A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce burden by shortening the treatment course, but the safety, feasibility, and acceptability of iTBS have not been established in MCI. METHODS: 24 older adults with amnestic MCI (aMCI) due to possible Alzheimer's disease enrolled in a phase I trial of open-label accelerated iTBS to the left dorsolateral prefrontal cortex (8 stimulation sessions of 600 pulses of iTBS/day for 3 days). Participants rated common side effects during and after each session and retrospectively (at post-treatment and 4-week follow-up). They completed brain MRI (for safety assessments and electric field modeling), neuropsychiatric evaluations, and neuropsychological testing before and after treatment; a subset of measures was administered at follow-up. RESULTS: Retention was high (95%) and there were no adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participants reported high acceptability, minimal side effects, and low desire to quit despite some rating the treatment as tiring. Electric field modeling data suggest that all participants received safe and therapeutic cortical stimulation intensities. We observed a significant, large effect size (d=0.98) improvement in fluid cognition using the NIH Toolbox Cognition Battery from pre-treatment to post-treatment. CONCLUSIONS: Our findings support the safety, feasibility, and acceptability of accelerated iTBS in aMCI. In addition, we provide evidence of target engagement in the form of improved cognition following treatment. These promising results directly inform future trials aimed at optimizing treatment parameters. TRIAL REGISTRATION NUMBER: NCT04503096.

Neuroversion: using electroconvulsive therapy as a bridge to deep brain stimulation implantation.

Parkinson's disease (PD) is a movement disorder with significant neuropsychiatric comorbidities. Electroconvulsive therapy (ECT) is effective in treating these neuropsychiatric symptoms; however, clinicians are reluctant to use ECT in patients with deep brain stimulation (DBS) implantations for fear of damaging the device, as well as potential cognitive side effects. Right unilateral ultra-brief pulse (RUL UBP) ECT has a more favorable cognitive side-effect profile yet has never been reported in PD patients with DBS implants. We present a case series of three patients with a history of PD that all presented with psychiatric decompensation immediately prior to planned DBS surgery. All three patients had DBS electrode(s) in place at the time and an acute course of ECT was utilized in a novel method to "bridge" these individuals to neurosurgery. The patients all experienced symptom resolution (psychosis and/or depression and/or anxiety) without apparent cognitive side effects. This case series not only illustrates that right unilateral ultra-brief pulse can be utilized in patients with DBS electrodes but also illustrates that this intervention can be utilized as a neuromodulatory "bridge", where nonoperative surgical candidates with unstable psychiatric symptoms can be converted to operative candidates in a manner similar to electrical cardioversion.

Reward circuit DBS improves Parkinson's gait along with severe depression and OCD.

A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry.

Integrity of the nucleus basalis of meynert and self-reported cognitive dysfunction during wearing-off periods in parkinson's disease.

BACKGROUND: Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. METHODS: Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). RESULTS: The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. CONCLUSIONS: Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

Subthalamic functional connectivity associated with freezing of gait dopa-response.

INTRODUCTION: Freezing of gait (FOG) is a prevalent and debilitating feature of Parkinson's Disease (PD). The subthalamic nucleus (STN) is a center for controlled locomotion and a common DBS target. The objective of this study was to identify STN circuitry associated with FOG response to dopaminergic medication. In this study, we compare BOLD functional connectivity of the subthalamic nucleus (STN) in participants with and without dopa-responsive FOG. METHODS: 55 PD participants either with FOG (n = 38) or without FOG (n = 17) were recruited. Among FOG participants 22 were dopa-responsive and 16 were dopa-unresponsive. STN whole-brain connectivity was performed using CONN toolbox. The relationship between the degree of self-reported FOG dopa-response and STN connectivity was evaluated using partial correlations corrected for age, disease duration, and levodopa equivalent daily dose. RESULTS: Right STN connectivity with the cerebellar locomotor region and the temporal/occipital cortex was greater in the dopa-responsive FOG group (voxel threshold p < 0.01, FWE corrected p < 0.05). Left STN connectivity with the occipital cortex was greater in the dopa-responsive FOG group and connectivity with the postcentral gyrus was greater in the dopa-unresponsive FOG group. Strength of connectivity to these regions correlated with l-dopa induced improvement in UPDRS Item-14 (FOG), but not UPDRS Part-III (overall motor score). DISCUSSION: We demonstrate that dopa-unresponsive FOG is associated with changes in BOLD functional connectivity between the STN and locomotor as well as sensory processing regions. This finding supports the conceptual framework that effective treatment for freezing of gait likely requires the engagement of both locomotor and sensory brain regions.

