An update on advanced therapies for Parkinson's disease: From gene therapy to neuromodulation.

Advanced Parkinson's disease (PD) is characterized by increasingly debilitating impaired movements that include motor fluctuations and dyskinesias. At this stage of the disease, pharmacological management can result in unsatisfactory clinical benefits and increase the occurrence of adverse effects, leading to the consideration of advanced therapies. The scope of this review is to provide an overview of currently available therapies for advanced PD, specifically levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion, radiofrequency ablation, stereotactic radiosurgery, MRI-guided focused ultrasound, and deep brain stimulation. Therapies in clinical trials are also discussed, including novel formulations of subcutaneous carbidopa/levodopa, gene-implantation therapies, and cell-based therapies. This review focuses on the clinical outcomes and adverse effects of the various therapies and also considers patient-specific characteristics that may influence treatment choice. This review can equip providers with updated information on advanced therapies in PD to better counsel patients on the available options.

Automatic extraction of upper-limb kinematic activity using deep learning-based markerless tracking during deep brain stimulation implantation for Parkinson's disease: A proof of concept study.

Optimal placement of deep brain stimulation (DBS) therapy for treating movement disorders routinely relies on intraoperative motor testing for target determination. However, in current practice, motor testing relies on subjective interpretation and correlation of motor and neural information. Recent advances in computer vision could improve assessment accuracy. We describe our application of deep learning-based computer vision to conduct markerless tracking for measuring motor behaviors of patients undergoing DBS surgery for the treatment of Parkinson's disease. Video recordings were acquired during intraoperative kinematic testing (N = 5 patients), as part of standard of care for accurate implantation of the DBS electrode. Kinematic data were extracted from videos post-hoc using the Python-based computer vision suite DeepLabCut. Both manual and automated (80.00% accuracy) approaches were used to extract kinematic episodes from threshold derived kinematic fluctuations. Active motor epochs were compressed by modeling upper limb deflections with a parabolic fit. A semi-supervised classification model, support vector machine (SVM), trained on the parameters defined by the parabolic fit reliably predicted movement type. Across all cases, tracking was well calibrated (i.e., reprojection pixel errors 0.016-0.041; accuracies >95%). SVM predicted classification demonstrated high accuracy (85.70%) including for two common upper limb movements, arm chain pulls (92.30%) and hand clenches (76.20%), with accuracy validated using a leave-one-out process for each patient. These results demonstrate successful capture and categorization of motor behaviors critical for assessing the optimal brain target for DBS surgery. Conventional motor testing procedures have proven informative and contributory to targeting but have largely remained subjective and inaccessible to non-Western and rural DBS centers with limited resources. This approach could automate the process and improve accuracy for neuro-motor mapping, to improve surgical targeting, optimize DBS therapy, provide accessible avenues for neuro-motor mapping and DBS implantation, and advance our understanding of the function of different brain areas.

Quantifying neuro-motor correlations during awake deep brain stimulation surgery using markerless tracking.

The expanding application of deep brain stimulation (DBS) therapy both drives and is informed by our growing understanding of disease pathophysiology and innovations in neurosurgical care. Neurophysiological targeting, a mainstay for identifying optimal, motor responsive targets, has remained largely unchanged for decades. Utilizing deep learning-based computer vision and related computational methods, we developed an effective and simple intraoperative approach to objectively correlate neural signals with movements, automating and standardizing the otherwise manual and subjective process of identifying ideal DBS electrode placements. Kinematics are extracted from video recordings of intraoperative motor testing using a trained deep neural network and compared to multi-unit activity recorded from the subthalamic nucleus. Neuro-motor correlations were quantified using dynamic time warping with the strength of a given comparison measured by comparing against a null distribution composed of related neuro-motor correlations. This objective measure was then compared to clinical determinations as recorded in surgical case notes. In seven DBS cases for treatment of Parkinson's disease, 100 distinct motor testing epochs were extracted for which clear clinical determinations were made. Neuro-motor correlations derived by our automated system compared favorably with expert clinical decision making in post-hoc comparisons, although follow-up studies are necessary to determine if improved correlation detection leads to improved outcomes. By improving the classification of neuro-motor relationships, the automated system we have developed will enable clinicians to maximize the therapeutic impact of DBS while also providing avenues for improving continued care of treated patients.

Novel targets in deep brain stimulation for movement disorders.

The neurosurgical treatment of movement disorders, primarily via deep brain stimulation (DBS), is a rapidly expanding and evolving field. Although conventional targets including the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) for Parkinson's disease and ventral intermediate nucleus of the thalams (VIM) for tremor provide substantial benefit in terms of both motor symptoms and quality of life, other targets for DBS have been explored in an effort to maximize clinical benefit and also avoid undesired adverse effects associated with stimulation. These novel targets primarily include the rostral zona incerta (rZI), caudal zona incerta (cZI)/posterior subthalamic area (PSA), prelemniscal radiation (Raprl), pedunculopontine nucleus (PPN), substantia nigra pars reticulata (SNr), centromedian/parafascicular (CM/PF) nucleus of the thalamus, nucleus basalis of Meynert (NBM), dentato-rubro-thalamic tract (DRTT), dentate nucleus of the cerebellum, external segment of the globus pallidus (GPe), and ventral oralis (VO) complex of the thalamus. However, reports of outcomes utilizing these targets are scattered and disparate. In order to provide a comprehensive resource for researchers and clinicians alike, we have summarized the existing literature surrounding these novel targets, including rationale for their use, neurosurgical techniques where relevant, outcomes and adverse effects of stimulation, and future directions for research.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

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.

