Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation.

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

Severe headache trajectory following aneurysmal subarachnoid hemorrhage: the association with lower sodium levels.

BACKGROUND: A clinical hallmark of aneurysmal SAH (aSAH) is headache. Little is known about post-aSAH headache factors which may point to underlying mechanisms. In this study, we aimed to characterize the severity and trajectory of headaches in relation to clinical features of patients with aSAH. METHODS: This is a retrospective longitudinal study of adult patients admitted to an academic tertiary care center between 2012 and 2019 with aSAH who could verbalize pain scores. Factors recorded included demographics, aneurysm characteristics, analgesia, daily morning serum sodium concentration, and occurrence of vasospasm. Group-based trajectory modeling was used to identify headache pain trajectories, and clinical factors were compared between trajectories. RESULTS: Of 91 patients included in the analysis, mean age was 57 years and 20 (22%) were male. Headache score trajectories clustered into two groups: patients with mild-moderate and moderate-severe pain. Patients in the moderate-severe pain group were younger (P<0.05), received more opioid analgesia (P<0.001), and had lower sodium concentrations (P<0.001) than patients in the mild-moderate pain group. CONCLUSION: We identified two distinct post-aSAH headache pain trajectory cohorts and identified an association with age, analgesia, and sodium levels. Future prospective studies considering sodium homeostasis and volume status under standardized analgesic regimens are warranted.

Therapeutic Advances in the Treatment of Holmes Tremor: Systematic Review.

OBJECTIVE: We aimed to formulate a practical clinical treatment algorithm for Holmes tremor (HT) by reviewing currently published clinical data. MATERIALS AND METHODS: We performed a systematic review of articles discussing the management of HT published between January 1990 and December 2018. We examined data from 89 patients published across 58 studies detailing the effects of pharmacological or surgical interventions on HT severity. Clinical outcomes were measured by a continuous 1-10 ranked scale. The majority of studies addressing treatment response were case series or case reports. No randomized control studies were identified. RESULTS: Our review included 24 studies focusing on pharmacologic treatments of 25 HT patients and 34 studies focusing on the effect of deep brain stimulation (DBS) in 64 patients. In the medical intervention group, the most commonly used drugs were levetiracetam, trihexyphenidyl, and levodopa. In the surgically treated group, the thalamic ventralis intermedius nucleus (VIM) and globus pallidus internus (GPi) were the most common brain targets for neuromodulation. The two targets accounted for 57.8% and 32.8% of total cases, respectively. Overall, compared to the medically treated group, DBS provided greater tremor suppression (p = 0.025) and was more effective for the management of postural tremor in HT. Moreover, GPi DBS displayed greater benefit in the resting tremor component (p = 0.042) and overall tremor reduction (p = 0.022). CONCLUSIONS: There is a highly variable response to different medical treatments in HT without randomized clinical trials available to dictate treatment decisions. A variety of medical and surgical treatment options can be considered for the management of HT. Collaborative research between different institutions and researchers are warranted and needed to improve our understanding of the pathophysiology and management of this condition. In this review, we propose a practical treatment algorithm for HT based on currently available evidence.

Parkinsonian Beta Dynamics during Rest and Movement in the Dorsal Pallidum and Subthalamic Nucleus.

