<p>Deep brain stimulation (DBS) is an effective therapy for motor symptoms in Parkinson's disease (PD). DBS efficacy depends on the stimulation parameters, and the current gold standard therapy is high-frequency stimulation (>100 Hz) with constant interpulse intervals and short pulse widths (<210 &#956;s). However, the temporal pattern of stimulation is a novel parameter dimension that has not been thoroughly explored. We used non-regular temporal patterns of DBS to pursue two goals: to better understand the mechanisms of DBS, and to increase the efficacy and efficiency of DBS for PD.</p><p>First, we designed high frequency patterns of non-regular stimulation with distinct features proposed to be important for efficacy and evaluated these patterns in human subjects with PD. Unexpectedly, some non-regular patterns of stimulation improved performance of an alternating finger-tapping task-a proxy for bradykinesia-compared to high frequency regular stimulation. Performance in the motor task was correlated with suppression of beta band power in a computational model of the basal ganglia suggesting a possible mechanism for effective stimulation patterns.</p><p>Inspired by the increased clinical efficacy of non-regular patterns of stimulation with high average frequencies, we developed a non-regular pattern of stimulation that reduced motor symptoms in PD using a low average stimulation frequency. Since the number of potential combinations of interpulse intervals is exceedingly large and it is unclear how such timing should be selected, we applied computational evolution to design an optimal temporal pattern of deep brain stimulation to treat the symptoms of PD. Next, we demonstrated the efficacy of the resulting pattern of stimulation in hemi-parkinsonian rats and humans with PD. Both the optimized stimulation pattern and high frequency stimulation suppressed abnormal oscillatory activity in the basal ganglia in the rat and human, providing a shared mechanism of action for effective stimulation patterns. This innovation could allow patients to achieve battery life savings compared to traditional high frequency stimulation, which will reduce the costs and risks of frequent battery replacement procedures. Further, our approach can be used to design novel temporal patterns of stimulation in other applications of neural stimulation.</p><p>Finally, we explored evoked field potentials in the subthalamic nucleus (STN) in response to DBS. These potentials were evoked by stimulation through one of the contacts on the DBS lead and recorded from the two surrounding contacts. Subthalamic DBS local evoked potentials (DLEPs) have never before been recorded. We characterized the DLEPs, differences across DBS frequencies and time, their relationship to beta frequency oscillations and phase-amplitude coupling, and their dependence on electrode contact location.</p><p>A 3-dimensional biophysical model of DBS in the subthalamic nucleus-globus pallidus externus (GPe) subcircuit was built to explore the neural origin of the DLEPs. The computational model could reproduce the DLEP signal, and it revealed that the quasi-periodic DLEP oscillations are caused by excitatory synaptic currents in STN interrupted periodically by inhibition from GPe.</p><p>DLEP power was correlated with beta band oscillation power in the recordings without DBS, and significant phase-amplitude coupling was observed in a subset of subjects with robust DLEP responses. Together, all available evidence suggested the contact location was an important determinant for the presence and characteristics of DLEP signals. Predictions were made concerning contact location relative to the boundaries of the STN based on the DLEP recordings and insights gained using the computational model, and the predictions were in agreement with blinded post hoc imaging based contact localization for ~70% of contacts predicted to be within STN.</p><p>DLEPs are an exciting new signal with several useful applications. DLEPs could help neurosurgeons verify accurate DBS lead placement or optimal stimulation parameters, probe the pathological basal ganglia, and elucidate the mechanisms of DBS.</p> / Dissertation

The current study examined cognitive effects of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients. Neuropsychological evaluations were conducted at baseline and follow-up. Data was collected from 28 unilateral STN DBS patients (15 English- and 13 Spanish-speaking), and 15 English-speaking matched PD control patients. English-speaking DBS patients demonstrated significant declines in verbal fluency and attention/executive function, whereas PD control patients did not experience significant cognitive decline. Cognitive performance did not differ based on side of DBS. Spanish-speaking DBS patients experienced significant declines in verbal fluency, confrontational naming and visuospatial abilities. Among Spanish-speaking DBS patients, older age and later age of disease onset predicted verbal fluency decline, even after controlling for education.

