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Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons and dysregulation of the basal ganglia. Cardinal motor symptoms include bradykinesia, rigidity, and tremor. Deep brain stimulation (DBS) of select subcortical nuclei is standard-of-care for medication-refractory PD. Conventional open-loop DBS delivers continuous stimulation with fixed parameters that do not account for a patient's dynamic activity state or medication cycle. In comparison, closed-loop, or adaptive DBS (aDBS) adjusts stimulation based on biomarker feedback that correlates with clinical state. Recent work has identified several neurophysiological biomarkers in local field potential recordings from PD patients, the most promising of which are: 1) elevated beta (~13-30 Hz) power in the subthalamic nucleus (STN), 2) increased beta synchrony throughout basal ganglia-thalamocortical circuits, notably, observed as coupling between the STN beta phase and cortical broadband gamma (~50-200 Hz) amplitude, and 3) prolonged beta bursts in the STN and cortex. In this review, we highlight relevant frequency and time domain features of STN beta measured in PD patients and summarize how spectral beta power, oscillatory beta synchrony, phase-amplitude coupling, and temporal beta bursting informs PD pathology, neurosurgical targeting, and DBS therapy. We then review how STN beta dynamics inform predictive, biomarker-driven aDBS approaches for optimizing PD treatment. We therefore provide clinically useful and actionable insight that can be applied towards aDBS implementation for PD.

DYT-TUBB4A, formerly known as DYT4, has not been comprehensively described as only one large family and three individual cases have been published. We have recently described an in depth genetic and protein structural analysis of eleven additional cases from four families with four new pathogenic variants. We aim to report on the phenomenology of these cases suffering from DYT-TUBB4A and to perform a comprehensive review of the clinical presentation and treatment responses of all DYT-TUBB4A cases reported in the literature.The clinical picture was typically characterized by laryngeal dystonia (more than three quarters of all cases), associated with cervical dystonia, upper limb dystonia and frequent generalization. Extension of the dystonia to the lower limbs, creating the famous "hobby horse" gait, was present in more than 20% of cases (in only one of ours). Globus pallidus pars interna (GPi) deep brain stimulation (DBS), performed in 4 cases, led to a good improvement with greatest benefit in motoric and less benefit in laryngeal symptoms. Medical treatment was generally rather poorly effective, except some benefit from propranolol, tetrabenazine and alcohol intake.Laryngeal involvement is a hallmark of DYT-TUBB4A. Symptomatic treatment with GPi-DBS led to the greatest benefit in motoric symptoms. Nevertheless

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these “imaging pearls” into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

Background: Globus pallidus internus (GPi) deep brain stimulation (DBS) and thalamotomy are interventions for writer’s cramp (WC). Ventralis intermedius nucleus (VIM) DBS is targeted for tremor, however, many aspects of VIM DBS remained underexplored in WC. Case Report: A 62-year-old man with WC underwent DBS. Dystonic tremor improved intraoperatively with ventralis oralis anterior (VoA)/ventral oralis posterior (VoP) and with subthalamic nucleus stimulation; although greatest benefit was obtained with VIM stimulation. Sustained benefit with VIM DBS at ten months post-operative was obtained. Discussion: This case demonstrates an intraoperative approach in target selection and supports benefits of VIM DBS for WC. Highlights: This case highlights the intraoperative approach and clinical effects of VIM DBS in the treatment of medically refractory writer’s cramp (WC). We contextualize our results from this case with previous reports of VoA/VoP stimulation for WC.

Objective: to report four novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization. Background: DYT-TUBB4A, formerly known as DYT4, has only been described in one large family and two individual cases. The clinical picture highlighted in the original family comprises laryngeal and cervical dystonia extending to generalized dystonia, plus a “hobby horse” gait disorder. The variant identified as causative in the original family was a heterozygous missense mutation R2G in exon 1 of the TUBB4A gene. Methods: we screened four families including a total of eleven definitely affected members with a clinical picture resembling the original description. Results: four novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, R121W . In silico modeling showed that all variants have similar characteristics to R2G. The variants segregate with the disease in three of the families with evidence of incomplete penetrance in two of them. All four variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The “hobby horse” gait was evident in only one patient in this case series. Interpretation: laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.