In Parkinson's disease (PD), pathologically high levels of beta activity (12-30 Hz) reflect specific symptomatology and normalize with pharmacological or surgical intervention. Although beta characterization in the subthalamic nucleus (STN) of PD patients undergoing deep brain stimulation (DBS) has now been translated into adaptive DBS paradigms, a limited number of studies have characterized beta power in the globus pallidus internus (GPi), an equally effective DBS target. Our objective was to compare beta power in the STN and GPi during rest and movement in people with PD undergoing DBS. Thirty-seven human female and male participants completed a simple behavioral experiment consisting of periods of rest and button presses, leading to local field potential recordings from 19 (15 participants) STN and 26 (22 participants) GPi nuclei. We examined overall beta power as well as beta time-domain dynamics (i.e., beta bursts). We found higher beta power during rest and movement in the GPi, which also had more beta desynchronization during movement. Beta power was positively associated with bradykinesia and rigidity severity; however, these clinical associations were present only in the GPi cohort. With regards to beta dynamics, bursts were similar in duration and frequency in the GPi and STN, but GPi bursts were stronger and correlated to bradykinesia-rigidity severity. Beta dynamics therefore differ across basal ganglia nuclei. Relative to the STN, beta power in the GPi may be readily detected, modulates more with movement, and relates more to clinical impairment. Together, this could point to the GPi as a potentially effective target for beta-based adaptive DBS.SIGNIFICANCE STATEMENT It is known that subthalamic nucleus (STN) beta activity is linked to symptom severity in Parkinson's disease (PD), but few studies have characterized beta activity in the globus pallidus internus (GPi), another effective target for deep brain stimulation (DBS). We compared beta power in the STN and GPi during rest and movement in 37 people with PD undergoing DBS. We found that beta dynamics differed across basal ganglia nuclei. Our results show that, relative to the STN, beta power in the GPi may be readily detected, modulates more with movement, and relates more to clinical impairment. Together, this could point to the GPi as a potentially effective target for beta-based adaptive DBS.

Pallidal Connectivity Profiling of Stimulation-Induced Dyskinesia in Parkinson's Disease.

OBJECTIVES: The aim of this study is to identify anatomical regions related to stimulation-induced dyskinesia (SID) after pallidal deep brain stimulation (DBS) in Parkinson's disease (PD) patients and to analyze connectivity associated with SID. METHODS: This retrospective study analyzed the clinical and imaging data of PD patients who experienced SID during the monopolar review after pallidal DBS. We analyzed structural and functional connectivity using normative connectivity data with the volume of tissue activated (VTA) modeling. Each contact was assigned to either that producing SID (SID VTA) or that without SID (non-SID VTA). Structural and functional connectivity was compared between SID and non-SID VTAs. "Optimized VTAs" were also estimated using the DBS settings at 6 months after implantation. RESULTS: Of the 68 consecutive PD patients who underwent pallidal implantation, 20 patients (29%) experienced SID. SID VTAs were located more dorsally and anteriorly compared with non-SID and optimized VTAs and were primarily in the dorsal globus pallidus internus (GPi) and dorsal globus pallidus externus (GPe). SID VTAs showed significantly higher structural connectivity than non-SID VTAs to the associative cortex and supplementary motor area/premotor cortex (P < 0.0001). Simultaneously, non-SID VTAs showed greater connectivity to the primary sensory cortex, cerebellum, subthalamic nucleus, and motor thalamus (all P < 0.0004). Functional connectivity analysis showed significant differences between SID and non-SID VTAs in multiple regions, including the primary motor, premotor, and prefrontal cortices and cerebellum. CONCLUSION: SID VTAs were primarily in the dorsal GPi/GPe. The connectivity difference between the motor-related cortices and subcortical regions may explain the presence and absence of SID. © 2020 International Parkinson and Movement Disorder Society.

Gait worsening and the microlesion effect following deep brain stimulation for essential tremor.

OBJECTIVE: To investigate the effects of unilateral thalamic deep brain stimulation (DBS) on walking in persons with medication-refractory essential tremor (ET). METHODS: We performed laboratory-based gait analyses on 24 persons with medication-refractory ET before and after unilateral thalamic DBS implantation. Normal and tandem walking parameters were analysed across sessions (PRE-DBS/DBS OFF/DBS ON) by repeated measures analyses of variance. Pearson's correlations assessed whether changes in walking after DBS were global (ie, related across gait parameters). Baseline characteristics, lead locations and stimulation parameters were analysed as possible contributors to gait effects. RESULTS: DBS minimally affected gait at the cohort level. However, 25% of participants experienced clinically meaningful gait worsening. Walking speed decreased by >30% in two participants and by >10% in four others. Decreased walking speed correlated with increased gait variability, indicating global gait worsening in affected participants. The worsening persisted even after the stimulation was turned off. Participants with worse baseline tandem walking performance may be more likely to experience post-DBS gait worsening; the percentage of tandem missteps at baseline was nearly three times higher and tandem walking speeds were approximately 30% slower in participants who experienced gait worsening. However, these differences in tandem walking in persons with gait worsening as compared with those without worsening were not statistically significant. Lead locations and stimulation parameters were similar in participants with and without gait worsening. CONCLUSION: Global gait worsening occurred in 25% of participants with unilateral DBS for medication-refractory ET. The effect was present on and off stimulation, likely indicating a microlesion effect.