Deep brain stimulation for essential tremor versus essential tremor plus: should we target the same spot in the thalamus?

Background: Although ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways. Methods: A retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb. Results: Sixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset (p = 0.185) and underwent surgery at a younger age (p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups (n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia. Conclusion: VIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups.

Anterocollis and camptocormia in parkinsonism: a current assessment.

Postural deformities in parkinsonian syndromes are well recognized, but poorly understood and largely refractory to available therapies. In recent times a number of hypotheses have been proposed to explain the underlying etiology of anterocollis and camptocormia, but currently there is no consensus. As these conditions are more precisely characterized we begin to uncover that this is a heterogeneous and evolving phenomenon. These conditions bring to light the inadequacies of our current tools to study biomechanics of posture, neuromuscular disorders, and dystonic muscular contractions. The development of objective, accurate tools to directly study and measure the severity of these postural disorders will allow for further understanding of the pathophysiology, the development of novel therapeutics, and adequate clinical trial design.

A feasibility study of objective outcome measures used in clinical trials of freezing of gait.

BACKGROUND: Freezing of gait (FOG) is notoriously difficult to quantify, which has led to the use of multiple markers as outcomes for clinical trials. The instrumented timed up and go (TUG) and the many parameters that can be derived from it are commonly used as objective markers of FOG severity in clinical trials; however, it is unknown if they represent actual FOG severity. OBJECTIVE: To determine the specificity and responsiveness of objective surrogate markers of FOG severity commonly utilized in FOG studies. METHODS: Study design: We compared the specificity and responsiveness of commonly used markers in FOG clinical trials. Markers compared included velocity, step/stride length, step/stride length variability, TUG, and turn duration. Data was collected in four conditions (ON and OFF dopaminergic drugs, with and without a dual task). Unified Parkinson's Disease Rating Scale (UPDRS) was administered in the ON and OFF states. RESULTS: Thirty-three subjects were recruited (17 PD subjects without FOG (PD-control) and 16 subjects with PD and dopa-responsive FOG PD-FOG). The UPDRS motor scores were 24.9 for the PD-control group in the ON state, 24.8 for the FOG group in the ON state, and 42.4 for the FOG group in the OFF state. Significant mean differences between the ON and OFF conditions were observed with all surrogate markers (p < 0.01). However, only dual task turn duration and step variability showed trends toward significance when comparing PD-control and ON-FOG (p = 0.08). Test-retest reliability was high (ICC > 0.90) for all markers except standard deviations. Step length variability was the only marker to show an area under the ROC curve analysis > 0.70 comparing ON-FOG vs. PD-control. CONCLUSIONS: Multiple candidate surrogate markers for FOG severity showed responsiveness to levodopa challenge; however, most were not specific for FOG severity.

Genetic profile in genes associated with muscle injuries and injury etiology in professional soccer players.