Use of Three-Dimensional Printed Brain Models During Deep Brain Stimulation Surgery Consultation for Patient Health Literacy: A Randomized Controlled Investigation.

BACKGROUND: Advanced therapies in neurosurgery, such as deep brain stimulation (DBS), would benefit from improved patient education materials. Three-dimensional (3D) printed anatomical models represent a recent development for improving patient education for neurosurgical procedures. METHODS: In this study, 40 patients undergoing DBS surgery consultation were randomly assigned to 1 of 2 groups: an experimental group, which received a demonstration of DBS therapeutic neuroanatomical targets in a 3D printed brain model plus standard patient education (PE), or a control group, which received standard PE alone. RESULTS: Patients in the DBS model plus PE group showed a significant increase in patient confidence and understanding of the brain structures targeted during a DBS procedure compared with patients in the PE-only group (P < 0.01). There was no difference in perceived risk, comfort, or anxiety related to the procedure. CONCLUSIONS: In the first randomized controlled study to our knowledge of 3D printed models for DBS consultation, our results demonstrate that patients had improved understanding of their therapy with the models. However, the models alone did not affect risk evaluation or comfort with surgery. A 3D printed brain model may help improve patient understanding of DBS surgery.

Discrete changes in brain volume after deep brain stimulation in patients with Parkinson's disease.

OBJECTIVES: Deep brain stimulation (DBS), targeting the subthalamic nucleus (STN) and globus pallidus interna, is a surgical therapy with class 1 evidence for Parkinson's disease (PD). Bilateral DBS electrodes may be implanted within a single operation or in separate staged surgeries with an interval of time that varies patient by patient. In this study, we used the variation in the timing of implantation from the first to the second implantation allowing for examination of potential volumetric changes of the basal ganglia in patients with PD who underwent staged STN DBS. METHODS: Thirty-two patients with a mean time interval between implantations of 141.8 (±209.1; range: 7-700) days and mean duration of unilateral stimulation of 244.7 (±227.7; range: 20-672) days were included in this study. Using volumetric analysis of whole hemisphere and subcortical structures, we observed whether implantation or stimulation affected structural volume. RESULTS: We observed that DBS implantation, but not the duration of stimulation, induced a significant reduction of volume in the caudate, pallidum, putamen and thalamus ipsilateral to the implanted hemisphere. These findings were not dependent on the trajectory of the implanted electrode nor on first surgery pneumocephalus (0.07%: %Δ for intracranial volume between first and second surgery). In addition, unique regional atrophy differences were evident in each of the structures. CONCLUSION: Our results demonstrate that DBS implantation surgery may affect hemisphere volume at the level of subcortical structures connected to the surgical target.

Neural Circuit and Clinical Insights from Intraoperative Recordings During Deep Brain Stimulation Surgery.

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.

Colonic mucosal a-synuclein lacks specificity as a biomarker for Parkinson disease.

OBJECTIVE: To determine the utility of detecting a-synuclein (aSyn) in colonic mucosal biopsy tissue as a potential diagnostic biomarker for Parkinson disease (PD). METHODS: 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 129­phosphorylated aSyn (Ser129p-aSyn) were assessed by PET blot and conventional immunohistochemistry. RESULTS: PET blot­resistant 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. CONCLUSION: 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.

Deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) for the treatment of neurologic diseases has markedly increased in popularity over the past 15 years. This review primarily focuses on movement disorder applications and efficacy of DBS, but also briefly reviews other promising new and old uses of DBS. REVIEW SUMMARY: A multidisciplinary team consisting of a movement disorders neurologist, a functional neurosurgeon, and a neuropsychologist optimally selects patients for DBS. Patients must be significantly disabled despite optimal medical therapy and be cognitively healthy without significant psychiatric disorders. Although this surgery is elective, it should not be withheld until the patient suffers marked loss of quality of life. Patients must have support from caregivers and postoperatively multiple DBS programming visits may be required. DBS of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) significantly improves motor performance, activities of daily living, and quality of life in advanced Parkinson disease. In addition, STN DBS allows for marked reductions of antiparkinson medication. Stimulation of the ventralis intermedius nucleus of the thalamus is an effective treatment for essential tremor with sustained long-term effects. The GPi may be the preferred site of stimulation for dystonia with movement scores typically improved by 75% in patients with primary dystonia. CONCLUSIONS: DBS is an effective surgical treatment for movement disorders with sustained long-term benefits. Further research is ongoing to better understand the mechanism of DBS, refine the hardware to improve efficacy and reduce adverse effects, and identify additional applications and new anatomic targets.