Against the Overgrowth Hypothesis: Shorter Costal Cartilage Lengths in Pectus Excavatum.

BACKGROUND: Pectus excavatum is a common chest wall deformity with no known cause. A common hypothesis is that in patients with pectus excavatum, there is an overgrowth of costal cartilage relative to healthy individuals. MATERIALS AND METHODS: We obtained radiological curvilinear three-dimensional measurements of the fourth to eighth costal cartilage and associated ribs in 16 patients with pectus excavatum and 16 age- and gender-matched controls between the ages of 6 and 32 y. An analysis of variance was used to compare bone length, cartilage length, and their ratios between patients and controls. RESULTS: Relative to bone length, patients with pectus excavatum overall had shorter costal cartilage lengths (P < 0.001), especially on the left side (P < 0.05). We were unable to localize this observation to specific ribs during post hoc analysis. CONCLUSIONS: This is the first study to empirically test the overgrowth hypothesis of pectus excavatum for ribs 4 through 8. Although we and others have found no evidence to support this hypothesis, we surprisingly found the alternate hypothesis to be true: patients with pectus excavatum tend to have shorter costal cartilages. Future studies should expand on these results with larger sample sizes and consider volumetric measurements longitudinally during thoracic development.

A causal Bayesian network model of disease progression mechanisms in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system initiated by a single genetic mutation which results in the oncogenic fusion protein Bcr-Abl. Untreated, patients pass through different phases of the disease beginning with the rather asymptomatic chronic phase and ultimately culminating into blast crisis, an acute leukemia resembling phase with a very high mortality. Although many processes underlying the chronic phase are well understood, the exact mechanisms of disease progression to blast crisis are not yet revealed. In this paper we develop a mathematical model of CML based on causal Bayesian networks in order to study possible disease progression mechanisms. Our results indicate that an increase of Bcr-Abl levels alone is not sufficient to explain the phenotype of blast crisis and that secondary changes such as additional mutations are necessary to explain disease progression and the poor therapy response of patients in blast crisis.

Co-Occurrence of Apathy and Impulse Control Disorders in Parkinson Disease: Variation across Multiple Measures.

OBJECTIVE: To determine if the co-occurrence of apathy and impulse control disorders (ICDs) in Parkinson disease is dependent on instrument selection and assess the concurrent validity of three motivation measures by examining interrelationships between them. METHOD: Ninety-seven cognitively normal individuals with idiopathic Parkinson disease (PD) completed the Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease-Rating Scale (QUIP-RS) and three apathy measures: the Apathy Scale, Lille Apathy Rating Scale, and Item 4 of the Movement Disorder Society-Unified Parkinson Disease Rating Scale. RESULTS: Fifty (51.5%) participants were classified as apathetic on at least one measure, and only four individuals (4.3%) obtained clinically elevated scores on all three measures. The co-occurrence of apathy and ICD varied across measures. CONCLUSIONS: We observed a co-occurrence of apathy and ICDs in PD patients with each apathy instrument; however, limited concurrent validity exists across measures. This is important for future investigations into shared pathophysiology and the design of future clinical trials aimed at improving the early detection and treatment of these debilitating syndromes.

Evaluating analgesic medications utilized in the treatment of aneurysmal subarachnoid hemorrhage and association with delayed cerebral ischemia.

