No description available.

No description available.

Our understanding of the pathophysiology Parkinson’s disease has transformed over the last decade as we have come to appreciate the importance of changes in neuronal firing pattern that occur within the motor network in the dopamine deficient state. These changes in firing pattern, particularly increased synchrony result in oscillations that can be recorded as local field potentials. This thesis concerns itself with the study of beta oscillations which are characteristic of Parkinson’s disease. Firstly, I investigate whether beta oscillations play a pathophysiological role in Parkinson’s disease or whether they are purely epiphenomenal by augmenting beta with low frequency deep brain stimulation. In this study I show that rigidity is increased by ~25% with low frequency stimulation providing significant further evidence for a patho-physiological role of beta in Parkinson’s disease. Next I investigate whether beta oscillations correlate with Parkinsonian severity at rest and could therefore potentially be used as a biomarker of clinical state. I demonstrate that the variability of beta amplitude recorded from the subthalamic nucleus strongly correlates with symptom severity at rest and also in response to levodopa administration. I then use beta amplitude as a biomarker for a trial of adaptive deep brain stimulation in Parkinson’s disease. I show that by using beta amplitude to control stimulation, time on stimulation is reduced by >50% but despite this, clinical outcome is improved by 25% relative to conventional continuous high frequency stimulation. Finally, I investigate the bilateral subcortical beta network and its response to levodopa. I report statistically significant bilateral functional connectivity in the beta range which is driven by phase locking and modulated by levodopa in the low beta range with implications for bilateral adaptive deep brain stimulation. These findings further our understanding of the pathophysiological role of beta oscillations in Parkinson’s disease and provide new avenues for treatment development.

Parkinson’s disease (PD) and dystonia are movement disorders related to dysfunctions of basal ganglia (BG). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) are treatments for PD and dystonia. Previous research indicated that abnormally elevated oscillatory activities at the theta (3-10 Hz) beta frequency bands (11-30 Hz) may be related to parkinsonian and dystonic motor symptoms but their precise roles are not well understood. Recently, DBS of the pedunculopontine nucleus region (PPNR) has been used to treat PD patients with postural and gait dysfunctions, but movement-related PPNR activities had not been explored. We aimed to investigate movement-related local field potentials (LFP) recorded from the BG and PPNR in PD and dystonia patients. We recorded STN LFP from PD patients and subsequently applied the intrinsic STN theta, beta, and gamma (31-100 Hz) frequencies through DBS to study their effects on PD motor signs. We also recorded movement-related PPNR LFP in PD patients and movement-related GPi activities in patients with primary dystonia. Finally, we simultaneously recorded movement-related activities from the GPi and the motor thalamus in a patient with secondary dystonia. We found that DBS at the dopamine-dependent and movement-related intrinsic STN gamma frequencies, were as effective as traditionally used high frequencies (130-185 Hz) in reducing PD motor signs, but theta and beta frequencies did not worsen motor symptoms. Voluntary movements modulated two discrete movement-related frequencies in the theta and beta bands in the PPNR and these two frequencies interacted with the sensorimotor and frontal cortices during movements. We showed that voluntary movements modulated beta and gamma frequencies in the GPi. A resting ~5-18 Hz coherence between the GPi bilaterally was attenuated during movements in patients, which may be related to dystonia because this 5-18Hz coherence was also present between the GPi and motor thalamus in the patient with secondary dystonia. Our findings indicated that intrinsic STN gamma frequency oscillations were likely prokinetic rhythms but theta and beta frequencies may not contribute to PD motor symptoms. Voluntary movements modulated theta and beta frequencies in the PPNR, which may explain why PPNR DBS uses lower frequencies than those of the BG. The 5-18 Hz oscillatory activities in the BG-thalamic circuit may be a feature of dystonia.

Parkinson’s disease (PD) and dystonia are movement disorders related to dysfunctions of basal ganglia (BG). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) are treatments for PD and dystonia. Previous research indicated that abnormally elevated oscillatory activities at the theta (3-10 Hz) beta frequency bands (11-30 Hz) may be related to parkinsonian and dystonic motor symptoms but their precise roles are not well understood. Recently, DBS of the pedunculopontine nucleus region (PPNR) has been used to treat PD patients with postural and gait dysfunctions, but movement-related PPNR activities had not been explored. We aimed to investigate movement-related local field potentials (LFP) recorded from the BG and PPNR in PD and dystonia patients. We recorded STN LFP from PD patients and subsequently applied the intrinsic STN theta, beta, and gamma (31-100 Hz) frequencies through DBS to study their effects on PD motor signs. We also recorded movement-related PPNR LFP in PD patients and movement-related GPi activities in patients with primary dystonia. Finally, we simultaneously recorded movement-related activities from the GPi and the motor thalamus in a patient with secondary dystonia. We found that DBS at the dopamine-dependent and movement-related intrinsic STN gamma frequencies, were as effective as traditionally used high frequencies (130-185 Hz) in reducing PD motor signs, but theta and beta frequencies did not worsen motor symptoms. Voluntary movements modulated two discrete movement-related frequencies in the theta and beta bands in the PPNR and these two frequencies interacted with the sensorimotor and frontal cortices during movements. We showed that voluntary movements modulated beta and gamma frequencies in the GPi. A resting ~5-18 Hz coherence between the GPi bilaterally was attenuated during movements in patients, which may be related to dystonia because this 5-18Hz coherence was also present between the GPi and motor thalamus in the patient with secondary dystonia. Our findings indicated that intrinsic STN gamma frequency oscillations were likely prokinetic rhythms but theta and beta frequencies may not contribute to PD motor symptoms. Voluntary movements modulated theta and beta frequencies in the PPNR, which may explain why PPNR DBS uses lower frequencies than those of the BG. The 5-18 Hz oscillatory activities in the BG-thalamic circuit may be a feature of dystonia.

