Uncovering the Neural Basis for Bradykinesia in Parkinson’s disease: Causality of Beta-frequency Oscillations

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2018

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Abstract

Substantial correlative evidence links the synchronized, oscillatory neural firing patterns that emerge in Parkinson’s disease (PD) in the frequency range of 13-30Hz (termed “beta band”) with the development of bradykinesia and akinesia. Yet, a causal link between these beta frequency oscillations and symptoms of bradykinesia has not been demonstrated. I tested the hypothesis that the synchronized beta oscillations that emerge in PD are causal of symptoms of bradykinesia/akinesia through studies in intact and parkinsonian animals as well as PD patients.

Regarding the rat studies, I designed novel stimulation patterns to mimic the temporal characteristics of the beta oscillatory bursting pattern seen in single units in PD rats and patients. I applied these beta frequency patterned stimulus trains along with continuous frequency controls over a range of amplitudes via stimulating electrodes implanted unilaterally into the subthalamic nucleus (STN) of healthy and PD rats and assessed the effects on unit activity in the substantia nigra reticulata (SNr) and performance in motor tasks designed to assess forelimb bradykinesia and gross locomotor activity. I quantified the degree of unit entrainment in the SNr as a function of pattern and amplitude by calculation of the excitatory effective pulse fraction (eEPF) [1]. I further quantified the increase in SNr unit spectral beta frequency power due to the applied stimulation paradigms. I found that the beta-patterned paradigms were superior to low frequency controls at entrainment and induction of beta power in downstream substantia nigra reticulata (SNr) neurons. However, I found no deleterious effects on motor performance across a wide battery of validated behavioral tasks.

In PD patients, my objective was to determine how beta frequency oscillatory activity varies with disease progression and severity in human PD patients using cortical electroencephalogram (EEG). I recorded EEG in twenty-five PD patients of varying disease severity after overnight abstinence from PD medication. I recorded EEG at rest (eyes open and closed) and while patients performed various hand motor tasks. These tasks included one-handed isometric grip and rapid open/close movements. For each EEG channel data-stream for each patient, I calculated the total percent of spectral power in the beta band (PSP-β) with respect to movement state. I used stepwise regression to predict UPDRSIII scores from the normalized PSP-β values calculated for each channel during the ‘Eyes Open Rest’ state and found a significant, predictive regression equation. I assessed the relationship between UPDRSIII score and cortical coherence using linear regression and found significant, positive correlations between UPDRSIII score and coherence at beta band frequencies between pre-motor-motor and motor-somatosensory cortical areas. I observed phase amplitude coupling (PAC) between beta and gamma (30-200Hz) frequencies at rest and found it to be significantly altered by task, but found no effect of motor symptom progression on mean PAC.

My data suggest that certain metrics of beta band activity in pre-motor, motor, and somatosensory brain regions at rest may serve as a marker for degree of motor impairment, but that beta frequency oscillations may be an epiphenomenon and not necessary or sufficient for the generation of bradykinesia/akinesia in PD.

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Behrend, Christina (2018). Uncovering the Neural Basis for Bradykinesia in Parkinson’s disease: Causality of Beta-frequency Oscillations. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/16783.

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