BACKGROUND: Spontaneous aneurysmal subarachnoid hemorrhage (aSAH) recovery may be hampered by delayed cerebral ischemia (DCI). Herein, we sought to identify whether frequently administered medications in the intensive care unit (ICU) are associated with DCI. METHODS: In this retrospective study, patients admitted to a tertiary care center neuro-ICU between 2012 and 2019 with aSAH who could verbalize pain intensity scores were included. Medication dosages and clinical characteristics were abstracted from the medical record. Both paired and unpaired analyses were utilized to measure individual DCI risk for a given patient in relation to drug dosages. RESULTS: 119 patients were included; average age was 61.7 ± 15.2 (SD) years, 89 (74.7%) were female, and 32 (26.9%) experienced DCI during admission. Patients with DCI had longer length of stay (19.3 ± 7.4 vs 12.7 ± 5.3 days, p < 0.0001). The combination medication of acetaminophen 325 mg/butalbital 50 mg/caffeine 40 mg (A/B/C) was associated with decreased DCI on paired (2.3 ± 2.0 vs 3.1 ± 1.9 tabs, p = 0.034) and unpaired analysis (1.84 ± 2.4 vs 2.6 ± 2.4 tabs, p < 0.001). No associations were found between DCI and opioids, dexamethasone, levetiracetam, or acetaminophen. Max and mean daily headache pain was not associated with DCI occurrence. CONCLUSION: We identified an association between a commonly administered analgesic and DCI. A/B/C is associated with decreased DCI in this study, while other medications are not associated with DCI risk.

Course of Impulse Control Disorder Symptoms in Parkinson's Disease: Deep Brain Stimulation Versus Medications.

Background: The effect of surgery on impulse control disorders (ICDs) remains unclear in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS). Objective: To examine changes in ICD symptoms in PD patients undergoing DBS compared to a medication-only control group. Methods: The study was a 2-center, 12-month, prospective, observational investigation of PD patients undergoing DBS and a control group matched on age, sex, dopamine agonist use, and baseline presence of ICDs. Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) and total levodopa equivalent daily dose (LEDD) were collected at baseline, 3, 6, and 12 months. Linear mixed-effects models assessed changes in mean QUIP-RS score (sum of buying, eating, gambling, and hypersexuality items). Results: The cohort included 54 participants (DBS = 26, controls = 28), mean (SD) age 64.3 (8.1) and PD duration 8.0 (5.2) years. Mean baseline QUIP-RS was higher in the DBS group at baseline (8.6 (10.7) vs. 5.3 (6.9), P = 0.18). However, scores at 12 months follow-up were nearly identical (6.6 (7.3) vs. 6.0 (6.9) P = 0.79). Predictors of change in QUIP-RS score were baseline QUIP-RS score (ß = 0.483, P < 0.001) and time-varying LEDD (ß = 0.003, P = 0.02). Eight patients (four in each group) developed de novo ICD symptoms during follow-up, although none met diagnostic criteria for an impulse control disorder. Conclusions: ICD symptoms (including de novo symptoms) at 12 months follow-up were similar between PD patients undergoing DBS and patients treated with pharmacological therapy only. Monitoring for emergence of ICD symptoms is important in both surgically- and medication-only-treated PD patients.

Weight and survival after deep brain stimulation for Parkinson's disease.

BACKGROUND: Weight loss in Parkinson's disease (PD) is common and associated with increased mortality. The clinical significance of weight changes following deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is unclear. OBJECTIVES: To address (1) whether PD patients exhibit progressive weight loss, (2) whether staged DBS surgery is associated with weight changes, and (3) whether survival after DBS correlates with post-DBS weight. METHODS: This is a single-center, longitudinal, retrospective cohort study of 1625 PD patients. We examined trends in weight over time and the relationship between weight and years survival after DBS using regression and mixed model analyses. RESULTS: There was a decline in body weight predating motor symptom onset (n = 756, 0.70 ± 0.03% decrease per year, p < 0.001). Weight decline accelerated in the decade preceding death (n = 456, 2.18 ± 0.31% decrease per year, p < 0.001). DBS patients showed a weight increase of 2.0 ± 0.33% at 1 year following the first DBS lead implant (n = 455) and 2.68 ± 1.1% at 3 years if a contralateral DBS lead was placed (n = 249). The bilateral STN DBS group gained the most weight after surgery during 6 years of follow up (vs bilateral GPi, 3.03 ± 0.45% vs 1.89 ± 0.31%, p < 0.01). An analysis of the DBS cohort with date of death available (n = 72) revealed that post-DBS weight (0-12 months after the first or 0-36 months after the second surgery) was positively associated with survival (R2 = 0.14, p < 0.001). DISCUSSION: Though PD is associated with significant weight loss, DBS patients gained weight following surgery. Higher post-operative weight was associated with increased survival. These results should be replicated in other cohorts.

