more posterior and laterally in the cerebellar cortex and dentate neurons encode nonmotor, task-related signals such as visual cues. These results suggest that cerebellar neurons provide a complement of information about motor behaviors. We assert that additional single unit studies are needed using rich movement paradigms, given the power of this approach to directly test specific hypotheses about cerebellar function.

The effects of lingual exercise in stroke patients with dysphagia.

OBJECTIVE: To examine the effects of lingual exercise on swallowing recovery poststroke. DESIGN: Prospective cohort intervention study, with 4- and 8-week follow-ups. SETTING: Dysphagia clinic, tertiary care center. PARTICIPANTS: Ten stroke patients (n=6, acute: < or =3mo poststroke; n=4, chronic: >3mo poststroke), age 51 to 90 years (mean, 69.7y). INTERVENTION: Subjects performed an 8-week isometric lingual exercise program by compressing an air-filled bulb between the tongue and the hard palate. MAIN OUTCOME MEASURES: Isometric and swallowing lingual pressures, bolus flow parameters, diet, and a dysphagia-specific quality of life questionnaire were collected at baseline, week 4, and week 8. Three of the 10 subjects underwent magnetic resonance imaging at each time interval to measure lingual volume. RESULTS: All subjects significantly increased isometric and swallowing pressures. Airway invasion was reduced for liquids. Two subjects increased lingual volume. CONCLUSIONS: The findings indicate that lingual exercise enables acute and chronic dysphagic stroke patients to increase lingual strength with associated improvements in swallowing pressures, airway protection, and lingual volume.

The effects of lingual exercise on swallowing in older adults.

OBJECTIVES: To determine the effects of an 8-week progressive lingual resistance exercise program on swallowing in older individuals, the most "at risk" group for dysphagia. DESIGN: Prospective cohort intervention study. SETTING: Subjects were recruited from the community at large. PARTICIPANTS: Ten healthy men and women aged 70 to 89. INTERVENTION: Each subject performed an 8-week lingual resistance exercise program consisting of compressing an air-filled bulb between the tongue and hard palate. MEASUREMENTS: At baseline and Week 8, each subject completed a videofluoroscopic swallowing evaluation for kinematic and bolus flow assessment of swallowing. Swallowing pressures and isometric pressures were collected at baseline and Weeks 2, 4, and 6. Four of the subjects also underwent oral magnetic resonance imaging (MRI) to measure lingual volume. RESULTS: All subjects significantly increased their isometric and swallowing pressures. All subjects who had the MRI demonstrated increased lingual volume of an average of 5.1%. CONCLUSION: The findings indicate that lingual resistance exercise is promising not only for preventing dysphagia due to sarcopenia, but also as a treatment strategy for patients with lingual weakness and swallowing disability due to frailty or other age-related conditions. The potential effect of lingual exercise on reducing dysphagia-related comorbidities (pneumonia, malnutrition, and dehydration) and healthcare costs while improving quality of life is encouraging.