Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition.

Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αß complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

BACKGROUND AND OBJECTIVES: Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. METHODS: We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. RESULTS: We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). CONCLUSIONS: Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Smile without euphoria induced by deep brain stimulation: a case report.

Poststroke central pain (PSCP) can be a debilitating medication-refractory disorder. We report a single case where right unilateral ventral capsule/ventral striatum (VC/VS) deep brain stimulation was used to treat PSCP and inadvertently induced a smile without euphoria. The patient was a 69 year-old woman who had a stroke with resultant dysesthesia and allodynia in her left hemibody and also a painful left hemibody dystonia. In her case, VC/VS stimulation induced a smile phenomenon, but without a euphoric sensation. This phenomenon was different from the typical smile responses we have observed in obsessive-compulsive disorder cases. This difference was considered to be possibly attributable to impairment in the emotional smile pathway.

Blepharoclonus in Parkinsonism.

Background and Objectives: In clinical practice, we have observed that patients with Parkinson disease (PD) often have blepharoclonus, but its prevalence is not well described in the literature. Understanding the relative frequencies of blepharoclonus in PD and atypical parkinsonian syndromes may shed light on the diagnostic utility of this clinical sign. We aimed to assess (1) the frequency of blepharoclonus in patients with PD in a single-center cohort; (2) the association of blepharoclonus with disease stage, tremor severity, and non-motor symptoms; and (3) the frequency of blepharoclonus in synucleinopathy vs non-synucleinopathy-associated parkinsonism. Methods: We prospectively enrolled 85 patients, 75 with PD and 10 with atypical parkinsonism. Blepharoclonus was considered present if eyelid fluttering was sustained for >5 seconds after gentle eye closure. For each patient, demographics were collected, and we completed selected questions from the MDS-UPDRS (Unified Parkinson's Disease Rating Scale) part 2, REM Sleep Behavior Disorder Questionnaire, and MDS-UPDRS part 3 tremor assessments and recorded the presence/absence of dyskinesia. Results: 63 of 75 patients with PD (84%) had blepharoclonus. Among the 10 patients with atypical parkinsonism, 5 had synucleinopathy syndromes. Blepharoclonus was present in 3 of 5 patients with synucleinopathy and 0 of 5 patients with non-synucleinopathy-associated parkinsonian syndromes. Discussion: Blepharoclonus is prevalent in our PD cohort, suggesting possible utility as a clinical marker for PD. The absence of blepharoclonus in a patient with parkinsonism may suggest a non-synucleinopathy (e.g., tauopathy). Analysis of a larger cohort of both PD and atypical parkinsonism would be needed to establish whether blepharoclonus distinguishes PD from atypical parkinsonism, or synucleinopathy from non-synucleinopathy.

A General Neurologist's Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders: A Consensus Statement.

Purpose of Review: The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral. Recent Findings: We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals. Summary: We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases.

Time perception reflects individual differences in motor and non-motor symptoms of Parkinson's disease.

Decreasing dopaminergic function is at the core of Parkinson's disease (PD) motor symptoms and changes in dopaminergic action are associated with many comorbid non-motor symptoms in PD. Notably, dopaminergic signaling in the striatum has been shown to play a critical role in the perception of time. We hypothesize that patients with PD perceive time differently and in accordance with their specific comorbid non-motor symptoms and clinical state. This means that individual differences in clinical symptoms may be reflected in individual differences in timing behavior. To test this hypothesis, we recruited patients with PD and compared individual differences in patients' clinical state with their ability to judge intervals of time ranging from 500 ms to 1100 ms while on and off their prescribed dopaminergic medications. We show that medication state (on vs. off medications) did not affect timing behavior, but individual differences in timing behavior are able to predict individual differences in comorbid non-motor symptoms, duration of PD diagnosis, and prescribed dopaminergic medications. We show that comorbid impulse control disorder is associated with temporal overestimation; depression is associated with decreased temporal accuracy; and increased PD duration and prescribed levodopa monotherapy are associated with reduced temporal precision and accuracy. Observed differences in time perception are consistent with hypothesized dopaminergic mechanisms thought to underlie the respective motor and non-motor symptoms in PD. In future work, time perception tasks may augment clinical diagnosis strategies, or help disentangle the neural and cognitive mechanisms underlying PD motor and non-motor symptom etiology.