Clinical risk factors associated with cerebrospinal fluid leak in facial trauma: A retrospective analysis.

OBJECTIVE: Cerebrospinal fluid (CSF) leak occurs most commonly following skull fracture, with a CSF leakage complicating up to 2% of all head traumas. This study aims to identify demographic and injury characteristics correlated with the highest risk of CSF leak in patients with known facial fractures. METHODS: Retrospective data was collected from a previously described trauma registry from 2010 to 2019. Patients over 18 years old with any type of facial fracture, known CSF leak status, available neuroimaging, and hospital admission were included. Chi-Square analysis for demographic and injury characteristic data were utilized. RESULTS: A total of 79 patients with CSF leak and 4907 patients without CSF leak were included in the database. Patients with CSF leak tended to be younger than those without CSF leak (38.45 +/- 0.28 vs 44.08 +/- 0.28, M +/- SE, p = 0.0197). CSF leak depended on the mechanism of injury (MOI; X2 =27.02, df=2, p = 0.0000013), with CSF leak rates highest in penetrating injuries (4.87%) and motor vehicle accidents (1.78%) compared to blunt injuries (0.95%); age did not significantly differ between the MOI groups (p = 0.11). CSF leak was also more common in patients with a lower Glasgow coma scale (GCS; 7.95 +/- 0.58 vs 12.21 +/- 0.10, p = 10-15), LeFort type 2&3 and pan-facial fractures compared to all other facial fracture types (8.9% vs 1.2%, p = 10-15), and radiographic midline shift (29.4% vs 9.1%, p = 10-15). There was a trend towards a higher proportion of males in those with CSF leak compared to those without (83.3% vs 73.7% males, p = 0.073), and in patients with prolonged loss of consciousness (LOC; 9.43% with LOC > 1 h vs 2.69% LOC < 1 h, p = 0.056). CONCLUSION: Facial fractures often present with CSF leak, and certain demographic and injury risk factors including younger age, worse GCS score, evidence of midline shift, and certain mechanisms of injury (penetrating and motor vehicle) are correlated with increased risk and warrant close screening and follow-up for CSF leak detection. LeFort type 2&3 and pan-facial fractures are at high risk of CSF leak.

From pleasure to punding: Distinct patterns of anhedonia and impulsivity linked to motivational disturbances in Parkinson disease.

INTRODUCTION: Apathy and impulse control disorders (ICD) are common comorbid motivational syndromes in Parkinson disease (PD). This study aimed to determine if patients with these motivational disturbances exhibit different patterns of anhedonia and trait impulsivity. METHODS: Sixty-four non-demented patients with PD completed questionnaires assessing apathy and ICD symptoms, which were used to classify participants into one of the following groups: apathy only, ICD only, both, and neither. Participants also completed multidimensional measures of anhedonia and trait impulsivity, which were compared across groups defined by motivational status. RESULTS: Individuals with both apathy and ICD had significantly greater symptoms of positive and negative urgency than all other groups and had significantly greater consummatory anhedonia and lack of premeditation and perseverance than those with ICD only and neither. Patients with apathy only also reported significantly greater anticipatory anhedonia than those with ICD only and the neither group. There were no significant between-group differences in sensation seeking. CONCLUSION: Distinct patterns of impulsivity and anhedonia characterize unique behavioral phenotypes of motivational disturbances in PD and may reflect important differences in the underlying neurobiological mechanisms. Clinicians should be aware that motivational disturbances may be more severe in cases where apathy co-occurs with one or more ICD.HIGHLIGHTSHighlights are mandatory for all submissions except letters. They consist of a short collection of bullet points that convey the core findings of the article and should be submitted in a separate file in the online submission system. Please use "Highlights" in the file name and include 3-5 bullet points (maximum 85 characters, including spaces, per bullet point). See https://www.elsevier.com/highlights for examples.

