Psychiatric and Cognitive Effects of Deep Brain Stimulation for Parkinson’s Disease

Deep brain stimulation (DBS) is effective for Parkinson’s disease (PD), dystonia, and essential tremor (ET). While motor benefits are well documented, cognitive and psychiatric side effects from the subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS for PD are increasingly recognized. Underlying disease, medications, microlesions, and post-surgical stimulation likely all contribute to non-motor symptoms (NMS).     

Deep Brain Stimulation for Alzheimer’s Disease: Tackling Circuit Dysfunction

ObjectivesTreatments for Alzheimer’s disease are urgently needed given its enormous human and economic costs and disappointing results of clinical trials targeting the primary amyloid and tau pathology. On the other hand, deep brain stimulation (DBS) has demonstrated success in other neurological and psychiatric disorders leading to great interest in DBS as a treatment for Alzheimer’s disease.Materials and MethodsWe review the literature on 1) circuit dysfunction in Alzheimer’s disease and 2) DBS for Alzheimer’s disease. Human and animal studies are reviewed individually.ResultsThere is accumulating evidence of neural circuit dysfunction at the structural, functional, electrophysiological, and neurotransmitter level. Recent evidence from humans and animals indicate that DBS has the potential to restore circuit dysfunction in Alzheimer’s disease, similarly to other movement and psychiatric disorders, and may even slow or reverse the underlying disease pathophysiology.ConclusionsDBS is an intriguing potential treatment for Alzheimer’s disease, targeting circuit dysfunction as a novel therapeutic target. However, further exploration of the basic disease pathology and underlying mechanisms of DBS is necessary to better understand how circuit dysfunction can be restored. Additionally, robust clinical data in the form of ongoing phase III clinical trials are needed to validate the efficacy of DBS as a viable treatment.     

StimVision v2: Examples and Applications in Subthalamic Deep Brain Stimulation for Parkinson’s Disease

ObjectiveSubthalamic deep brain stimulation (DBS) is an established therapy for Parkinson’s disease. Connectomic DBS modeling is a burgeoning subfield of research aimed at characterizing the axonal connections activated by DBS. This article describes our approach and methods for evolving the StimVision software platform to meet the technical demands of connectomic DBS modeling in the subthalamic region.Materials and MethodsStimVision v2 was developed with Visualization Toolkit (VTK) libraries and integrates four major components: 1) medical image visualization, 2) axonal pathway visualization, 3) electrode positioning, and 4) stimulation calculation.ResultsStimVision v2 implemented two key technological advances for connectomic DBS analyses in the subthalamic region. First was the application of anatomical axonal pathway models to patient-specific DBS models. Second was the application of a novel driving-force method to estimate the response of those axonal pathways to DBS. Example simulations with directional DBS electrodes and clinically defined therapeutic DBS settings are presented to demonstrate the general outputs of StimVision v2 models.ConclusionsStimVision v2 provides the opportunity to evaluate patient-specific axonal pathway activation from subthalamic DBS using anatomically detailed pathway models and electrically detailed electric field distributions with interactive adjustment of the DBS electrode position and stimulation parameter settings.     

Survey of U.S. Neurologists’ Attitudes Towards Deep Brain Stimulation for Parkinson’s Disease

Objectives: Deep brain stimulation (DBS) for Parkinson's disease (PD) was approved by the Food and Drug Administration in 2002 and has demonstrated clinical benefit in advanced PD. Our aim was to assess attitudes of U.S. neurologists towards the role of DBS in management of advanced PD. Materials and Methods: We sent a 40‐item Internet‐based survey assessing opinions regarding the role of medical and surgical therapies in managing PD to 7722 neurologists in the American Medical Association Physician MasterFile data base. Results: The response rate was low (4.2%). In total, 78 of the 298 (26%) responders self‐identified as movement disorders specialists. Specialists and non‐specialists had differences on a number of medical strategies used to manage PD. There were no statistically significant differences in reasons for or against referring patients for DBS, except for the number of non‐specialists who agreed with referring a patient who had a “poor or absent response to levodopa” (71% vs. 16%, p < 0.001). Both groups indicated a need for more information concerning appropriate indications for DBS, adverse effects of surgery, and postoperative programming. Conclusions: Movement disorders specialists and non‐specialists were in general agreement towards the beneficial role of DBS in management of advanced PD except for whether to refer patients with poor or absent response to levodopa.     