Observations using invasive neural recordings from patient populations undergoing neurosurgical interventions have led to critical breakthroughs in our understanding of human neural circuit function and malfunction. The opportunity to interact with patients during neurophysiological mapping allowed for early insights in functional localization to improve surgical outcomes, but has since expanded into exploring fundamental aspects of human cognition including reward processing, language, the storage and retrieval of memory, decision-making, as well as sensory and motor processing. The increasing use of chronic neuromodulation, via deep brain stimulation, for a spectrum of neurological and psychiatric conditions has in tandem led to increased opportunity for linking theories of cognitive processing and neural circuit function. Our purpose here is to motivate the neuroscience and neurosurgical community to capitalize on the opportunities that this next decade will bring. To this end, we will highlight recent studies that have successfully leveraged invasive recordings during deep brain stimulation surgery to advance our understanding of human cognition with an emphasis on reward processing, improving clinical outcomes, and informing advances in neuromodulatory interventions.

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts.

Background/Aims: Interleaving stimulation (ILS) in deep brain stimulation (DBS) provides individualized stimulation of 2 contacts delivered in alternating order. Currently, limited information on the utility of ILS exists. The aims of this study were to determine the practical applications and outcomes of ILS DBS in Parkinson’s disease (PD), tremor, and dystonia. Methods: We performed a single-center, unblinded, retrospective chart review of all patients with DBS attempted on ILS at our referral center assessing for rationale and outcomes. Results: Fifty patients (PD, n = 27; tremor, n = 7; dystonia, n = 16 patients) tried ILS for 2 rationales: management of adverse effects (n = 29) and to improve clinical efficacy (n = 21). A total of 19 patients demonstrated improvement with ILS for adverse effect management predominately for the treatment of dyskinesias (n = 12). In the vast majority of dyskinetic patients, a contact added into the rostral zona incerta with ILS was performed. Nine out of 21 patients demonstrated improved clinical efficacy with ILS with all 6 PD patients who tried ILS for this rationale demonstrating benefit. Conclusions: In PD, ILS provided benefits for dyskinesias and parkinsonism, with minimal improvement of other adverse effects. In tremor and dystonia, marginal effects in terms of mitigation of adverse effects and improvement of clinical outcomes were evident.

Objective To examine sex differences and trends in comorbid disease and health care utilization in individuals with newly diagnosed Parkinson disease (PD). Design Retrospective cohort study. Participants Over 133,000 Medicare beneficiaries with a new PD diagnosis in 2002 followed through 2008. Methods We compared the prevalence and cumulative incidence of common medical conditions, trends in survival and health care utilization between men and women with PD. Results Female PD patients had higher adjusted incidence rate ratio (IRR) of depression (IRR: 1.28, 1.25–1.31), hip fracture (IRR: 1.51, 1.45–1.56), osteoporosis (3.01, 2.92–3.1), and rheumatoid/osteoarthritis (IRR: 1.47, 1.43–1.51) than men. In spite of greater survival, women with PD used home health and skilled nursing facility care more often, and had less outpatient physician contact than men throughout the study period. Conclusions Women experience a unique health trajectory after PD diagnosis as suggested by differing comorbid disease burden and health care utilization compared to men. Future studies of sex differences in care needs, care quality, comorbidity related disability, PD progression, and non-clinical factors associated with disability are needed to inform research agendas and clinical guidelines that may improve quality survival for women with PD.

Objective:To examine rehabilitation therapy utilization for Parkinson disease (PD).Methods:We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST).Results:Outpatient rehabilitation fee-for-service use was low. In 2007, only 14.2% of individuals with PD had claims for PT or OT, and 14.6% for ST. Asian Americans were the highest users of PT/OT (18.4%) and ST (18.4%), followed by Caucasians (PT/OT 14.4%, ST 14.8%). African Americans had the lowest utilization (PT/OT 7.8%, ST 8.2%). Using logistic regression models that accounted for repeated measures, we found that African American patients (adjusted odds ratio [AOR] 0.63 for PT/OT, AOR 0.63 for ST) and Hispanic patients (AOR 0.97 for PT/OT, AOR 0.91 for ST) were less likely to have received therapies compared to Caucasian patients. Patients with PD with at least one neurologist visit per year were 43% more likely to have a claim for PT evaluation as compared to patients without neurologist care (AOR 1.43, 1.30–1.48), and this relationship was similar for OT evaluation, PT/OT treatment, and ST. Geographically, Western states had the greatest use of rehabilitation therapies, but provider supply did not correlate with utilization.Conclusions:This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson9s disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep–wake cycle that contribute to our understanding of RBD.

Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of Alzheimer's disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid-β or APP. These clusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were similar to those described by others who also found extracelluar proteinous granules in the brains of non-DS mice engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD.