Many causes define injuries in professional soccer players. In recent years, the study of genetics in association with injuries has been of great interest. The purpose of this study was to examine the relationship between muscle injury-related genes, injury risk and injury etiology in professional soccer players. In a cross-sectional cohort study, one hundred and twenty-two male professional football players were recruited. AMPD1 (rs17602729), ACE (rs4646994), ACTN3 (rs1815739), CKM (rs8111989) and MLCK (rs2849757 and rs2700352) polymorphisms were genotyped by using Single Nucleotide Primer Extension (SNPE). The combined influence of the six polymorphisms studied was calculated using a total genotype score (TGS). A genotype score (GS) of 2 was assigned to the "protective" genotype for injuries, a GS of 1 was assigned to the heterozygous genotype while a GS of 0 was assigned to the "worst" genotype. Injury characteristics and etiology during the 2021/2022 season were classified following a Consensus Statement for injuries recording. The distribution of allelic frequencies in the AMPD1 and MLCK c.37885C>A polymorphisms were different between non-injured and injured soccer players (p < 0.001 and p = 0.003, respectively). The mean total genotype score (TGS) in non-injured soccer players (57.18 ± 14.43 arbitrary units [a.u.]) was different from that of injured soccer players (51.71 ± 12.82 a.u., p = 0.034). There was a TGS cut-off point (45.83 a.u.) to discriminate non-injured from injured soccer players. Players with a TGS beyond this cut-off had an odds ratio of 1.91 (95%CI: 1.14-2.91; p = 0.022) to suffer an injury when compared with players with lower TGS. In conclusion, TGS analysis in muscle injury-related genes presented a relationship with professional soccer players at increased risk of injury. Future studies will help to develop this TGS as a potential tool to predict injury risk and perform prevention methodology in this cohort of football players.

Injury Incidence Increases after COVID-19 Infection: A Case Study with a Male Professional Football Team.

Background: The SARS-CoV-2 virus disease has caused numerous changes in sports routines in the last two years, showing the influence on an increase in sports injuries. The aim of this study was to prospectively analyze the incidence and characteristics of injuries in male professional football players diagnosed with COVID-19 when they return to play after recovering from this illness. Methods: Injury characteristics of professional male football players were recorded for the 2020−2021 season following the international consensus statement from the International Olympic Committee (IOC). SARS-CoV-2 infection in the football players was certified by PCR analysis. Injury epidemiology was compared in players infected by the SARS-CoV-2 virus before and after being diagnosed with COVID-19. Results: 14 players (53.8%) were diagnosed with COVID-19 during 2020−2021 season and 12 (46.2%) were not infected (controls). Only three (21.4%) had suffered an injury before being diagnosed with COVID-19. Eleven players (78.6%) had injuries after being diagnosed with COVID-19 (p < 0.001). Among the players diagnosed with COVID-19, injury incidence increased on their return to play after the infection (3.8 to 12.4 injuries/1000 h of exposure, p < 0.001). Additionally, injury incidence during training (10.6 vs. 5.1 injuries/1000 h of exposure, p < 0.001) and matches (56.3 vs. 17.6 injuries/1000 h of exposure, p < 0.001) was ~two-fold higher on return to play after COVID-19 compared to controls (33.4 vs. 17.6 injuries/1000 h of exposure, respectively, p < 0.001). Conclusions: Injury incidence in professional football players who had been infected by the SARS-CoV-2 virus significantly increased compared to the injury rates that these same players had prior to the illness. Additionally, the injury incidence was higher when compared to players who were not infected by the SARS-CoV-2 virus during the season, especially during matches.

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

BACKGROUND: Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches. OBJECTIVE: We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy. METHODS: In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication). RESULTS: The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = -0.360, df = 30, p = 0.043) but not overall motor dopa-response. CONCLUSION: These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

Tardive dyskinesia.