Anorexia Nervosa (AN) has the highest mortality rate of any psychiatric condition, and despite its recognition for centuries, remains a significant treatment challenge. Marked by firmly entrenched maladaptive beliefs about body, weight and food, as well as high rates of psychiatric comorbidity, AN is a chronic illness in a large proportion of patients. The neural substrates of AN are now beginning to emerge, and appear to be related to dysfunctional, primarily limbic, circuits driving pathological thoughts and behaviours. Deep Brain Stimulation (DBS) is a neurosurgical procedure where implanted electrodes are used to regulate activity in critical nodes comprising such aberrant circuits. The promise of DBS in motor-circuit conditions, such as Parkinson’s Disease, has driven it’s investigation in other circuit-based disorders, including some psychiatric conditions. Converging evidence from clinical and imaging literatures suggests that AN is in large part a disorder of emotional processing, wherein disordered mood, anxiety, and affective dysregulation contribute to disease maintenance and are obstacles to effective treatment. The subcallosal cingulate (SCC), a key medial frontal structure involved in affective processing, has further been directly implicated in AN relevant pathways. As such, this work had three broad objectives: i) to establish the safety and initial efficacy of SCC DBS in a group of chronic and highly-refractory AN patients; ii) to show that SCC DBS can have network wide cerebral metabolic influence, on AN-relevant circuits and structures; and, iii) to investigate whether structural brain features, including hippocampal volume changes, are correlated with clinical outcomes of DBS. Our results showed that DBS is safe in AN, and associated in some patients with significant improvements in mood, anxiety and, over time, weight and treatment-response. Imaging results further showed DBS to be associated with substantial changes in glucose utilization in disease-relevant circuits, with preliminary evidence supporting a relationship between hippocampal volume changes and clinical improvements. In the context of highly refractory disease, these promising results suggest that DBS can inform AN circuit models, and be explored as a novel therapeutic option for treatment-resistant patients.

Anorexia Nervosa (AN) has the highest mortality rate of any psychiatric condition, and despite its recognition for centuries, remains a significant treatment challenge. Marked by firmly entrenched maladaptive beliefs about body, weight and food, as well as high rates of psychiatric comorbidity, AN is a chronic illness in a large proportion of patients. The neural substrates of AN are now beginning to emerge, and appear to be related to dysfunctional, primarily limbic, circuits driving pathological thoughts and behaviours. Deep Brain Stimulation (DBS) is a neurosurgical procedure where implanted electrodes are used to regulate activity in critical nodes comprising such aberrant circuits. The promise of DBS in motor-circuit conditions, such as Parkinson’s Disease, has driven it’s investigation in other circuit-based disorders, including some psychiatric conditions. Converging evidence from clinical and imaging literatures suggests that AN is in large part a disorder of emotional processing, wherein disordered mood, anxiety, and affective dysregulation contribute to disease maintenance and are obstacles to effective treatment. The subcallosal cingulate (SCC), a key medial frontal structure involved in affective processing, has further been directly implicated in AN relevant pathways. As such, this work had three broad objectives: i) to establish the safety and initial efficacy of SCC DBS in a group of chronic and highly-refractory AN patients; ii) to show that SCC DBS can have network wide cerebral metabolic influence, on AN-relevant circuits and structures; and, iii) to investigate whether structural brain features, including hippocampal volume changes, are correlated with clinical outcomes of DBS. Our results showed that DBS is safe in AN, and associated in some patients with significant improvements in mood, anxiety and, over time, weight and treatment-response. Imaging results further showed DBS to be associated with substantial changes in glucose utilization in disease-relevant circuits, with preliminary evidence supporting a relationship between hippocampal volume changes and clinical improvements. In the context of highly refractory disease, these promising results suggest that DBS can inform AN circuit models, and be explored as a novel therapeutic option for treatment-resistant patients.

Parkinson’s disease (PD) is a neurodegenerative movement disorder and a leading cause of neurological disability in the older adult population. Historically, the research and treatment of PD has focused on the associated motor symptoms. Now the non-motor symptoms such as sleep disturbance are becoming an increased focus for researchers. Deep brain stimulation (DBS) is a surgical intervention that has proven to be beneficial for PD motor symptom management. There are claims from the literature that DBS may assist with the phenomenon of sleep disturbance. A case study analysis was done to explore this concept in the DBS-PD patient population using the framework of the Symptom Management Theory. From the analysis of the subjective and objective data gathered it is clear that the phenomenon of sleep disturbance in this population is multifaceted and that DBS may play a role in managing the phenomenon of sleep disturbance for this population.

