Systematic review of rodent studies of deep brain stimulation for the treatment of neurological, developmental and neuropsychiatric disorders.

Deep brain stimulation (DBS) modulates local and widespread connectivity in dysfunctional networks. Positive results are observed in several patient populations; however, the precise mechanisms underlying treatment remain unknown. Translational DBS studies aim to answer these questions and provide knowledge for advancing the field. Here, we systematically review the literature on DBS studies involving models of neurological, developmental and neuropsychiatric disorders to provide a synthesis of the current scientific landscape surrounding this topic. A systematic analysis of the literature was performed following PRISMA guidelines. 407 original articles were included. Data extraction focused on study characteristics, including stimulation protocol, behavioural outcomes, and mechanisms of action. The number of articles published increased over the years, including 16 rat models and 13 mouse models of transgenic or healthy animals exposed to external factors to induce symptoms. Most studies targeted telencephalic structures with varying stimulation settings. Positive behavioural outcomes were reported in 85.8% of the included studies. In models of psychiatric and neurodevelopmental disorders, DBS-induced effects were associated with changes in monoamines and neuronal activity along the mesocorticolimbic circuit. For movement disorders, DBS improves symptoms via modulation of the striatal dopaminergic system. In dementia and epilepsy models, changes to cellular and molecular aspects of the hippocampus were shown to underlie symptom improvement. Despite limitations in translating findings from preclinical to clinical settings, rodent studies have contributed substantially to our current knowledge of the pathophysiology of disease and DBS mechanisms. Direct inhibition/excitation of neural activity, whereby DBS modulates pathological oscillatory activity within brain networks, is among the major theories of its mechanism. However, there remain fundamental questions on mechanisms, optimal targets and parameters that need to be better understood to improve this therapy and provide more individualized treatment according to the patient's predominant symptoms.

Recommendations for the Management of Initial and Refractory Pediatric Status Dystonicus.

Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.

Epidural Spinal Cord Stimulation for Spasticity: a Systematic Review of the Literature.

OBJECTIVE: Spasticity is a form of muscle hypertonia secondary to various diseases, including traumatic brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis. Medical treatments are available; however, these often result in insufficient clinical response. This review evaluates the role of epidural spinal cord stimulation (SCS) in the treatment of spasticity and associated functional outcomes. METHODS: A systematic review of the literature was performed using the Embase, CENTRAL, and MEDLINE databases. We included studies that used epidural SCS to treat spasticity. Studies investigating functional electric stimulation, transcutaneous SCS, and animal models of spasticity were excluded. We also excluded studies that used SCS to treat other symptoms such as pain. RESULTS: Thirty-four studies were included in the final analysis. The pooled rate of subjective improvement in spasticity was 78% (95% confidence interval, 64%-91%; I2 = 77%), 40% (95% confidence interval, 7%-73%; I2 = 88%) for increased H-reflex threshold or decreased Hoffman reflex/muscle response wave ratio, and 73% (65%-80%; I2 = 50%) for improved ambulation. Patients with spinal causes had better outcomes compared with patients with cerebral causes. Up to 10% of patients experienced complications including infections and hardware malfunction. CONCLUSIONS: Our review of the literature suggests that SCS may be a safe and useful tool for the management of spasticity; however, there is significant heterogeneity among studies. The quality of studies is also low. Further studies are needed to fully evaluate the usefulness of this technology, including various stimulation paradigms across different causes of spasticity.

Postoperative cerebellar mutism syndrome is an acquired Autism-like network disturbance.

BACKGROUND: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. METHODS: In this study, we analyzed post-operative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and paediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n=427). RESULTS: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the paediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours. CONCLUSIONS: Our findings indicate that CMS-associated lesions result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

Evaluating the ability of a predictive vision-based machine learning model to measure changes in gait in response to medication and DBS within individuals with Parkinson's disease.