OPINION STATEMENT: Tardive dyskinesia (TD) is iatrogenic (drug-induced); hence the best strategy is prevention. Try to limit exposure to any dopamine receptor blocking agents (DRBAs) if possible. These agents may be unavoidable in some psychiatric conditions such as schizophrenia, but alternative therapies can be used in many situations, such as in the treatment of depression, anxiety, gastrointestinal conditions, and other neurologic conditions, including migraines and sleep disorders. When DRBAs are necessary, physicians should prescribe the smallest possible dose and try to taper and stop the drug at the earliest signs of TD. Abrupt cessation should be avoided, as this can worsen symptoms of TD. Always discuss and document the possibility of TD as an adverse effect when starting patients on DRBAs. If TD is mild and tolerable, the withdrawal of the offending agent is possible, and exposure to DRBAs was short, physicians should consider avoiding treatment and waiting for spontaneous recovery. When treatment is necessary, tetrabenazine (TBZ) is considered a potential first-line agent and is known to be one of the most effective drugs in treating TD, but it is expensive and adverse effects such as depression, akathisia and parkinsonism frequently occur. Therefore, second-line agents with better tolerability profiles are often tried first in practice. These include amantadine, benzodiazepines, beta-blockers, and levetiracetam. When using TBZ, adverse effects should be aggressively monitored. (Depression often can be managed with antidepressants, for instance). In patients with psychosis, withdrawal of the antipsychotic may not be possible. Switching to clozapine or quetiapine is one option to minimize TD. When these agents are contraindicated and the patient must continue using other atypical antipsychotic drugs, try to add dopamine-depleting agents such as TBZ or reserpine, but watch for the development of parkinsonism. When the symptoms are focal, such as tongue protrusion or blepharospasm, botulinum toxin injections can be very effective if spontaneous recovery does not occur. As a last resort, when disabling, life-threatening symptoms of TD persist despite all of the above-mentioned methods, some advocate resuming treatment with the DRBA to suppress symptoms of TD. This has the potential to worsen TD in the long run.

Executive function and dopamine response in Parkinson's disease freezing of gait.

BACKGROUND: This investigation examined whether aspects of attention and executive functioning differed between Parkinson's Disease (PD) patients with freezing of gait (FOG) based on responsiveness to dopamine. We also explored association of cognition with FOG severity and gait metrics. METHODS: Fifty-four individuals with PD completed the study protocol: 17 without freezing (PDC), 23 with dopa-responsive FOG (RFOG), and 14 with dopa-unresponsive (URFOG). Standardized neuropsychological tests assessed attention (focused and sustained), psychomotor speed, and set-switching (time and errors). FOG severity was measured using the new FOG Questionnaire (nFOG-Q). Metrics from timed up and go (TUG) tasks were obtained while "on" and "off" dopamine, with and without dual cognitive tasks. RESULTS: After controlling for clinical and demographic factors, analysis of covariance revealed a significant between-group difference for set-switching errors; planned contrasts revealed increased set-switching errors in URFOG relative to RFOG and PD control groups. Groups were not different in other cognitive domains. FOG severity was modestly associated with set-switching errors in RFOG but not URFOG. TUG performances while "on" were associated with set-switching errors in PD controls, and with focused attention in RFOG. CONCLUSION: PD patients with dopa-unresponsive FOG are more prone to set-switching errors than those who respond to treatment. Furthermore, executive function appears relevant to FOG severity only in patients who show dopamine response. Together, these findings suggest disruption of a common dopamine-mediated pathway for FOG and ability to monitor rules while alternating cognitive processes. Consideration of dopa-response could be useful in characterizing cohorts and treating FOG in PD.

Perioperative Botulinum Toxin A in the Surgical Management of Seizure-Related Shoulder Instability: A Case Report.

CASE: A 20-year-old woman presented with recurrent bilateral shoulder instability concurrent with severe, treatment-refractory epilepsy. Imaging revealed glenoid bone loss of 25% to 28% and large Hill-Sachs defects bilaterally. Bone graft augmentation of the glenoid and infill of the Hill-Sachs defects was performed bilaterally. Perioperative neuromuscular paralysis of shoulder girdle muscles with botulinum toxin was performed to facilitate recovery. Both shoulders at 2.5 and 4 years, respectively, demonstrate excellent stability and radiographic union despite continued seizure activity. CONCLUSION: Perioperative neuromuscular paralysis with botulinum toxin may provide early graft protection after the surgical treatment of glenohumeral instability because of seizures.

