Spatial and Temporal Properties of Tic-Related Neuronal Activity in the Cortico-Basal Ganglia Loop

Abstract

Motor tics are involuntary brief muscle contractions that interfere with ongoing behavior and appear as a symptom in several human disorders. While the pathophysiology of tics is still largely unknown, multiple lines of evidence suggest the involvement of the corticobasal ganglia loop in tic disorders. We administered local microinjections of bicuculline into the putamen of Macaca fascicularis monkeys to induce motor tics, while simultaneously recording neuronal activity from the primary motor cortex, putamen, and globus pallidus. These data were used to explore the spatial and temporal properties of tic-related neuronal activity within the cortico-basal ganglia system. In the putamen, tics were associated with brief bursts of activity of phasically active neurons (presumably the projection neurons) and complex excitation-inhibition patterns of tonically active neurons. Tic-related activity within the putamen was spatially focused and somatotopically organized. In the globus pallidus, tic-related activity was diffusely distributed throughout the motor territory. Ticrelated activity in the putamen usually preceded the tic-related activations in the cortex, but in the globus pallidus, tic-related activity was mostly later than the cortex. These findings shed new light on the role of the different basal ganglia nuclei in the generation of motor tics. Despite the early and somatotopically focused nature of tic-related activity in the input stage of the basal ganglia, tic-related activity in the output nucleus is temporally late and diffusely distributed, making it incompatible with a role in tic initiation. Instead, abnormal basal ganglia activity may serve to modulate motor patterns or activate learning mechanisms, thus augmenting further tic expression.

Deep Brain Stimulation Reduces Tic-Related Neural Activity via Temporal Locking with Stimulus Pulses

“…Consistent with previous reports, focal disinhibition of the striatum with bicuculline induced myoclonic-like motor tics, and the expression of tics was associated with widespread phasic changes in pallidal activity, suggesting that aberrant BG output leads to tourettism (McCairn et al, , 2012(McCairn et al, , 2013Bronfeld et al, 2011). It was our experience that periodic tic-related discharge was widespread in the GP, but early responding cells were localized in its posterior region.…”

“…Single-cell activity in the pallidum after bicuculline administration Consistent with previous reports (McCairn et al, , 2012(McCairn et al, , 2013Bronfeld et al, 2011), the majority of pallidal cells exhibited prominent tic-related responses. An example of simultaneously recorded EMG, GPe and GPi activity after tic induction is shown in Figure 4A.…”

“…Once well isolable neurons had been identified in the GPe and GPi, a small amount of bicuculline (2.0 -8.0 l) (Table 1)was administered into the sensorimotor putamen. The behavioral response to the microinjection was consistent with previous reports (Crossman et al, 1988;McCairn et al, , 2012McCairn et al, , 2013Worbe et al, 2009;Bronfeld et al, 2011): bicuculline infusion induced repetitive motor tics primarily in the orofacial region within minutes of injections (7.1 Ϯ 3.9 min; mean Ϯ SD) in most of the sessions (n ϭ 17) ( Table 1). It should be noted that prolonged maintenance of the tic state through supplementary injections of bicuculline (see Materials and Methods) did not allow for the testing of GPi-HF-DBS effects on the overall time that tics were present.…”

“…Recent studies in nonhuman primates (NHPs) have shown that during the expression of BG-mediated tics, widespread, phasic alterations in neuronal activity occur in the external and internal segments of globus pallidus (GPe and GPi, respectively) (McCairn et al, , 2012(McCairn et al, , 2013Bronfeld et al, 2011). The localization of pathological activity to the output nucleus of the basal ganglia provides a convenient target for neurosurgical intervention.…”

Tics and Tourette Syndrome

“…43 Ticlike generation in one of these models was not random, but in fact, followed the somatotopical distribution of respective disinhibited striatal motor areas. 44 In addition, structural neuroimaging studies in GTS patients have provided further evidence of abnormalities in CSTC loops. Smaller caudate volumes were found in a large sample of GTS children and adults with comorbid symptoms of ADHD and/or OCD (n 5 154, age range: 6-63 years).…”