Rapid-onset dystonia-parkinsonism is associated with reduced cerebral blood flow without gray matter changes.

Purpose: Previous research showed discrete neuropathological changes associated with rapid-onset dystonia-parkinsonism (RDP) in brains from patients with an ATP1A3 variant, specifically in areas that mediate motor function. The purpose of this study was to determine if magnetic resonance imaging methodologies could identify differences between RDP patients and variant-negative controls in areas of the brain that mediate motor function in order to provide biomarkers for future treatment or prevention trials. Methods: Magnetic resonance imaging voxel-based morphometry and arterial spin labeling were used to measure gray matter volume and cerebral blood flow, respectively, in cortical motor areas, basal ganglia, thalamus, and cerebellum, in RDP patients with ATP1A3 variants (n = 19; mean age = 37 ± 14 years; 47% female) and variant-negative healthy controls (n = 11; mean age = 34 ± 19 years; 36% female). Results: We report age and sex-adjusted between group differences, with decreased cerebral blood flow among patients with ATP1A3 variants compared to variant-negative controls in the thalamus (p = 0.005, Bonferroni alpha level < 0.007 adjusted for regions). There were no statistically significant between-group differences for measures of gray matter volume. Conclusions: There is reduced cerebral blood flow within brain regions in patients with ATP1A3 variants within the thalamus. Additionally, the lack of corresponding gray matter volume differences may suggest an underlying functional etiology rather than structural abnormality.

Interactive mobile application for Parkinson's disease deep brain stimulation (MAP DBS): An open-label, multicenter, randomized, controlled clinical trial.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. METHODS: We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. RESULTS: We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months. CONCLUSION: MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy.

Smile and laughter induction and intraoperative predictors of response to deep brain stimulation for obsessive-compulsive disorder.

We recently treated six patients for OCD utilizing deep brain stimulation (DBS) of the anterior limb of the internal capsule and the nucleus accumbens region (ALIC-NA). We individually tested leads via a scripted intraoperative protocol designed to determine DBS-induced side effects and mood changes. We previously published qualitative data regarding our observations of induced emotional behaviors in our first five subjects. We have now studied these same behaviors in the full cohort of six patients over 2 years of follow-up and have examined the relationship of these behaviors to intraoperative mood changes and postoperative clinical outcomes. Five patients experienced at least one smile response during testing. At higher voltages of stimulation, some of these smiles progressed to natural laughter. Smiles and laughter were associated with mood elevation. At stimulation locations at which smiles were observed, voltage and mood were significantly correlated (p=0.0004 for right brain and p<0.0001 for left brain). In contrast, at contacts where smiles were not observed, mood was negatively correlated with voltage (p=0.0591 for right brain and p=0.0086 for left). Smile and laughter-inducing sites were located relatively medial, posterior, and deep in the ALIC-NA. The presence of stimulation induced laughter predicted improvement in OCD symptoms at 2 years. The higher the percentage of laugh conditions experienced in an individual patient, the greater the reduction in YBOCS (24 months, p=0.034). Other correlations between clinical outcomes and percent of smile/laugh conditions were not significant. These stimulation-induced behaviors were less frequently observed with 1 and 2-month postoperative test stimulation and were not observed at subsequent test stimulation sessions. Intraoperative stimulation-induced laughter may predict long-term OCD response to DBS. Identifying other potential response predictors for OCD will become increasingly important as more patients are implanted with DBS devices. A larger study is needed to better delineate the relationship between induced intraoperative and postoperative emotional behavior and clinical outcome in patients treated with DBS therapy.

Should we consider Vim thalamic deep brain stimulation for select cases of severe refractory dystonic tremor.