Paired inhibitory stimulation and gait training modulates supplemental motor area connectivity in freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD). Evidence suggests patients with FOG have increased cortical control of gait. The supplementary motor area (SMA) may be a key structure due to its connectivity with locomotor and cognitive networks. The objectives of this study were to determine (1) if SMA connectivity is disrupted in patients with FOG and (2) if "inhibitory" repetitive transcranial magnetic stimulation can decrease maladaptive SMA connectivity. METHODS: Two experiments were performed. In experiment 1 resting-state (T2* BOLD imaging) was compared between 38 PD freezers and 17 PD controls. In experiment 2, twenty PD patients with FOG were randomized to either 10 sessions of real or sham rTMS to the SMA (1 Hz, 110% motor threshold, 1200 pulses/session) combined with daily gait training. RESULTS: (Experiment 1) Freezers had increased connectivity between the left SMA and the vermis of the cerebellum and decreased connectivity between the SMA and the orbitofrontal cortex (pFDR-corr <0.05). (Experiment 2) 10 sessions of active TMS reduced SMA connectivity with the anterior cingulate, angular gyrus and the medial temporal cortex, whereas sham TMS did not reduce SMA connectivity. From a behavioral perspective, both groups showed nFOG-Q improvements (F(4, 25.7) = 3.87, p = 0.014). CONCLUSIONS: The SMA in freezers is hyper-connected to the cerebellum, a key locomotor region which may represent maladaptive compensation. In this preliminary study, 1 Hz rTMS reduced SMA connectivity however, this was not specific to the locomotor regions. Intervention outcomes may be improved with subject specific targeting of SMA.

Therapeutic interventions in the primary hereditary ataxias.

OPINION STATEMENT: The treatment of hereditary ataxia is primarily supportive. With very few exceptions (eg, ataxia associated with vitamin E deficiency), there are no disease-modifying therapies. Despite the lack of disease-modifying treatments, there can be great value in obtaining an accurate diagnosis of hereditary ataxia subtype. Benefits include determining prognosis, facilitating family counseling, improving research access, and providing some psychological benefit in ending the often frustrating search for an accurate etiology. Hereditary ataxias may have certain clinical features that respond very well to symptomatic medical therapy. Parkinsonism, dystonia, spasticity, urinary urgency, sleep pathology, fatigue, and depression are all common in many of the ataxia subtypes and very often respond to pharmacologic intervention as in other diseases. Much of the clinical interaction between neurologist and ataxia patient should focus on identifying and treating these symptoms. Treatment of the core clinical feature of these diseases-ataxia-is predominantly rehabilitative. The value of good physical therapy far exceeds any potential benefit from medications that a physician might prescribe to improve balance and coordination. Speech and swallowing are often affected. In more severe cases, aspiration risk can be very significant and life-threatening. Routine monitoring of swallowing by speech therapists, often including modified barium swallowing tests, is indicated in most patients. Recently there have been very encouraging advances in clinical ataxia research. Collaborative study groups throughout the world have developed and validated ataxia rating scales and instrumented outcome measures and have begun to rigorously define the natural history of these diseases, thus laying the foundation for well-designed clinical trials. The promise of disease-modifying treatments is closer than ever.

Increased on-state cortico-mesencephalic functional connectivity in Parkinson disease with freezing of gait.

