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

Thesis (Ph. D.)--University of Oregon, 2002. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 195-205). Also available for download via the World Wide Web; free to University of Oregon users.

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

The effect of post-training self-stimulation on associations formed during classical conditioning was studied. In the first three experiments, rats experienced tone-shock, tone-water and tone-light pairings, respectively. Control groups experienced the same situations except that the temporal relationship between the stimuli excluded the possibility of an association being formed. Following this training period, the experimental animals pressed a bar for electrical self-stimulation of the brain; control animals did not self-stimulate. Retention of the association between the training stimuli was evaluated by measuring conditioned suppression of drinking (experiments 1 and 3), or extinction of secondary reinforcement. The results showed that self-stimulation can retroactively and non-contingently improve memory for associations in various classical conditioning situations, independently of the presence of a natural reinforcer or of the responses they elicit. In another experiment, the effects of varying amounts of tone preexposure (latent inhibition) and of varying amounts of post-training self-stimulation on retention of a tone-shock association, measured by the amount of tone-induced suppression of drinking, were studied. Increasing amounts of tone pre-exposure produced decreased retention over all levels of self-stimulation, and increasing amounts of self-stimulation produced increased retention over all levels of pre-exposure. The interaction of these two factors suggests that they both acted on the strength of the tone-shock association: the pre-exposure acted proactively to weaken the association; the self-stimulation acted retroactively to strengthen it. The effect of delaying the post-training stimulation for various times after the tone-shock pairings was also investigated. Retention was improved by self-stimulation delayed for 15 or 30 minutes, but was not affected by self-stimulation delayed for an hour. These experiments suggest that direct activation

A series of experiments was carried out to clarify the effects of morphine (0.3 - 10 mg/kg) on intracranial self-stimulation (ICS) and to compare these with the effects of the stimulant amphetamine on this behavior. It was shown that the enhancement of ICS by morphine requires repeated drug exposure, is prevented by pre-exposure to the drug in a non-ICS context, is mimicked by administration of vehicle, and is not reliably reversed by naloxone. In contrast, facilitation of ICS by amphetamine was immediate and remained stable over repeated days of testing. It was concluded that ICS facilitation induced by morphine, but not by amphetamine, is largely the outcome of a learned association between the drug effect and the ICS procedure, and does not appear to be a direct, opiate receptor-mediated effect. Finally, 6-OHDA lesions of ventral tegmental dopamine neurons were shown to block the facilitation of ICS by morphine but not by amphetamine. These lesions were also shown to delay the development of tolerance to morphine-induced catalepsy.

This thesis explored whether interpretations of the reinforcing effect of stimulation trains used in the self-administration of brain-stimulation (SABS) paradigm were artifacts of the reinforcement schedule chosen or whether it represented a genuine attempt by animals to maintain optimal levels of reward. Results demonstrate that stimulation trains used in SABS are reinforcing and that animals regulate pulse frequency to optimize the level of reward. The thesis then explored whether pedunculopontine tegmental nucleus (PPTg) lesions blocked the acquisition or maintenance of SABS, and the acquisition of eight-arm radial maze learning. Results showed that lesions confined to the PPTg block acquisition and maintenance of SABS, suggesting that the PPTg mediates the positive reinforcing effects of BSR. Further, PPTg lesions blocked win-shift and win-stay radial maze learning. However, results indicate that animals were not impaired in "shifting" or "staying" behavior. It is speculated that PPTg lesions block the reinforcing effects of food, which produce inefficient performance on both memory tasks.

The work reported here was aimed at extending previous findings suggesting that the medial and lateral substantia nigra (SN) are functionally different with regard to intracranial self-stimulation (ICSS) and circling. It was found that the effects of systemic D- and L-amphetamine on ICSS were different for medial and lateral SN sites. These differences were attributed to the presence of two subtypes of dopamine (DA) neurons in the SN. The circling results indicate that circling in opposite directions can be elicited from the medial and lateral parts of the nigrostriatal DA system from the same hemisphere suggesting that medial and lateral nigrostriatal DA have opposing roles in the expression of circling. It was further demonstrated that the superior colliculus is critical for the expression of medial SN derived circling and the midbrain reticular formation is critical for both medial and lateral SN derived circling.

With approximately 7% of the adult population reporting to have taken illicit substances over the course of a year and the chronically relapsing nature of substance use disorders there is a great need for effective forms of treatment and therapies to reduce relapse. Deep brain stimulation (DBS) is a process of neuromodulation where electrodes are implanted in a target region to modulate the electrophysiological activity of the target region. DBS has been postulated as a potential therapy for treatment-refractory addiction, with a great deal of focus on the nucleus accumbens (NAc). Forty male Long Evans rats were implanted with unilateral stimulating electrodes within the right NAc prior to exposure to chronic cocaine self-administration (0.5 mg/kg/infusion). Following self administration, the animals were withdrawn from cocaine and treated with 14 consecutive days of sham, low frequency (LF, 20 Hz) or high frequency (HF, 160 Hz) stimulation sessions (30 min/day). The animals underwent drug seeking tests on days 1, 15 and 30 of the withdrawal phase with context-induced relapse paired with a drug challenge (5 mg/kg i.p). Relapse rates were highest on day 15 after withdrawal, with both LF and HF attenuating cocaine during this drug-seeking test, however this was not the case for tests on days 1 and 30. Motivation to respond for saccharin solution (0.1 %) remained intact following both LF and HF stimulation intake sessions. These results demonstrate that unilateral DBS of the NAc effectively attenuated cocaine-seeking following chronic exposure to stimulation although these beneficial effects appeared to diminish following cessation of daily treatment with stimulation. The results obtained in this experiment provide support for DBS as a potential therapy for patients with treatment-resistant cases of substance use disorders.

Thesis (M.Sc.). / Written for the School of Computer Science. Title from title page of PDF (viewed 2008/05/30). Includes bibliographical references.