Dystonic tremor, which may present with many different clinical presentations (rhythmic oscillations, abnormal posture, pain, and/or a null point) has proven to be a challenge for the clinician to effectively treat. Although recent studies have demonstrated excellent outcomes in select cases following deep brain stimulation (DBS) of the internal globus pallidus, the optimal target for dystonia and particularly for dystonic tremor remains unknown. We report 3 cases of dystonic tremor which were successfully addressed through the use of ventral intermediate nucleus (Vim) DBS. We also review the literature concerning the efficacy of Vim DBS for addressing dystonia. This case series illustrates the potential use of Vim DBS for select cases of dystonic tremor.

Prevalence of Twiddler's syndrome as a cause of deep brain stimulation hardware failure.

We reviewed our deep brain stimulation patient database to describe hardware complications which resulted from implantable pulse generator mobility, a phenomenon referred to as Twiddler's syndrome. A prospectively collected database of adverse events for all patients operated on at the University of Florida was queried searching for hardware malfunctions. Of 362 total leads implanted in 226 patients since 2002, there were 17 hardware malfunctions. Three of them were due to Twiddler's syndrome, representing 1.3% of patients (3 of 226 patients) and 1.4% of leads (5 of 362 leads). The subjects had characteristic presentations including re-emergence of symptoms, pain along the path of the hardware, abnormal impedances/current drain and radiographic signs of twisting/fracture. In all cases securing the implantable pulse generator within the chest pocket resolved the issue. Twiddler's syndrome in the population of movement disorder patients treated with deep brain stimulation is an uncommon but important adverse event. It possesses a characteristic presentation and with appropriate diagnostic evaluation it is treatable and future occurrences are preventable.

A case of mania following deep brain stimulation for obsessive compulsive disorder.

Deep brain stimulation (DBS) of the basal ganglia is an effective treatment for select movement disorders, including Parkinson's disease, essential tremor and dystonia. Based on these successes, DBS has been explored as an experimental treatment for medication-resistant neuropsychiatric disease. During a multiyear experience employing DBS to treat patients for obsessive compulsive disorder (OCD) we encountered several unanticipated stimulation-induced psychiatric side effects. We present a case of a young woman treated for OCD with DBS of the anterior limb of the internal capsule and nucleus accumbens region, who subsequently manifested a manic episode. We aim to discuss the case details, treatment and potential neuroanatomical underpinnings of this response.

Auditory-Perceptual Evaluation of Deep Brain Stimulation on Voice and Speech in Patients With Dystonia.

OBJECTIVE: To determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on speech and voice quality of patients with primary, medically refractory dystonia. METHODS: Voices of 14 patients aged ≥18 years (males = 7 and females = 7) with primary dystonia (DYT1 gene mutation dystonia = 4, cervical dystonia = 6, and generalized dystonia = 4) with bilateral GPi DBS were assessed. Five blinded raters (two fellowship-trained laryngologists and three speech/language pathologists) evaluated audio recordings of each patient pre- and post-DBS. Perceptual voice quality was rated using the Grade, Roughness, Breathiness, Asthenia, and Strain scale and changes in speech intelligibility were assessed with the Clinical Global Impression scale of Severity instrument. Inter-rater and intrarater reliability rates for perceptual voice ratings were assessed using the kappa coefficient. RESULTS: Voice quality parameters showed mean improvements in Grade (P < 0.0001), Roughness (P = 0.0043), and Strain (P < 0.0001) 12 months post-DBS. Asthenia increased from baseline to 6 months (P = 0.0022) and declined significantly from 6 to 12 months (P = 0.0170). Breathiness did not change significantly over time. Speech intelligibility also improved from 6 to 12 months (P = 0.0202) and from pre-DBS to 12 months post-DBS (P = 0.0022). Grade and Strain ratings had nearly perfect and substantial inter-rater agreement (0.84 and 0.71, respectively). CONCLUSIONS: Voice and speech intelligibility improved after bilateral GPi DBS for dystonia. GPi DBS may emerge as a potential treatment option for patients with medically refractory laryngeal dystonia.

Auditory-perceptual voice and speech evaluation in ATP1A3 positive patients.

INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male = 21, female = 11) and 29 mutation negative controls (male = 15, female = 14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p < 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9-11 dysfunction (54%, p = 0.048), speech/swallowing dysfunction (96%, p = 0.0003); and oral dystonia (88%, p = 0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

A high resolution and high contrast MRI for differentiation of subcortical structures for DBS targeting: the Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR).

DBS depends on precise placement of the stimulating electrode into an appropriate target region. Image-based (direct) targeting has been limited by the ability of current technology to visualize DBS targets. We have recently developed and employed a Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR) 3T MRI sequence to more reliably visualize these structures. The FGATIR provides significantly better high resolution thin (1 mm) slice visualization of DBS targets than does either standard 3T T1 or T2-weighted imaging. The T1 subcortical image revealed relatively poor contrast among the targets for DBS, though the sequence did allow localization of striatum and thalamus. T2 FLAIR scans demonstrated better contrast between the STN, SNr, red nucleus (RN), and pallidum (GPe/GPi). The FGATIR scans allowed for localization of the thalamus, striatum, GPe/GPi, RN, and SNr and displayed sharper delineation of these structures. The FGATIR also revealed features not visible on other scan types: the internal lamina of the GPi, fiber bundles from the internal capsule piercing the striatum, and the boundaries of the STN. We hope that use of the FGATIR to aid initial targeting will translate in future studies to faster and more accurate procedures with consequent improvements in clinical outcomes.

Venous air embolism in deep brain stimulation.

BACKGROUND/AIMS: During the placement of electrodes for deep brain stimulation (DBS), patients are commonly in a seated position, awake, and spontaneously breathing. Air may be entrained through bone or dural veins causing venous air emboli (VAE) and this phenomenon can result in significant hemodynamic changes. Although VAEs have been described in many types of neurosurgical procedures, their incidence during DBS surgery is unknown. METHODS: Following approval from the Institutional Review Board, the University of Florida Movement Disorders Center database comprising 286 DBS leads placed since 2002 was reviewed. Intraoperative cough, which has been associated with VAE, as well as hemodynamic instability were the focus of the review. Additionally, a prospective evaluation of the incidence of VAE using precordial Doppler ultrasound was undertaken over a 3-month period (June 2007-August 2007). RESULTS: The retrospective review revealed a 3.2% incidence of cough per lead. Prospective monitoring in 21 consecutive patients with 22 leads yielded the detection of 1 VAE, and an incidence of 4.5% per lead. CONCLUSION: VAEs are rare but potentially serious complications of DBS surgery unless recognized. Patient positioning and the occurrence of cough are two important predictors to consider in VAE. Precordial Doppler is a safe, non-invasive monitor that can be used in the early detection of VAE in these procedures.

Analysis of the prevalence and onset of dysphonia and dysphagia symptoms in movement disorders at an academic medical center.

Voice and swallowing impairments are common in movement disorders, but their effect on patients' quality of life is not well known. This study was conducted to determine the onset and prevalence of patient-reported dysphonia and dysphagia symptoms in Parkinson's disease (PD), dystonia, Atypical Parkinsonian Syndromes (APS), and Essential Tremor (ET). Patients referred to a movement disorders clinic in a tertiary care academic medical center completed validated voice and swallowing specific Quality of Life (QOL) questionnaires: Voice Handicap Index-10 (VHI-10) and Eating Assessment Tool-10 (EAT-10). Patient demographics and clinical data were also collected. Two hundred and sixty-eight patients (males = 150, females = 118) completed the questionnaires (n was PD = 103, APS = 30, ET = 56, dystonia = 32, other = 47). Prevalence of patient-reported dysphagia symptoms was significantly higher in APS (63%) than PD (26%), ET (25%), and dystonia (31%). Prevalence of patient-reported dysphonia symptoms was significantly lower in ET (14%) compared to PD (34%) and APS (43%). Disease duration was shorter in PD and APS compared to ET and dystonia (p < 0.05) before reporting clinically significant dysphonia and dysphagia symptoms indicating an earlier onset of these symptoms. There were significant positive correlations between VHI-10 and EAT-10 scores and disease severity, as indicated by Unified Parkinson's Disease motor scores (p < 0.0001) and modified Fahn-Tolosa-Marin Tremor Rating sub-scores (p = 0.0013). Patient-reported dysphonia and dysphagia symptoms were present in one fourth of patients with PD, ET, dystonia, and almost two thirds in APS. Patient-reported QOL measures, such as VHI-10 and EAT-10, can help screen movement disorder patients for dysphonia and dysphagia symptoms.