BACKGROUND: The objective of this study was to evaluate ON-state resting state functional connectivity (FC) from the mesencephalic locomotor regions (MLR) to distributed sensorimotor cortical regions in patients with Freezing of Gait (FOG) and its association with gait performance. METHODS: 54 individuals with PD were recruited for this study (50% of whom had FOG). All individuals received a resting state functional MRI in the ON state, and underwent a series of gait assessments during single and dual task conditions. FC with the MLR was calculated using a whole brain seed to voxel approach wherein the left and right MLR seeds were extracted from a published atlas. General linear regression was used to determine differences in connectivity between the individuals with ('freezers') and without ('non-freezers') FOG as well as the correlation between MLR connectivity and gait performance in the freezers. RESULTS: Freezers had significantly higher MLR connectivity to a network of sensorimotor regions compared to non-freezers. Additionally, among the freezers, higher FC with these regions was related to longer single-task and dual-task performance. There were no regions in which non-freezers had higher connectivity than freezers (p < 0.05, FWE corrected clusters for all analyses). CONCLUSION: These data support the hypothesis that freezers have significantly higher ON-state FC between the MLR and a network of cortical structures than non-freezers. Additionally, this elevated connectivity is directly related to worsening FOG severity. These data add to a theoretical foundation which suggests that cortical hyperconnectivity to the MLR is central to the underlying pathophysiology of FOG.

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

Characterizing Thalamo-Cortical Structural Connectivity in Essential Tremor with Diffusional Kurtosis Imaging Tractography.

Background: Neuromodulation of the cerebello-thalamo-cortical (CTC) circuit via thalamic stimulation is an effective therapy for essential tremor (ET). In order to develop non-invasive neuromodulation approaches, clinically relevant thalamo-cortical connections must be elucidated. Methods: Twenty-eight subjects (18 ET patients and 10 controls) underwent MRI diffusional kurtosis imaging (DKI). A deterministic fiber-tracking algorithm based on DKI was used, with a seeding region placed at the ventral intermediate nucleus (Vim-located based on intraoperative physiology) to the ending regions at the supplementary motor area (SMA), pre-SMA, or primary motor cortex. One-tailed t-tests were performed to compare groups, and associations with tremor severity were determined by Pearson correlations. All p-values were adjusted for multiple comparisons using Bonferroni correction. Results: There was a decrease in the mean diffusivity (MD) in patients compared to controls in all three tracts: Vim-M1 (ET 0.87, control 0.96, p < 0.01), Vim-SMA (ET 0.86, control 0.96, p < 0.05), and Vim-pre-SMA (ET 0.87, control 0.95, p < 0.05). There was a significant positive correlation between Tremor Rating Scale score and MK (r = 0.471, p = 0.033) and mean FA (r = 0.438, p = 0.045) for the Vim-SMA tract, and no significant correlation for the Vim-pre-SMA or Vim-M1 tracts was found. Discussion: Patients with ET demonstrated a reinforcement of Vim-cortical connectivity, with higher Vim-SMA connectivity being associated with greater tremor severity. This finding suggests that the Vim-SMA connection is relevant to the underlying pathophysiology of ET, and inhibition of the SMA may be an effective therapeutic approach.

Neuritic pathology as a correlate of synaptic loss in dementia with lewy bodies.

Synaptic loss is present in Alzheimer's disease and correlates with the severity of dementia. Loss of synapses in dementia with Lewy bodies (DLB) does not correlate as clearly with cognitive status and its cause is unclear. To begin to understand the relationship between cognition and synaptic loss in DLB, we assessed immunoreactivity for the synaptic-terminal specific protein, synaptophysin, in the hippocampus in 14 DLB cases. Quantitative synaptic data were obtained using an Image-Pro semiautomated analysis system. We determined Braak stage, beta-amyloid, Lewy bodies (LBs), and Lewy neurites (LN). We found significant correlations (r = 0.617, P < .01) between Braak stage and synaptophysin score and marginal correlation between LN score and synaptophysin loss ( r = 0.694, P < .06). Correlations of beta-amyloid and of LB density with synaptophysin score were unimpressive. These data support the hypothesis that synaptic loss in DLB is related to neuritic degeneration.