INTRODUCTION: Gait impairments in Parkinson's disease (PD) are treated with dopaminergic medication or deep-brain stimulation (DBS), although the magnitude of the response is variable between individuals. Computer vision-based approaches have previously been evaluated for measuring the severity of parkinsonian gait in videos, but have not been evaluated for their ability to identify changes within individuals in response to treatment. This pilot study examines whether a vision-based model, trained on videos of parkinsonism, is able to detect improvement in parkinsonian gait in people with PD in response to medication and DBS use. METHODS: A spatial-temporal graph convolutional model was trained to predict MDS-UPDRS-gait scores in 362 videos from 14 older adults with drug-induced parkinsonism. This model was then used to predict MDS-UPDRS-gait scores on a different dataset of 42 paired videos from 13 individuals with PD, recorded while ON and OFF medication and DBS treatment during the same clinical visit. Statistical methods were used to assess whether the model was responsive to changes in gait in the ON and OFF states. RESULTS: The MDS-UPDRS-gait scores predicted by the model were lower on average (representing improved gait; p = 0.017, Cohen's d = 0.495) during the ON medication and DBS treatment conditions. The magnitude of the differences between ON and OFF state was significantly correlated between model predictions and clinician annotations (p = 0.004). The predicted scores were significantly correlated with the clinician scores (Kendall's tau-b = 0.301, p = 0.010), but were distributed in a smaller range as compared to the clinician scores. CONCLUSION: A vision-based model trained on parkinsonian gait did not accurately predict MDS-UPDRS-gait scores in a different PD cohort, but detected weak, but statistically significant proportional changes in response to medication and DBS use. Large, clinically validated datasets of videos captured in many different settings and treatment conditions are required to develop accurate vision-based models of parkinsonian gait.

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.

Chronic Pallidal Local Field Potentials Are Associated With Dystonic Symptoms in Children.

BACKGROUND: Novel deep brain stimulation devices can record local field potentials (LFPs), which represent the synchronous synaptic activity of neuronal populations. The clinical relevance of LFPs in patients with dystonia remains unclear. OBJECTIVES: We sought to determine whether chronic LFPs recorded from the globus pallidus internus (GPi) were associated with symptoms of dystonia in children. MATERIALS AND METHODS: Ten patients with heterogeneous forms of dystonia (genetic and acquired) were implanted with neurostimulators that recorded LFP spectral snapshots. Spectra were compared across parent-reported asymptomatic and symptomatic periods, with daily narrowband data superimposed in 24 one-hour bins. RESULTS: Spectral power increased during periods of registered dystonic symptoms: mean increase = 102%, CI: (76.7, 132). Circadian rhythms within the LFP narrowband time series correlated with dystonic symptoms: for delta/theta-waves, correlation = 0.33, CI: (0.18, 0.47) and for alpha waves, correlation = 0.27, CI: (0.14, 0.40). CONCLUSIONS: LFP spectra recorded in the GPi indicate a circadian pattern and are associated with the manifestation of dystonic symptoms.

Hemiatrophy-hemiparkinsonism and Poland syndrome: A causative or coincidental association?

Despite various neurologic symptoms of Poland syndrome (PS), parkinsonism was never reported in PS, and the response to the treatment of parkinsonism was not studied before. We report a case of ipsilateral parkinsonism in PS, similar to hemiatrophy-hemiparkinsonism, with a good response to levodopa and subthalamic deep brain stimulation.

Which is more deleterious to cognitive performance? Interictal epileptiform discharges vs anti-seizure medication.

Children with epilepsy commonly have comorbid neurocognitive impairments that severely affect their psychosocial well-being, education, and future career prospects. Although the provenance of these deficits is multifactorial, the effects of interictal epileptiform discharges (IEDs) and anti-seizure medications (ASMs) are thought to be particularly severe. Although certain ASMs can be leveraged to inhibit IED occurrence, it remains unclear whether epileptiform discharges or the medications themselves are most deleterious to cognition. To examine this question, 25 children undergoing invasive monitoring for refractory focal epilepsy performed one or more sessions of a cognitive flexibility task. Electrophysiological data were recorded to detect IEDs. Between repeated sessions, prescribed ASMs were either continued or titrated to <50% of the baseline dose. Hierarchical mixed-effects modeling assessed the relationship between task reaction time (RT), IED occurrence, ASM type, and dose while controlling for seizure frequency. Both presence (ß ± SE = 49.91 ± 16.55 ms, p = .003) and number of IEDs (ß ± SE = 49.84 ± 12.51 ms, p < .001) were associated with slowed task RT. Higher dose oxcarbazepine significantly reduced IED frequency (p = .009) and improved task performance (ß ± SE = -107.43 ± 39.54 ms, p = .007). These results emphasize the neurocognitive consequences of IEDs independent of seizure effects. Furthermore, we demonstrate that inhibition of IEDs following treatment with select ASMs is associated with improved neurocognitive function.

Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials.

