Browsing by Subject "Mechanisms"
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Item Open Access Analyzing the Mechanisms of Action of Thalamic Deep Brain Stimulation: Computational and Clinical Studies(2009) Birdno, Merrill JayDeep 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 patterns 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 irregular 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 irregular 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 pattern 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 `pauses,' `bursts,' and `irregularity, per se' to the inability of irregular stimulus trains to suppress tremor. Stimulus trains with pauses were significantly less effective at suppressing tremor than stimulus trains without pauses, while there were no significant changes in tremor suppression between trains with bursts and those without bursts, or between trains that were irregular and those that were periodic. 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.
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.
Item Open Access Mechanisms of Change within a Brief, Phone-Based, Behavioral Intervention for Graduate Burnout(2018) Fang, Caitlin MarieEmerging changes in health care reform have further accelerated the need for brief and cost-effective interventions. As such, the current study tested the efficacy of two brief, phone-administered, behavioral interventions derived from behavioral activation (BA) in reducing burnout among graduate students. 66 adults currently enrolled in a doctoral program in the state of North Carolina and demonstrating current burnout were randomly assigned to one of three intervention conditions: 1) Reward: a brief intervention to help participants increase pleasant, rewarding behaviors, 2) Approach: a brief intervention to help participants approach important goals that they have been avoiding due to emotion (fear, stress, sadness) or 3) Control: a condition that involves monitoring only. All participants completed three days of daily monitoring, conducted through an online survey platform, in order to attain baseline indices of mood and activities. They then received a brief intervention over the phone and completed 7 days of additional online self-monitoring while completing the intervention. Participants completed a self-report packet assessing burnout, perceived stress, behavioral activation, experiential avoidance, mastery, anxiety and depression symptoms, quality of life, and functional impairment at baseline, post-intervention, and a 1-week follow-up assessment.
The study found that individuals in the Approach condition showed significant reductions in burnout post-intervention and at a one-week follow-up assessment, compared to individuals in the Control condition. In addition, individuals in the Approach condition showed significant improvements in well-being and significant increases in behavioral activation, compared to individuals in the Control condition. These findings suggest that a one-time intervention designed to help individuals approach challenging, avoided tasks may significantly improve indices of distress and dysfunction among doctoral-level graduate students.
Item Open Access Mechanisms of Deep Brain Stimulation for the Treatment of Parkinson's Disease: Evidence from Experimental and Computational Studies(2012) So, Rosa Qi YueDeep brain stimulation (DBS) is used to treat the motor symptoms of advanced Parkinson's disease (PD). Although this therapy has been widely applied, the mechanisms of action underlying its effectiveness remain unclear. The goal of this dissertation was to investigate the mechanisms underlying the effectiveness of subthalamic nucleus (STN) DBS by quantifying changes in neuronal activity in the basal ganglia during both effective and ineffective DBS.
Two different approaches were adopted in this study. The first approach was the unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model. Using this animal model, we developed behavioral tests that were used to quantify the effectiveness of DBS with various frequencies and temporal patterns. These changes in behavior were correlated with changes in the activity of multiple single neurons recorded from the globus pallidus externa (GPe) and substantia nigra reticulata (SNr). The second approach was a computational model of the basal ganglia-thalamic network. The output of the model was quantified using an error index that measured the fidelity of transmission of information in model thalamic neurons. We quantified changes in error index as well as neural activity within the model GPe and globus pallidus interna (GPi, equivalent to the SNr in rats).
Using these two approaches, we first quantified the effects of different frequencies of STN DBS. High frequency stimulation was more effective than low frequency stimulation at reducing motor symptoms in the rat, as well as improving the error index of the computational model. In both the GPe and SNr/GPi from the rat and computational model, pathological low frequency oscillations were present. These low frequency oscillations were suppressed during effective high frequency DBS but not low frequency DBS. Furthermore, effective high frequency DBS generated oscillations in neural firing at the same frequency of stimulation. Such changes in neuronal firing patterns were independent of changes in firing rates.
Next, we investigated the effects of different temporal patterns of high frequency stimulation. Stimulus trains with the same number of pulses per second but different coefficients of variation (CVs) were delivered to the PD rat as well as PD model. 130 Hz regular DBS was more effective than irregular DBS at alleviating motor symptoms of the PD rat and improving error index in the computational model. However, the most irregular stimulation pattern was still more effective than low frequency stimulation. All patterns of DBS were able to suppress the pathological low frequency oscillations present in the GPe and SNr/GPi, but only 130 Hz stimulation increased high frequency 130 Hz oscillations. Therefore, the suppression of pathological low frequency neural oscillations was necessary but not sufficient to produce the maximum benefits of DBS.
The effectiveness of regular high frequency STN DBS was associated with a decrease in pathological low frequency oscillations and an increase in high frequency oscillations. These observations indicate that the effects of DBS are not only mediated by changes in firing rate, but also involve changes in neuronal firing patterns within the basal ganglia. The shift in neural oscillations from low to high frequency during effective STN DBS suggests that high frequency regular DBS suppresses pathological firing by entraining neurons to the stimulus pulses.
Therefore, results from this dissertation support the hypothesis that the underlying mechanism of effective DBS is its ability to entrain and regularize neuronal firing, therefore disrupting pathological patterns of activity within the basal ganglia.