<p>Deep brain stimulation (DBS) is an established treatment for movement disorders that has been implanted in more than 40,000 patients worldwide. Despite the successes of DBS, its mechanisms of action are not well understood. Early descriptions of the mechanisms of DBS focused on whether DBS excited or inhibited neurons in the stimulated nucleus. However, changes in the <italic>patterns</italic> of neuronal activity, and not just changes in the rate of neuronal activity, play a major role in the pathology of movement disorders. Therefore, we hypothesized that the temporal pattern of stimulation might be an important factor in determining the effectiveness of DBS. The purpose of this dissertation was to use temporally <italic>irregular</italic> patterns of stimulation (non-regular interpulse intervals) to probe the mechanisms of thalamic DBS in suppressing tremor. The clinical tremor measurements reported in this dissertation represent the first tremor data published during stimulation with temporally <italic>irregular</italic> stimulus trains in human subjects. First, we tested the effects of paired-pulse DBS on tremor suppression in human subjects with essential tremor and on the responses of a computational model of thalamic neurons. DBS was more effective at reducing tremor when pulses were evenly spaced than when there were large differences between intrapair and interpair pulse intervals, suggesting that tremor suppression is dependent on the <italic>pattern</italic> of DBS and not just the average rate of stimulation. Increasing the difference between the intrapair and interpair intervals in the computational model rendered model neurons more likely to fire synchronous bursts. Second, we quantified the effects of the degree of regularity of temporally random stimulus trains in human subjects with tremor. We pioneered an innovative preparation to conduct these experiments--during surgery to replace the implantable pulse generator--which allowed us to establish a direct connection to implanted DBS leads under stable conditions. Stimulus trains were less effective at relieving tremor as the temporal spacing between stimulus pulses in DBS trains became more irregular. However, the reasons for the decreased efficacy of the temporally irregular stimulus trains was not clear. Third, we evaluated the contributions of `<italic>pauses</italic>,' `<italic>bursts</italic>,' and `<italic>irregularity, per se</italic>' to the inability of irregular stimulus trains to suppress tremor. Stimulus trains with <italic>pauses</italic> were significantly less effective at suppressing tremor than stimulus trains without <italic>pauses</italic>, while there were no significant changes in tremor suppression between trains with <italic>bursts</italic> and those without <italic>bursts</italic>, or between trains that were <italic>irregular</italic> and those that were <italic>periodic</italic>. We also developed a computer-based biophysical model of a thalamic network to simulate the response of thalamic neurons to the same temporal patterns of DBS. Trains that effectively suppressed tremor in human subjects also suppressed fluctuations in transmembrane potential at the frequency associated with burst-driven cerebellar inputs to the thalamus. Both clinical and computational findings indicate that DBS suppresses tremor by masking cerebellar burst-driven input to the thalamus.</p><p>The work in this dissertation bridges an important gap between the hypothesis that high-frequency DBS masks pathological activity in the cerebello-thalamo-cortical circuit and the experimentally observed finding that DBS in the subthalamic area suppresses tremor more effectively than DBS in the Vim thalamus proper. We provided experimental and computational evidence that the mechanism of DBS is to mask the burst-driven cerebellar inputs to the thalamus. Hence, the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.</p> / Dissertation

This report will review critically the available research on deep brain stimulation and levodopa as a means of treatment for Parkinson’s disease in an attempt to determine why neither of these treatments improves speech. / text

No description available.