OBJECTIVE: The antiseizure effects of vagus nerve stimulation (VNS) are thought to be mediated by the modulation of afferent thalamocortical circuitry. Cross-frequency phase-amplitude coupling (PAC) is a mechanism of hierarchical network coordination across multiple spatiotemporal scales. In this study, we leverage local field potential (LFP) recordings from the centromedian (CM) (n = 3) and anterior (ATN) (n = 2) nuclei in five patients with tandem thalamic deep brain stimulation and VNS to study neurophysiological changes in the thalamus in response to VNS. MATERIALS AND METHODS: Bipolar LFP data were recorded from contact pairs spanning target nuclei in VNS "on" and "off" states. RESULTS: Active VNS was associated with increased PAC between theta, alpha, and beta phase and gamma amplitude in CM (q < 0.05). Within the ATN, PAC changes also were observed, although these were less robust. In both nuclei, active VNS also modulated interhemispheric bithalamic functional connectivity. CONCLUSIONS: We report that VNS is associated with enhanced PAC and coordinated interhemispheric interactions within and between thalamic nuclei, respectively. These findings advance understanding of putative neurophysiological effects of acute VNS and contextualize previous animal and human studies showing distributed cortical synchronization after VNS.

Deep brain stimulation in children and youth: perspectives of patients and caregivers gleaned through Twitter.

OBJECTIVE: This study aims to glean patient and caregiver perspectives surrounding deep brain stimulation (DBS) in children and youth through an analysis of patterns of social media usage. METHODS: The authors performed a comprehensive search of the Twitter Application Programming Interface (API) database for all tweets about DBS use in children and youth, with no date restriction. Data pertaining to each tweet were extracted for analysis. Results were analyzed using qualitative and quantitative methodologies. These included thematic analysis of tweets, accounts, and descriptive statistics. Sentiment analysis of extracted tweets was also performed. A multivariable regression model was used to identify predictors of higher engagement metrics (likes, retweets, and quotes). RESULTS: A comprehensive search of the Twitter database yielded 877 tweets from 816 unique accounts meeting study inclusion criteria. Most tweets were from patients or caregivers, researchers, or news media outlets. The most common themes among analyzed tweets were research discussing novel findings (45.2%) or personal experiences of patients or caregivers (27.4%). Sentiment analysis showed that 54.5% of tweets were positive, 35.1% were neutral, and 10.4% were negative. The presence of pictures or videos increased the tweet engagement count by an average of 10.5 (95% CI 7.3-13.6). Tweets about personal patient experiences (ß = 6, 95% CI 0.95-12) and tweets tagging other accounts (ß = 3.2, 95% CI 0.63-5.8) were also significantly associated with higher engagement metrics. CONCLUSIONS: The current study is the first to assess patient and caregiver perspectives surrounding pediatric DBS through a comprehensive analysis of social media usage. Given the nascent field, social media presents an opportunity to share experiences and promote patient and healthcare professional education surrounding pediatric DBS.

Concurrent Validity of Zeno Instrumented Walkway and Video-Based Gait Features in Adults With Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) presents with motor symptoms such as bradykinesia, rigidity, and tremor that can affect gait. To monitor changes associated with disease progression or medication use, quantitative gait assessment is often performed during clinical visits. Conversely, vision-based solutions have been proposed for monitoring gait quality in non-clinical settings. METHODS: We use three 2D human pose-estimation libraries (AlphaPose, Detectron, OpenPose) and one 3D library (ROMP) to calculate gait features from color video, and correlate them with those extracted by a Zeno instrumented walkway in older adults with PD. We calculate video-based gait features using a manual and automated heel-strike detection algorithm, and compare the correlations when the participants walk towards and away from the camera separately. RESULTS: Based on analysis of 67 bidirectional walking bouts from 25 adults with PD, moderate to strong positive correlations were identified between the number of steps, cadence, as well as the mean and coefficient of variation of step width calculated from Zeno and video using 2D pose-estimation libraries. We noted that our automated heel-strike annotation method struggled to identify short steps. CONCLUSION: Gait features calculated from 2D joint trajectories are more strongly correlated with the Zeno than analogous gait features calculated from ROMP. Based on our analysis, videos processed with 2D pose-estimation libraries can be used for longitudinal gait monitoring in individuals with PD. Future work will seek to improve the prediction of gait features using a comprehensive machine learning model to predict gait features directly from color video without relying on intermediate extraction of joint trajectories.

The anterior and centromedian thalamus: Anatomy, function, and dysfunction in epilepsy.