Neurology steering board effects change for a major electronic health record vendor.

Neurologists are among the least satisfied physicians with their current electronic health record (EHR), with many known pain points and great opportunities for improved tools and workflows. Improved EHR functionality can have major implications for patient care, physician efficiency, and prevention of burnout. We describe the advocacy of the American Academy of Neurology for improved EHR usability and the resultant formation and subsequent accomplishments of a Neurology Subspecialty Steering Board at 1 major EHR vendor (Epic).

Low-frequency versus high-frequency subthalamic nucleus deep brain stimulation on postural control and gait in Parkinson's disease: a quantitative study.

BACKGROUND: High frequency stimulation (HFS) of the subthalamic nucleus (STN-DBS) has been shown to have little impact on postural control and gait improvements in Parkinson's disease (PD). There is a lack of consensus and quantitative evidence to suggest that stimulating STN at a lower frequency (LFS) as compared to HFS will be superior in improving symptoms. OBJECTIVE/HYPOTHESIS: To determine if postural control and gait characteristics of persons with PD improve at an LFS (60 Hz) compared to HFS (>100 Hz). We hypothesized that persons with PD would perform better on postural control and gait measures at LFS. METHODS: Nineteen participants with bilateral STN-DBS underwent UPDRS, static and dynamic postural control using gait initiation, and gait evaluations in three stimulation conditions (baseline voltage stable across conditions: OFF, LFS of 60 Hz, and HFS of >100 Hz). Additionally 10/19 participants were also stimulated at 30 Hz and 60 Hz and at higher voltages. A one-way ANOVA was performed to compare the conditions. RESULTS: Total UPDRS-III score, step length and velocity during gait initiation, and gait speed significantly improved during 60 Hz and >100 Hz conditions when compared to the OFF condition (P < 0.05). There were no significant differences between 60 Hz and >100 Hz conditions. Using LFS at higher voltage showed no improvement over >100 Hz condition. CONCLUSIONS: The positive effects of both LFS and HFS on postural control and gait were similar and clinical changes were relatively small. LFS may not help improve postural control, and gait particularly for persons with PD who do not develop gait-related disorders after HFS.

Tractography Activation Patterns in Dorsolateral Prefrontal Cortex Suggest Better Clinical Responses in OCD DBS.

BACKGROUND: Medication resistant obsessive-compulsive disorder (OCD) patients can be successfully treated with Deep Brain Stimulation (DBS) which targets the anterior limb of the internal capsule (ALIC) and the nucleus accumbens (NA). Growing evidence suggests that in patients who respond to DBS, axonal fiber bundles surrounding the electrode are activated, but it is currently unknown which discrete pathways are critical for optimal benefit. Our aim was to identify axonal pathways mediating clinical effects of ALIC-NA DBS. METHODS: We created computational models of ALIC-NA DBS to simulate the activation of fiber tracts and to identify connected cerebral regions. The pattern of activated axons and their cortical targets was investigated in six OCD patients who underwent ALIC-NA DBS. RESULTS: Modulation of the right anterior middle frontal gyrus (dorsolateral prefrontal cortex) was associated with an excellent response. In contrast, non-responders showed high activation in the orbital part of the right inferior frontal gyrus (lateral orbitofrontal cortex/anterior ventrolateral prefrontal cortex). Factor analysis followed by step-wise linear regression indicated that YBOCS improvement was inversely associated with factors that were predominantly determined by gray matter activation results. DISCUSSION: Our findings support the hypothesis that optimal therapeutic results are associated with the activation of distinct fiber pathways. This suggests that in DBS for OCD, focused stimulation of specific fiber pathways, which would allow for stimulation with lower amplitudes, may be superior to activation of a wide array of pathways, typically associated with higher stimulation amplitudes.