<p>Modulation of neural activity with electrical stimulation is a widespread therapy for treating neurological disorders and diseases. Two notable applications that have had striking clinical success are deep brain stimulation (DBS) for the treatment of movement disorders (e.g., Parkinson's disease) and spinal cord stimulation (SCS) for the treatment of chronic low back and limb pain. In these therapies, the battery life of the stimulators is much less than the required duration of treatment, requiring patients to undergo repeated battery replacement surgeries, which are costly and obligate them to incur repeatedly the risks associated with surgery. Further, deviations in lead position of 2-3 mm can preclude some or all potential clinical benefits, and in some cases, generate side-effects by stimulation of non-target regions. Therefore, despite the success of DBS and SCS, their efficiency and ability to activate target neural elements over non-target elements, termed selectivity, are inadequate and need improvement.</p><p>We combined computational models of volume conduction in the brain and spine with cable models of neurons to design novel electrode configurations for efficient and selective electrical stimulation of nervous tissue. We measured the efficiency and selectivity of prototype electrode designs in vitro and in vivo. Stimulation efficiency was increased by increasing electrode area and/or perimeter, but the effect of increasing perimeter was not as pronounced as increasing area. Cylindrical electrodes with aspect (height to diameter) ratios of > 5 were the most efficient for stimulating neural elements oriented perpendicular to the axis of the electrode, whereas electrodes with aspect ratios of < 2 were the most efficient for stimulating parallel neural elements.</p><p>Stimulation selectivity was increased by combining two or more electrodes in multipolar configurations. Asymmetric bipolar configurations were optimal for activating parallel axons over perpendicular axons; arrays of cathodes with short interelectrode spacing were optimal for activating perpendicular axons over parallel axons; anodes displaced from the center of the target region were optimal for selectively activating terminating axons over passing axons; and symmetric tripolar configurations were optimal for activating neural elements based on their proximity to the electrode. The performance of the efficient and selective designs was not be explained solely by differences in their electrical properties, suggesting that field-shaping effects from changing electrode geometry and polarity can be as large as or larger than the effects of decreasing electrode impedance.</p><p>Advancing our understanding of the features of electrode geometry that are important for increasing stimulation efficiency and selectivity facilitates the design of the next generation of stimulation electrodes for the brain and spinal cord. Increased stimulation efficiency will increase the battery life of IPGs, increase the recharge interval of rechargeable IPGs, and potentially reduce stimulator volume. Greater selectivity may improve the success rate of DBS and SCS by mitigating the sensitivity of clinical outcomes to malpositioning of the electrode.</p> / Dissertation

Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in Europe. Besides motor dysfunction, PD is characterized by several non-motor and secondary motor features, such as weight change, sialorrhea, constipation and swallowing problems. Of these, swallowing is one of the most critical, as it is associated with aspiration pneumonia and consequently is the comorbidity with the highest mortality rate. Swallowing problems affect four of every five patients with PD, and even mild swallowing problems have notable psychosocial effects for patients and their caregivers. Consequently, it is essential to find treatment strategies for PD that may alleviate symptoms for patients with swallowing problems and their potential consequences. Deep Brain Stimulation (DBS) is a surgical treatment option for PD, which improves overall motor function and quality of life, but its effect on swallowing function is not clear. The purpose of this thesis was to contribute to the understanding of the effect of deep brain stimulation in the subthalamic nucleus (STN DBS) and the caudal zona incerta (cZI DBS) on pharyngeal swallowing function and on swallow-specific quality of life in patients with PD. The specific aims were to assess longitudinally the effect of STN DBS and cZI DBS on swallowing at 6 and 12 months postoperatively, in order to identify possible effects of the DBS on swallowing function. In addition, the effects of cZI DBS on ratings of swallowing-related non-motor and secondary motor features such as body weight changes, sialorrhea and speech problems were to be assessed. Methods Eleven PD patients with STN DBS (Paper I) and seventeen patients with cZI DBS (Paper II-IV) were included in this thesis. All patients were evaluated preoperatively and 6 and 12 months postoperatively. The effect of STN DBS and cZI DBS on swallowing was assessed with Fibreoptic-Endoscopic Evaluation of Swallowing (FEES) according to a predefined protocol including Penetration-Aspiration scale, Secretion Severity scale, preswallow spillage, pharyngeal residue, and pharyngeal clearance. Self-assessments were addressed using a visual analogue scale. The cZI DBS patients also completed the Swallowing Quality of Life (SWAL-QOL) questionnaire. Weight changes measured by Body Mass Index, and specific items from the Unified Parkinson’s Disease Rating Scale were also examined. Nine controls without PD were included in Paper IV, by answering the SWAL-QOL questionnaire. Results No clear effect of DBS on swallowing function or swallow-specific quality of life could be observed. There was no effect of DBS on the occurrence of aspiration, secretion, pharyngeal residue or clearance in the study groups with STN DBS or cZI DBS. Patients with STN DBS reported a subjective improvement in swallowing function with DBS stimulation turned on at 6 and 12 months after surgery. In patients with cZI DBS, the median body mass index was postoperatively increased with 1.1kg/m2 and the median increase in weight were +3.0 kg after 12 months with cZI DBS. The scores from the SWAL-QOL questionnaire were high overall in the group with cZI DBS, and the scores were unaffected by the cZI DBS surgery and stimulation. The SWAL-QOL total score was not significantly different between the PD patients and the controls, but the scores from the ‘burden’ and the ‘symptom’ subscales were worse in PD patients. Conclusions STN DBS or cZI DBS did not have a negative effect on swallowing function or ratings of swallow-specific ‘quality of life’ aspects in this cohort. Patients with STN DBS reported a self-perceived improvement in swallowing function when DBS was turned on. With regard to swallowing, patients with cZI DBS had an overall good quality of life throughout the conduct of the study and their swallow-specific quality of life was not negatively affected by cZI DBS. There seems to be no increased risk for aspiration or penetration due to surgery or stimulation for either the STN DBS or the cZI DBS groups. cZI DBS caused weight gain postoperatively. Since the sample sizes in these cohorts are small, the findings need to be confirmed in larger studies.