The thalamus is a densely connected collection of nuclei that play a critical role in gating information flow across the neocortex. Through diffuse reciprocal cortico-thalamo-cortical connectivity, the anterior and centromedian nuclei exert remarkable control over cortically expressed activity. Consequently, mounting evidence implicates these thalamic centres in both the genesis and propagation of aberrant epileptiform activity across the brain. The present work reviews existing literature with regards to the anatomy, function, and dysfunction of the anterior and centromedian thalamic nuclei as they relate to epileptogenesis and ictal dynamics in humans. A confluence of electrophysiological, anatomical, and neuromodulatory evidence links these thalamic hubs to a variety of epilepsy syndromes. These data are discussed as they relate to targeted thalamic neuromodulation.

Progressive Worsening of Gait and Motor Abnormalities in Older Adults With Dravet Syndrome.

BACKGROUND AND OBJECTIVES: Relative to the pediatric population, there is limited information about Dravet syndrome (DS) in adults. In addition to some of the gait abnormalities reported in children with DS (such as crouch gait and ataxia), adults with this condition have other gait and motor disturbances. Our primary objective was to examine gait and motor manifestations in adults with DS. METHODS: This study includes a prospective arm where 6 patients (mean age, 32 years) were examined through a modified version of the Unified Parkinson's Disease Rating Scale (mUPDRS) in 2014 and again in 2019. mUPDRS scores were assigned to gait, resting tremors, facial expression, arising from a chair, posture, and body bradykinesia. The cross-sectional arm includes mUPDRS testing in patients who were not evaluated in 2014 and an instrumental gait analysis (IGA). These cross-sectional tests were done in the 2019-2020 period. The IGA was performed using ProtoKinetics software with a gait mat built with sensors and 2 cameras capturing the sagittal and coronal planes. The IGA was performed in a group of 17 patients with DS (mean age, 31 years); the control group consisted of 81 healthy individuals, whose mean age was 62 years. Regression analyses were performed for the IGA and mUPDRS data. RESULTS: Five out of 6 participants evaluated prospectively over 5 years experienced worsening of their parkinsonian manifestations, including gait. Two patients (47 and 51 years of age) who were initially ambulatory could no longer walk 5 years later. The cross-sectional analysis of mUPDRS in a larger group of adults showed that worse scores for arising from a chair (p = 0.04), body bradykinesia (p = 0.01), and gait (p = 0.0003) were positively associated with age. The IGA cross-sectional arm revealed that all 17 adults with DS had abnormal gait measures in all domains tested. This group of patients performed worse than the healthy and older control group. DISCUSSION: Although seizures may decrease in older adults with DS, this prospective and cross-sectional study showed that their motor symptoms and gait become progressively worse as they age.

Local Field Potential-Based Programming: A Proof-of-Concept Pilot Study.

OBJECTIVES: Programming deep brain stimulation (DBS) is still based on a trial-and-error approach, often becoming a time-consuming process for both treating physicians and patients. Several strategies have been proposed to streamline DBS programming, most of which are preliminary and mainly address Parkinson's disease, a condition readily responsive to DBS adjustments. In the present proof-of-principle pilot study, we successfully demonstrate that local field potential (LFP)-based programming can be an effective approach when used for DBS indications that have a delayed temporal onset of benefit. MATERIALS AND METHODS: A recently commercialized implantable pulse generator (IPG) with the capability to non-invasively and chronically stream live and/or record LFPs from a DBS electrode after implantation was used to program one pediatric patient with generalized dystonia and an adult with seizures refractory to multiple medications and vagal nerve stimulation. RESULTS: The IPG survey function detected a peak in the delta range (1.95 Hz) in the left globus pallidus of the first patient. This LFP was detected when recording in the brain area adjacent to contacts 9 and 10 and absent when recording from other areas. The chronic recording of the 1.95 Hz LFP with two sets of stimulation showed a greater power increase with the settings associated with a worsening of dystonia. Broadband LFP home recording of "absence seizure" and "focal/partial seizure" was used in the second patient and reviewer with the IPG "timeline" and "event" functions. The chronic recording of the 2.93 Hz and 8.79 Hz (spit sensing) showed a reduced power with the stimulation setting associated with seizure control. CONCLUSIONS: The approach presented in this pilot proof-of-concept study may inform and streamline the DBS programming for conditions requiring clinicians and patients to wait weeks before appreciating any clinical benefit. Prospective studies on larger samples of patients are warranted.