Pathological network activity in Parkinson's disease: from neural activity and connectivity to causality?

Abstract

Pathophysiological changes in the basal ganglia thalamocortical loops, first described ∼20 years ago by Alexander et al . (1990), are commonly assumed to underlie key symptoms of Parkinson's disease. In their model, Alexander et al . (1990) described a large network of inhibitory and excitatory connections between different subnuclei of basal ganglia, thalamus and cortex. In the normal (i.e. physiological) state, two distinct loops regulate basal ganglia activity: a direct loop between the striatum and the internal segment of the globus pallidus; and an indirect loop between this structure and the striatum (in this loop, activity is relayed via the subthalamic nucleus). In the healthy state, these two loops are balanced resulting in well-regulated activity of the internal segment of the globus pallidus and the tightly connected pars reticulata of the substantia nigra. Besides its influence on brainstem activity, the ‘output-region’ of this basal ganglia network is assumed to project to the thalamus, thereby modulating thalamo-cortical interactions. Albeit simplistic, the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra is to date considered the key neuropathological change underlying Parkinson's disease. Based upon neuropathological findings, after degeneration of dopaminergic cells in the substantia nigra the Alexander et al .'s (1990) model proposes affection of the indirect loop leading to reduced inhibition of the subthalamic nucleus, and stronger excitation of the internal segment of the globus pallidus and the pars reticulata of the substantia nigra. Conversely, the model predicts that the direct inhibitory projections of the striatum to the internal segment of the globus pallidus and the pars reticulata of the substantia are reduced. The sum effects of these changes are ‘overactivity’ in the internal segment of the globus pallidus and the pars reticulata of the substantia and an inhibition of thalamo-cortical interactions. This model could then …