Parkinson’s disease (PD) is a neurodegenerative movement disorder and a leading cause of neurological disability in the older adult population. Historically, the research and treatment of PD has focused on the associated motor symptoms. Now the non-motor symptoms such as sleep disturbance are becoming an increased focus for researchers. Deep brain stimulation (DBS) is a surgical intervention that has proven to be beneficial for PD motor symptom management. There are claims from the literature that DBS may assist with the phenomenon of sleep disturbance. A case study analysis was done to explore this concept in the DBS-PD patient population using the framework of the Symptom Management Theory. From the analysis of the subjective and objective data gathered it is clear that the phenomenon of sleep disturbance in this population is multifaceted and that DBS may play a role in managing the phenomenon of sleep disturbance for this population.

Thesis (Ph. D.)--Case Western Reserve University, 2010. / [School of Medicine] Department of Biomedical Engineering. Includes bibliographical references.

Alzheimer's disease (AD) is the neurodegenerative disease responsible for the majority of dementia cases across the United States. Its pathology involves the accumulation of protein plaques in areas of the brain directly involved with learning and memory formation, causing cognitive impairments and loss of independence in everyday life. Deep brain stimulation (DBS) is a relatively young field in medicine that has gained a great deal of traction with its efficacious clinical outcomes in neurological diseases including Parkinson's disease, epilepsy, depression and obsessive-compulsive disorder. More recently, researchers have sought to discover the proper application of DBS to improve the formation of episodic memory to provide a comparable or superior therapy for AD. Many experiments have been performed using different electrical parameters, hardware, or locations stimulated in the brain, which produced mixed results for benefits in memory reinforcement. Of the various brain structures available to target, the Entorhinal Cortex (EC) has been shown to lead to numerous positive outcomes. Additionally, one study used a novel approach, applying DBS in response to the neural activity of the individual brain during memory encoding tasks, which produced improvements in memory performance. This proposal aims to use these modalities in concert - a closed-loop stimulation approach that monitors neural activity and targeting the EC - in AD dementia patients to act as an adjuvant therapy to current acetylcholinesterase inhibitor medications that provide weak efficacy when used alone. This will be conducted in a 2 year, multicenter, double-blind, randomized controlled clinical trial comparing treatment with dual therapy consisting of DBS and an acetylcholinesterase inhibitor, to those with acetylcholinesterase inhibitor monotherapy. Participants will have mild or moderate AD at baseline, evaluated using the Mini-Mental State Examination and their progress in both experimental arms will be recorded using the 13 item Alzheimer's Disease Assessment Subscale-Cognitive over a 2-year period. Investigators will study the primary outcome of delaying cognitive decline, with secondary effects involving the differences between age groups, stages of AD and how frequently stimulation was received in those within the DBS and standard therapy group. The results from this study have the potential to further improve future approaches involving DBS in the treatment of AD dementia, as the projected number of those affected by the disease continues to grow with advances in modern medicine.

Parkinson's disease is a progressively debilitating disease that affects about 1% of the world's population, and does not differentiate between genders or races. The disease is caused by the death of the dopaminergic neurons in the basal ganglia nuclei, especially those in the substantia nigra pars compacta. Subsequent loss of dopamine production engenders the cardinal symptoms of bradykinesia, rigidity, akinesia, and postural instability found in all patients with Parkinson's disease. While there are several types of Parkinson's disease, the majority of the cases are made up of the idiopathic and Levodopa responsive type. The current consensus on treatment is to use medications until the patient becomes refractory to all medicines. It is only at this point will the surgical option deep brain stimulation be considered. while this procedure comes with a higher risk of post surgery complications, the benefits it offers patients with advanced Parkinson's disease are far superior to those offered patients by medications. It reasons then that patients would benefit more if they received this treatment earlier in the course of the disease. The mechanisms, side effects, costs, cost-effectiveness, and long term effects on quality of life of deep brain stimulation will be compared with those of medications to assess whether it is worthwhile to use this treatment for patients with mild Parkinson's disease.

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