Model and Analysis for the Onset of Parkinsonian Firing Patterns in a Simplified Basal Ganglia

Parkinson’s disease (PD) is a degenerative neurological disease that disrupts the movement cycle in the basal ganglia. As the disease progresses, dopamine depletion leads to changes to how the basal ganglia functions as well as the appearance of abnormal beta oscillations. There is much debate on just exactly how these connection strengths change and just how the oscillations emerge. One leading hypothesis claims that the oscillations develop in the globus pallidus external, subthalamic nucleus, and globus pallidus internal loop. We introduce a mathematical model that calculates the average firing rates of this loop while still accounting for the larger closed loop of the entire basal ganglia system. This model is constructed such that physiologically realistic results can be obtained while not sacrificing the use of analytic methods. Because of this, it is possible to determine how the change in the connection strengths can drive the necessary changes in firing rates seen in recordings and account for the generation of trademark beta oscillations of PD without relying on highly specific time delays, stochastic approaches, or numerical approximations. Additionally, we find that the entire cortico-basal ganglia-thalamo-cortical loop is essential for abnormal oscillations to originate.

Nigrostriatal Lesion and Dopamine Agonists Affect Firing Patterns of Rodent Entopeduncular Nucleus Neurons

Altered activity of the entopeduncular nucleus, the rodent homologue of the globus pallidus internal segment in primates, is thought to mediate behavioral consequences of midbrain dopamine depletion in rodents. Few studies, however, have examined dopaminergic modulation of spiking activity in this nucleus. This study characterizes changes in entopeduncular neuronal activity after nigrostriatal dopaminergic lesion and the effects of systemic treatment with selective D1(SKF 38393) and D2 (quinpirole) agonists in lesioned rats. Extracellular single-unit recordings were performed in awake immobilized rats, either in neurologically intact animals ( n = 42) or in animals that had received unilateral 6-hydroxydopamine infusion into the medial forebrain bundle several weeks previously ( n = 35). Nigrostriatal lesion altered baseline activity of entopeduncular neurons in several ways. Interspike interval distributions had significantly decreased modes and significantly increased coefficient of variation, skewness and kurtosis; yet interspike interval mean (the inverse of firing rate) was not affected. Also, spectral analysis of autocorrelograms indicated that lesion significantly reduced the incidence of regular-spiking neurons and increased the incidence of neurons with 4–18 Hz oscillations. Dopamine agonist treatment reversed some lesion-induced effects: quinpirole reversed changes in interspike interval distribution mode and coefficient of variation, while combined quinpirole and SKF 38393 blocked the appearance of 4–18 Hz oscillations. However, no agonist treatment normalized all aspects of entopeduncular activity. Additionally, inhibition of firing rates by D1 or combined D1/D2 receptor activation indicated that dopamine agonists affected the overall level of entopeduncular activity in a manner similar to that found in the substantia nigra pars reticulata and globus pallidus internal segment after dopamine neuron lesion. These data demonstrate that lesion of the nigrostriatal tract leads to modifications of several aspects of firing pattern in the rodent entopeduncular nucleus and so expand on similar findings in the rodent substantia nigra pars reticulata and in the globus pallidus internal segment in humans and nonhuman primates. The results support the view that dysfunction in the basal ganglia after midbrain dopamine neuron loss relates more consistently to abnormal activity patterns than to net changes in firing rate in the basal ganglia output nuclei, while overall decreases in firing rate in these structures may play a more important role in adverse motor reactions to dopamine agonist treatments.

Context Dependency in the Globus Pallidus Internal Segment During Targeted Arm Movements

Extracellular discharges from single neurons in the internal segment of the globus pallidus (GPi) were recorded and analyzed for rate changes associated with visually guided forearm rotations to four different targets. We sought to examine how GPi neurons contribute to movement preparation and execution. Unit discharge from 108 GPi neurons recorded in 35 electrode penetrations was aligned to the time of various behavioral events, including the onset of cued and return movements. In total, 39 of 108 GPi neurons (36%) were task-modulated, demonstrating statistically significant changes in discharge rate at various times between the presentation of visual cues and movement generation. Most often, strong modulation in discharge rate occurred selectively during either the cued ( n = 32) or return ( n = 2) phases of the task, although a few neurons ( n = 5) were well-modulated during both movement phases. Of the 34 neurons that were modulated exclusively during cued or return movements, 50% ( n = 17) were modulated similarly in association with movements to any target. The remaining 17 neurons exhibited considerable diversity in their discharge properties associated with movements to each target. Cued phases of behavior were always rewarded if executed correctly, whereas return phases were never rewarded. Overall, these data reveal that many GPi neurons discharged in a context-dependent manner, being modulated during cued, rewarded movements, but not during similar self-paced, unrewarded movements. When considered in the light of other observations, the context-dependence we have observed seems likely to be influenced by the animal's expectation of reward.

Voice and Speech Characteristics of Persons With Parkinson’s Disease Pre- and Post-Pallidotomy Surgery

Pallidotomy surgery, lesioning the globus pallidus internal, has been performed to alleviate Parkinsonian symptoms and drug-induced dyskinesias. Improvements in limb motor function have been reported in recent years following pallidotomy surgery. The purpose of this preliminary study was to determine the effect of pallidotomy surgery on select voice and speech characteristics of 6 patients with Parkinson’s disease. Acoustic measures were analyzed pre-pallidotomy surgery and again at 3 months following surgery. Preliminary findings indicated that all participants demonstrated positive changes in at least one acoustic measure; 2 of the participants consistently demonstrated positive changes in phonatory and articulatory measures, whereas 3 participants did not consistently demonstrate positive changes postsurgery. The results are discussed relative to the differential effects observed across participants.