Prediction of Movement Ratings and Deep Brain Stimulation Parameters in Idiopathic Parkinson’s Disease

BackgroundDeep brain stimulation (DBS) parameter fine-tuning after lead implantation is laborious work because of the almost uncountable possible combinations. Patients and practitioners often gain the perception that assistive devices could be beneficial for adjusting settings effectively.ObjectiveWe aimed at a proof-of-principle study to assess the benefits of noninvasive movement recordings as a means to predict best DBS settings.Materials and MethodsFor this study, 32 patients with idiopathic Parkinson’s disease, under chronic subthalamic nucleus stimulation with directional leads, were recorded. During monopolar review, each available contact was activated with currents between 0.5 and 5 mA, and diadochokinesia, rigidity, and tapping ability were rated clinically. Moreover, participants’ movements were measured during four simple hand movement tasks while wearing a commercially available armband carrying an inertial measurement unit (IMU). We trained random forest models to learn the relations between clinical ratings, electrode settings, and movement features obtained from the IMU.ResultsFirstly, we could show that clinical mobility ratings can be predicted from IMU features with correlations of up to r = 0.68 between true and predicted values. Secondly, these features also enabled a prediction of DBS parameters, which showed correlations of up to approximately r = 0.8 with clinically optimal DBS settings and were associated with congruent volumes of tissue activated.ConclusionMovement recordings from customer-grade mobile IMU carrying devices are promising candidates, not only for remote symptom assessment but also for closed-loop DBS parameter adjustment, and could thus extend the list of available aids for effective programming beyond imaging techniques.     

Acute effects of adaptive Deep Brain Stimulation in Parkinson’s disease

BackgroundBeta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson’s disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed.MethodsTo determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson’s Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT).ResultsMean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p = .001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p = .002), and did not achieve significance during cDBS (p = .08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p = .009), but not in aDBS (p = .407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS.ConclusionBeta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy.     

Machine learning for automated EEG-based biomarkers of cognitive impairment during Deep Brain Stimulation screening in patients with Parkinson’s Disease

ObjectiveA downside of Deep Brain Stimulation (DBS) for Parkinson’s Disease (PD) is that cognitive function may deteriorate postoperatively. Electroencephalography (EEG) was explored as biomarker of cognition using a Machine Learning (ML) pipeline.MethodsA fully automated ML pipeline was applied to 112 PD patients, taking EEG time-series as input and predicted class-labels as output. The most extreme cognitive scores were selected for class differentiation, i.e. best vs. worst cognitive performance (n = 20 per group). 16,674 features were extracted per patient; feature-selection was performed using a Boruta algorithm. A random forest classifier was modelled; 10-fold cross-validation with Bayesian optimization was performed to ensure generalizability. The predicted class-probabilities of the entire cohort were compared to actual cognitive performance.ResultsBoth groups were differentiated with a mean accuracy of 0.92; using only occipital peak frequency yielded an accuracy of 0.67. Class-probabilities and actual cognitive performance were negatively linearly correlated (β = −0.23 (95% confidence interval (−0.29, −0.18))).ConclusionsParticularly high accuracies were achieved using a compound of automatically extracted EEG biomarkers to classify PD patients according to cognition, rather than a single spectral EEG feature.SignificanceAutomated EEG assessment may have utility for cognitive profiling of PD patients during the DBS screening.     

The Need for Digital Health Solutions in Deep Brain Stimulation for Parkinson’s Disease in the Time of COVID-19 and Beyond

ObjectivesDeep brain stimulation (DBS) is a well-established therapy for the management of patients with advanced Parkinson’s disease and other movement disorders. Patients implanted with DBS require life-long management of the medical device as well as medications. Patients are often challenged to frequently visit the specialized DBS centers and such challenges are aggravated depending on geography, socioeconomic factors, and support systems. We discuss the need for digital health solutions to overcome these barriers to better and safely take care of patients, especially in the current COVID-19 pandemic.Materials and MethodsA review of the literature was conducted for technology and logistics necessary in forming a digital health program.ResultsDigital health encounters can take place in both a synchronous and asynchronous manner. Factors involving patients include cognitive capacity, physical safety, physical capacity, connectivity, and technological security. Physician factors include examining the patient, system diagnostics, and adjusting stimulation or medications. Technology is focused on bridging the gap between patient and physician through integrating the DBS lead, implantable pulse generator (IPG), programmer, novel devices/applications to grade motor function, and teleconference modalities.ConclusionsFor patients with Parkinson’s disease, digital health has the potential to drastically change the landscape after DBS surgery. Furthermore, technology is fundamental in connectivity, diagnostic evaluation, and security in order to create stable and useful patient-focused care.     

Deep Brain Stimulation–Withdrawal Syndrome in Parkinson’s Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency

Background and ObjectivesSubthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson’s disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called “DBS-withdrawal syndrome.” In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation.Materials and MethodsWe conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation.ResultsA long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p < 0.005). In addition, a trend for older age at the event and higher Unified Parkinson’s Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p < 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state.ConclusionsThe patients’ clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.     

High-frequency Stimulation of Subthalamic Nucleus for Treatment of Parkinson’s Disease

Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine,leading to loss of movement control.     