Degradable polymers have been used successfully in a wide variety of peripheral applications from tissue regeneration to drug delivery. These polymers induce little inflammatory response and appear to be well accepted by the host environment. Their use in the brain, for neural tissue reconstruction or drug delivery, also could be advantageous in treating neurodegenerative disorders. Because the brain has a unique immune response, a polymer that is compatible in the body may not be so in the brain. In the present study, polyethylene glycol (PEG)-based hydrogels were implanted into the striatum and cerebral cortex of nonhuman primates. Four months after implantation, brains were processed to evaluate the extent of astrogliosis and scaring, the presence of microglia/macrophages, and the extent of T-cell infiltration. Hydrogels with 20% w/v PEG implanted into the brain stimulated a slight increase in astrocytic and microglial/macrophage presence, as indicated by a small increase in glial fibrillary acidic protein (GFAP) and CD68 staining intensity. This increase was not substantially different from that found in the sham-implanted hemispheres of the brain. Staining for CD3+ T cells indicated no presence of peripheral T-cell infiltration. No gliotic scarring was seen in any implanted hemisphere. The combination of low density of GFAP-positive cells and CD68-positive cells, the absence of T cells, and the lack of gliotic scarring suggest that this level of immune response is not indicative of immunorejection and that the PEG-based hydrogel has potential to be used in the primate brain for local drug delivery or neural tissue regeneration.

The finger tapping test evaluates bradykinesia, focusing on decrement in rate, amplitude, or both with repetitive action. Vertical positioning of the hands during this task may also be clinically relevant. We developed a "TAP score," measuring the vertical level above the lap where the patient performs the finger tapping ranging from 1 (task performed with the hand close to the lap) to 4 (above the head). In this pilot study, we retrospectively applied the TAP score in addition to usual motor scales during acute levodopa challenge in 123 PD patients (of whom 88 presented l-dopa-induced dyskinesia [LID]). TAP ON was higher than TAP OFF. Patients with LID presented higher TAP ON. TAP ON was related to LID severity, whereas TAP OFF was inversely related to the OFF motor symptoms. The TAP score may be a measure of proximal movement amplitude representing an easy method to evaluate defective or excessive motor output in patients with advanced disease.

To determine the utility of detecting a-synuclein (aSyn) in colonic mucosal biopsy tissue as a potential diagnostic biomarker for Parkinson disease (PD).We used the paraffin-embedded tissue (PET) blot, which degrades physiologic nonaggregated aSyn using proteinase K and enhances antigen retrieval allowing sensitive and selective detection of remaining protein aggregates, to detect aSyn in colonic mucosal biopsies from 15 patients with early PD (,3 years), 7 patients with later PD (.5 years), and 11 individuals without PD. aSyn and serine 129–phosphorylated aSyn (Ser129p-aSyn) were assessed by PET blot and conventional immunohistochemistry.PET blot–resistant aggregated aSyn and Ser129p-aSyn was present in 12 of 15 individuals with early PD, 7 of 7 individuals with later PD, and 11 of 11 control subjects. The number of biopsies positive by PET blot relative to conventional immunohistochemistry was significantly lower in both PD groups compared with the control group for both aSyn and Ser129p-aSyn,whereas routine immunohistochemistry was positive more often in PD, but was positive in as many as 9 of 11 control individuals.Strong evidence of the presence of aggregated hyperphosphorylated aSyn in individuals with and without PD, using such a sensitive and specific method as the PET blot, suggests that colonic deposition of aSyn is not a useful diagnostic test for PD. The utility of detecting aSynin the colon as a biomarker in combination with other assessments remains to be determined.

Despite limited data on humans, previous studies suggest that there is an association between the duration of daily muscle activity and the proportion of type I muscle fibers. We quantified the activity of limb muscles in healthy men and women during normal use and compared these measurements with published reports on fiber-type proportions. Seven men (age range = 21–28 yr) and seven women (age range = 18–26 yr) participated in two 10-h recording sessions. Electromyogram (EMG) activity of four muscles in nondominant upper (first dorsal interosseus and biceps brachii) and lower limbs (vastus medialis and vastus lateralis) was recorded with surface electrodes. Hand and arm muscles were active for 18% of the recording time, whereas leg muscles were active for only 10% of the recording time. On average, upper-limb muscles were activated 67% more often than lower-limb muscles. When lower-limb muscles were activated, however, the mean amplitude of each burst was greater in leg muscles [18 and 17% maximum voluntary contraction (MVC)] compared with hand (8% MVC) and arm (6% MVC) muscles. Temporal association in activity between pairs of muscles was high for the two lower-limb muscles ( r 2 = 0.7) and relatively weak for the two upper-limb muscles ( r 2 = 0.09). Long-term muscle activity was only different between men and women for the biceps brachii muscle. We found no relation between duration of muscle activity in 10-h recordings and the reported values of type I fibers in men and women.