Online vs Face-to-Face Administration of Impulse Control Disorder Questionnaires in Parkinson Disease: Does Method Matter?

Background and Objective: Social desirability bias, the tendency to underreport undesirable behaviors, may be one reason patients with Parkinson disease (PD) underreport symptoms of impulse control disorders (ICDs). Methods: We compared rates of ICD endorsement on questionnaires administered face-to-face and online in 60 patients with mild-to-moderate idiopathic PD. Participants also completed a self-report measure of social desirability. Results: We found a significantly higher prevalence of any ICD based on online (56.7%) vs in-person (33.3%) administration. Significantly higher endorsement of items related to hypersexuality in men and compulsive eating and buying in women were found with online administration. Social desirability bias was positively correlated with ICD symptom endorsement across all items and subscales. Discussion: The results highlight the importance of social context/setting and the need for sensitivity and discretion when screening for ICD symptoms. Although a higher level of symptom endorsement does not necessarily imply a greater level of accuracy, more work is needed to determine which method of administration is most accurate for clinical and research practice.

Embedded Human Closed-Loop Deep Brain Stimulation for Tourette Syndrome: A Nonrandomized Controlled Trial.

Importance: Because Tourette syndrome (TS) is a paroxysmal disorder, symptomatic relief in individuals with TS may be possible through the application of stimulation only during the manifestation of human tic neural signatures. This technique could be capable of suppressing both motor and vocal tics and would have similar effectiveness to conventional continuous deep brain stimulation (DBS). Objective: To evaluate the feasibility, safety, and clinical effectiveness of bilateral centromedian-parafascicular complex thalamic closed-loop DBS as a treatment for medication-refractory TS. Design, Setting, and Participants: This single-center double-blinded safety and feasibility trial was conducted between February 2014 and June 2020. Six individuals with TS were screened and recruited from the Norman Fixel Institute at the University of Florida. The primary outcome was measured at 6 months, and participants were followed up for the duration of the neurostimulator battery life. Independent ratings that compared closed-loop and conventional DBS were videotaped. The first 2 of 6 individuals with TS were excluded from the study because the technology for embedded closed-loop capability was not yet available. The date of analysis was August 2020. Interventions: DBS therapy controlled by an embedded closed-loop stimulation system. Main Outcomes and Measures: The primary clinical outcome measure was a minimum of a 40% reduction in the YGTSS score at 6 months following DBS. There was also a comparison of conventional DBS with closed-loop DBS using the Modified Rush Videotape Rating Scale for Tic. Results: The mean (SD) age at TS diagnosis for the cohort was 8.5 (2.9), and the mean (SD) disease duration was 23.7 (5.8) years. Four individuals with TS were analyzed (2 male, 2 female; mean [SD] age, 23.7 [5.8] years). The study showed the closed-loop approach was both feasible and safe. One of the novelties of this study was that a patient-specific closed-loop paradigm was created for each participant. The features and stimulation transition speed were customized based on the signal quality and the tolerance to adverse reactions. The mean (SD) therapeutic outcome with conventional DBS was 33.3% (35.7%) improvement on the YGTSS and 52.8% (21.9%) improvement on the Modified Rush Videotape Rating Scale. Two of 4 participants had a primary outcome variable improvement of 40% meeting the primary efficacy target. When comparing closed-loop DBS with conventional DBS using a Wilcoxon sign-rank test, there was no statistical difference between tic severity score and both approaches revealed a lower tic severity score compared with baseline. The study was feasible in all 4 participants, and there were 25 total reported adverse events with 3 study-related events (12%). The most common adverse events were headache and anxiety. Conclusions and Relevance: Embedded closed-loop deep DBS was feasible, safe, and had a comparable outcome to conventional TS DBS for the treatment of tics. Trial Registration: ClinicalTrials.gov Identifier: NCT02056873.