Quality of Life and Motor Outcomes in Patients With Parkinson’s Disease 12 Months After Deep Brain Stimulation in China

BackgroundLong-term levodopa use is frequently associated with fluctuations in motor response and can have a serious adverse effect on the quality of life (QoL) of patients with Parkinson’s disease (PD). Deep brain stimulation (DBS) is effective in improving symptoms of diminished levodopa responsiveness. QoL improvements with DBS have been shown in several randomized control trials, mostly in Europe and the United States; however, there is a need for evidence from regions around the world.ObjectiveThe study aimed to demonstrate improvement in PD-related QoL in patients undergoing DBS in a prospective, multicenter study conducted in China.Materials and MethodsTo evaluate the effect of neurostimulation on the QoL of patients with PD, a Parkinson’s Disease Questionnaire (PDQ-8); Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, III, and IV; and EuroQol 5-dimension questionnaire (EQ-5D) were administered at baseline and 12 months after DBS implantation. The mean change and percent change from baseline were reported for these clinical outcomes.ResultsAssessments were completed for 85 of the 89 implanted patients. DBS substantially improved patients’ QoL and function. Implanted patients showed statistically significant mean improvement in PDQ-8 and UPDRS III (on stimulation/off medication). In the patients who completed the 12-month follow-up visit, the percent change was ?22.2% for PDQ-8 and ?51.6% for UPDRS III (on stimulation/off medication). Percent change from baseline to 12 months for UPDRS I, II, III, and IV and EQ-5D were ?16.8%, ?39.4%, ?18.5%, and ?50.0% and 22.7%, respectively. The overall rate of incidence for adverse events was low at 15.7%. Favorable outcomes were also reported based on patient opinion; 95.3% were satisfied with DBS results.ConclusionsThese data were comparable to other studies around the world and showed alignment with the ability of DBS to meaningfully improve the QoL of patients with PD. More studies investigating DBS therapy for patients with PD are necessary to accurately characterize clinical outcomes for the global PD population.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for this study is NCT02937688.     

Biomarkers for Parkinson’s Disease: Recent Advancement

As a multi-factorial degenerative disease, Parkinson’s disease (PD) leads to tremor, gait rigidity, and hypokinesia, thus hampering normal living. As this disease is usually detected in the later stages when neurons have degenerated completely, cure is on hold, ultimately leading to death due to the lack of early diagnostic techniques. Thus, biomarkers are required to detect the disease in the early stages when prevention is possible. Various biomarkers providing early diagnosis of the disease include those of imaging, cerebrospinal fluid, oxidative stress, neuroprotection, and inflammation. Also, biomarkers, alone or in combination, are used in the diagnosis and evolution of PD. This review encompasses various biomarkers available for PD and discusses recent advances in their development.     

Epigenome-Wide Association Study for Parkinson’s Disease

A methylation-based EWAS on carefully phenotyped individuals with Parkinson’s disease (PD) was conducted to reveal prioritised genes and pathways with statistically significant and sizable changes in PD and in the anxiety that often accompanies it. This was followed by subsequent replication of top-ranked CpG sites. Using the Infinium^® HumanMethylation 450K beadchip (Illumina Inc., USA), twenty unique genes with a sizable difference in methylation (P _adjusted < 0.05, Δβ ≥ 0.2), after correction for multiple testing, were identified between PD and controls, while seventeen were identified between PD with anxiety and PD without anxiety. Twelve top ranked, significantly associated loci in PD were evaluated in an independent replicate population using Sequenom EpiTYPER for 219 individuals with similar phenotypes to the cross-sectional case–control discovery design. FANCC cg14115740 and TNKS2 cg11963436 show significant differential methylation between PD cases and controls using both techniques and their Δβ values, which have the same direction of effect, are reasonable to warrant further investigation.     

Parkinson’s Disease Dementia

Dementia associated with Parkinson’s disease (PDD) is a common problem and one that is associated with significant morbidity and mortality. Over the past decade, increasing research efforts and funding have been directed toward an improved understanding of PDD. Despite these efforts, fundamental gaps remain in our knowledge. Consequently, therapeutic progress has been frustratingly slow and incomplete. To significantly affect PDD, novel “disease-modifying” agents, rather than more traditional neurotransmitter replacement approaches, likely will be required.     

Deep brain stimulation for Parkinson’s disease: Australian referral guidelines

The advent of deep brain stimulation (DBS) has been an important advance in the treatment of Parkinson’s disease (PD). DBS may be employed in the management of medication-refractory tremor or treatment-related motor complications, and may benefit between 4.5% and 20% of patients at some stage of their disease course. In Australia, patients with PD are reviewed by specialised DBS teams who assess the likely benefits and risks associated with DBS for each individual. The aim of these guidelines is to assist neurologists and general physicians identify patients who may benefit from referral to a DBS team. Common indications for referral are motor fluctuations and/or dyskinesias that are not adequately controlled with optimised medical therapy, medication-refractory tremor, and intolerance to medical therapy. Early referral for consideration of DBS is recommended as soon as optimised medical therapy fails to offer satisfactory motor control.