Network perspectives on the mechanisms of deep brain stimulation.
ABSTRACT Deep brain stimulation (DBS) is an established medical therapy for the treatment of movement disorders and shows great promise for several other neurological disorders. However, after decades of clinical utility the underlying therapeutic mechanisms remain undefined. Early attempts to explain the mechanisms of DBS focused on hypotheses that mimicked an ablative lesion to the stimulated brain region. More recent scientific efforts have explored the wide-spread changes in neural activity generated throughout the stimulated brain network. In turn, new theories on the mechanisms of DBS have taken a systems-level approach to begin to decipher the network activity. This review provides an introduction to some of the network based theories on the function and pathophysiology of the cortico-basal-ganglia-thalamo-cortical loops commonly targeted by DBS. We then analyze some recent results on the effects of DBS on these networks, with a focus on subthalamic DBS for the treatment of Parkinson's disease. Finally we attempt to summarize how DBS could be achieving its therapeutic effects by overriding pathological network activity.
Article: Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque.[show abstract] [hide abstract]
ABSTRACT: Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.Journal of Neurophysiology 07/2005; 93(6):3165-76. · 3.32 Impact Factor
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ABSTRACT: Views of the anatomy and function of the basal ganglia and their role in motor and nonmotor disorders have undergone major revisions during the past decades. The basal ganglia are now appreciated as components of parallel, reentrant cortico-subcortical circuits, which originate from individual cortical areas, traverse the basal ganglia and thalamus, and terminate in their respective areas of origin in the frontal lobe. Further research and clinical experience have resulted in new insights and perspectives on the details of the circuitry and on the role of these structures in Parkinson disease and other basal ganglia disorders. On the basis of anatomical and physiological studies and the striking success of focused surgical interventions, it seems appropriate to view these varied clinical disorders as circuit disorders, resulting from pathologic disturbances in neuronal activity throughout specific cortico-subcortical loops.Archives of Neurology 02/2007; 64(1):20-4. · 7.58 Impact Factor
Article: Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits.[show abstract] [hide abstract]
ABSTRACT: Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.Journal of Neuroscience 03/2005; 25(6):1523-31. · 7.11 Impact Factor