Distinct Roles of the Human Subthalamic Nucleus and Dorsal Pallidum in Parkinson's Disease Impulsivity.

BACKGROUND: Impulsivity and impulse control disorders are common in Parkinson's disease and lead to increased morbidity and reduced quality of life. Impulsivity is thought to arise from aberrant reward processing and inhibitory control, but it is unclear why deep brain stimulation of either the subthalamic nucleus (STN) or globus pallidus internus (GPi) affects levels of impulsivity. Our aim was to assess the role of the STN and GPi in impulsivity using invasive local field potential (LFP) recordings from deep brain stimulation electrodes. METHODS: We measured LFPs during a simple rewarding Go/NoGo paradigm in 39 female and male human patients with Parkinson's disease manifesting variable amounts of impulsivity who were undergoing unilateral deep brain stimulation of either the STN (18 nuclei) or GPi (28 nuclei). We identified reward-specific LFP event-related potentials and correlated them to impulsivity severity. RESULTS: LFPs in both structures modulated during reward-specific Go and NoGo stimulus evaluation, reward feedback, and loss feedback. Motor and limbic functions were anatomically separable in the GPi but not in the STN. Across participants, LFP reward processing responses in the STN and GPi uniquely depended on the severity of impulsivity. CONCLUSIONS: This study establishes LFP correlates of impulsivity within the STN and GPi regions. We propose a model for basal ganglia reward processing that includes the bottom-up role of the GPi in reward salience and the top-down role of the STN in cognitive control.

A novel local field potential-based functional approach for targeting the centromedian-parafascicular complex for deep brain stimulation.

BACKGROUND: The centromedian-parafascicular (Cm-Pf) complex of the thalamus is a common deep brain stimulation (DBS) target for treatment of Tourette syndrome (TS). Currently, there are no standardized functional intraoperative neurosurgical targeting approaches. Collectively, these issues have led to variability in DBS lead placement. Therefore, more defined methods are needed to improve targeting accuracy. OBJECTIVE: The objective of this observational study was to develop and to verify a functional mapping task capable of differentiating the Cm-Pf region from the nearby ventral intermediate (Vim) nucleus region of the thalamus. The overarching goal was to improve the reproducibility of DBS targeting in the Cm-Pf region. METHODS: Seven TS patients completed a modified Go/NoGo task (five in the post-operative setting and two in the intra-operative setting). Post-operative neural signals from Cm-Pf region were collected using sensing-enabled implanted neural stimulators, and intraoperative neural signals from the Cm-Pf region were collected using an external amplifier. Event-related potential (ERP) features were identified by using the grand-average of stimulus onset signals derived from the postoperative participants. These features were correlated with anatomical locations for the specific electrode recordings. The same features were extracted from the intraoperative patients in order to verify electrode positions in the operating room environment. RESULTS: Two features - a positive and a negative deflection - were identified in the average ERP from the post-operative participants. The peak amplitudes of both features were significantly correlated with the electrode depth position (p = 0.025 for positive deflection and p = 0.039 for negative deflection). The same result was reproduced intra-operatively in the two most recent patients, where more ventral electrode contacts revealed stronger peak amplitudes in comparison to the dorsal electrode contacts. CONCLUSION: This process was used to physiologically confirm accurate lead placement in the operating room setting. The modified Go/NoGo task elicited robust neural responses in the Cm-Pf region however the signal was not present in the Vim nucleus region of thalamus along the DBS electrode trajectory. We conclude that the differences in ERP responses may be a potentially novel LFP based functional approach for future targeting of the Cm-Pf complex for TS DBS.

Wearable sensor-driven responsive deep brain stimulation for essential tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. OBJECTIVE: The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. METHODS: Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. RESULTS: Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. CONCLUSIONS: The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.