Doctor of Philosophy

dissertationParkinson's Disease (PD) motor symptoms, characterized most commonly by bradykinesia, akinesia, rigidity, and tremor, are brought about through the degeneration of dopaminergic neurons in the substantia nigra pars compacta, which leads to changes in electrophysiological activity throughout the basal ganglia. These symptoms are often effectively treated in the early stages of the disease by dopamine replacement therapies. However, as the disease progresses, the therapeutic window of pharmacological approaches reduces and patients develop significant side effects, even under minimally effective doses. When the disease reaches this stage, surgical therapies, such as high-frequency deep brain stimulation (DBS), are considered. DBS of the subthalamic nucleus partially treats the motor symptoms of PD and has been implemented to treat PD over 50,000 times worldwide, but its mechanisms are unclear. In this work, we set out to advance the understanding of the mechanisms, function, and malfunction of DBS as a treatment for PD, keeping in mind the idea that DBS treats PD symptoms without restoring basal ganglia neural activity to that seen under healthy conditions. First, we demonstrated that neuronal information directed from the basal ganglia to the thalamus is pathologically increased in the parkinsonian condition and reduced by DBS in a standard 6-OHDA rat model of PD. Next, we developed a rodent model of DBSs role in the exacerbation of hypokinetic dysarthria, providing a framework for the study of this poorly understood side effect of DBS. Finally, we found that DBS creates action suppression deficits independently from a parkinsonian state, and that PD creates apathy that is not rescued by DBS. Our specific results led to the interpretation that DBS, in its current form, might inherently create side effects that are largely unavoidable. Our work fits into the following overarching idea. DBS successfully treats some motor symptoms of PD through the reduction of pathological information transmission. However, the fact that reducing pathological information does not restore neural activity to that present under healthy conditions underlies some of its failures to improve certain symptoms, as well as its exacerbations and side effects

Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson’s Disease::A Scoping Review

Non-invasive focused ultrasound stimulation (FUS) is a non-ionising neuromodulatory technique that employs acoustic energy to acutely and reversibly modulate brain activity of deep-brain structures. It is currently being investigated as a potential novel treatment for Parkinson’s disease (PD). This scoping review was carried out to map available evidence pertaining to the provision of FUS as a PD neuromodulatory tool. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews, a search was applied to Ovid MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials on 13 January 2022, with no limits applied. In total, 11 studies were included: 8 were from China and 1 each from Belgium, South Korea and Taiwan. All 11 studies were preclinical (6 in vivo, 2 in vitro, 2 mix of in vivo and in vitro and 1 in silico). The preclinical evidence indicates that FUS is safe and has beneficial neuromodulatory effects on motor behaviour in PD. FUS appears to have a therapeutic role in influencing the disease processes of PD, and therefore holds great promise as an attractive and powerful neuromodulatory tool for PD. Though these initial studies are encouraging, further study to understand the underlying cellular and molecular mechanisms is required before FUS can be routinely used in PD

Deep Brain Stimulation Programming 2.0: Future Perspectives for Target Identification and Adaptive Closed Loop Stimulation

Deep brain stimulation has developed into an established treatment for movement disorders and is being actively investigated for numerous other neurological as well as psychiatric disorders. An accurate electrode placement in the target area and the effective programming of DBS devices are considered the most important factors for the individual outcome. Recent research in humans highlights the relevance of widespread networks connected to specific DBS targets. Improving the targeting of anatomical and functional networks involved in the generation of pathological neural activity will improve the clinical DBS effect and limit side-effects. Here, we offer a comprehensive overview over the latest research on target structures and targeting strategies in DBS. In addition, we provide a detailed synopsis of novel technologies that will support DBS programming and parameter selection in the future, with a particular focus on closed-loop stimulation and associated biofeedback signals

Involvement of the cortico-basal ganglia-thalamocortical loop in developmental stuttering

Stuttering is a complex neurodevelopmental disorder that has to date eluded a clear explication of its pathophysiological bases. In this review, we utilize the Directions Into Velocities of Articulators (DIVA) neurocomputational modeling framework to mechanistically interpret relevant findings from the behavioral and neurological literatures on stuttering. Within this theoretical framework, we propose that the primary impairment underlying stuttering behavior is malfunction in the cortico-basal ganglia-thalamocortical (hereafter, cortico-BG) loop that is responsible for initiating speech motor programs. This theoretical perspective predicts three possible loci of impaired neural processing within the cortico-BG loop that could lead to stuttering behaviors: impairment within the basal ganglia proper; impairment of axonal projections between cerebral cortex, basal ganglia, and thalamus; and impairment in cortical processing. These theoretical perspectives are presented in detail, followed by a review of empirical data that make reference to these three possibilities. We also highlight any differences that are present in the literature based on examining adults versus children, which give important insights into potential core deficits associated with stuttering versus compensatory changes that occur in the brain as a result of having stuttered for many years in the case of adults who stutter. We conclude with outstanding questions in the field and promising areas for future studies that have the potential to further advance mechanistic understanding of neural deficits underlying persistent developmental stuttering.R01 DC007683 - NIDCD NIH HHS; R01 DC011277 - NIDCD NIH HHSPublished versio