FIG. 1.

Schematic diagram of the major connections of the basal ganglia associated with Tourette's syndrome. In the sensorimotor and motor circuits excitatory glutamatergic cortical neurons converge on the matrisomal (MS) γ-aminobutyric acid (GABA)–containing medium spiny neurons in the dorsal lateral striatum. These circuits are likely to be critically involved in the initiation and completion of tics. These cortical projections are organized somatotopically (with specific regions devoted to specific body regions). These MSs then project to the internal segment of the globus pallidus (GPi) and the pars reticulata of the substantia nigra (SNr), either directly or indirectly via both the external segment of the globus pallidus (GPe) and the subthalamus nucleus (STN). Inhibitory GABAergic projection neurons in the GPi and SNr, in turn, project to the specific or nonspecific (intralaminar) thalamic nuclei as well as brainstem nuclei. This loop is then completed by excitatory glutamatergic thalamocortical projection neurons to cortical neurons in the supplementary motor area. Both the specific and nonspecific thalamic excitatory glutamatergic nuclei project to both inhibitory fast spiking cortical GABAergic interneurons, as well as glutamatergic pyramidal projection neurons in the cortex (not shown). The ‘cognitive’ cortico-striato-thalamo-cortical (CSTC) circuit (not depicted in this figure) consists of cortical neurons in the prefrontal cortex that project to the head of the caudate nucleus. These signals are then relayed through the GP to the excitatory glutamatergic thalamocortical projection neurons. This circuit is likely to play a key mediating role in the therapeutic efficacy of habit reversal training. In addition to the motor, sensorimotor, oculomotor, and cognitive association circuits, limbic loops have also been characterized. The limbic system mediates emotional states, threat appraisal and motivation. It consists of cortical projections from limbic, pre- and perilimbic regions such as the hippocampus and amygdala to striosomial (SSs) medium spiny neurons in the ventral medial striatum. These inhibitory GABAergic cells in turn project to dopaminergic cells in the pars compacts of the substantia nigra (SNc) as well as to cholinergic neurons identified as tonically active neurons (TANs). The TANs receive input from both dopaminergic cells in the SNc and excitatory glutamatergic cortical neurons, synapse on fast-spiking neurons (FSNs) in the striatum. The FSNs appear to play a key role modulating the activity of the MSs (described above, see text). Excitatory glutamatergic projections are depicted as black solid arrows. They arise from cortical and thalamic sites. The STN also has excitatory glutamatergic projections. Inhibitory GABAergic projections are depicted as dashed arrows. They arise from medium spiny neurons in the striatum (both MSs and SSs) as well as the GPe and the basal ganglia output neurons in the SNr and GPi. The fast-spiking interneurons of the thalamus and cortex are also GABAergic, as are the FSNs in the striatum. FSNs can form gap junctions with other FSNs so that multiple cells can fire in unison (depicted as the solid line between the two FSNs). The location of their synapses on the cell bodies and proximal dendrites of the MSs also means that they can be very powerful inhibitors of the activity of MSs. The GABAergic interneurons in the cortex and thalamus as well as the FSNs, and some of the GABAergic cells in the SNr, GPi and GPe contain parvalbumin and share a common origin early in brain development. Dopaminergic projections (single large arrow) from the SNc are diffuse and can affect each cell type depicted in the striatum (not shown). The cholinergic projections from the schematic TANs are also depicted as solid lines. (Reprinted, with permission, from Leckman et al. 2006.)