A neural network for tics: insights from causal brain lesions and deep brain stimulation

Abstract

Brain lesions are a rare cause of tic disorders. However, they can provide unique insights into tic pathophysiology and can also inform on possible neuromodulatory therapeutic targets. Based on a systematic literature review, we identified 22 cases of tics causally attributed to brain lesions and employed ‘lesion network mapping’ to interrogate whether tic-inducing lesions would be associated with a common network in the average human brain. We probed this using a normative functional connectome acquired in 1,000 healthy participants. We then examined the specificity of the identified network by contrasting tic-lesion connectivity maps to those seeding from 717 lesions associated with a wide array of neurological and/or psychiatric symptoms within the Harvard Lesion Repository. Finally, we determined the predictive utility of the tic-inducing lesion network as a therapeutic target for neuromodulation. Specifically, we collected retrospective data of 30 individuals with Tourette disorder, who underwent either thalamic (n = 15; centromedian/ventrooralis internus) or pallidal (n = 15; anterior segment of globus pallidus internus) deep brain stimulation and calculated whether connectivity between deep brain stimulation sites and the lesion network map could predict clinical improvements. Despite spatial heterogeneity, tic-inducing lesions mapped to a common network map, which comprised the insular cortices, cingulate gyrus, striatum, globus pallidus internus, thalami, and the cerebellum. Connectivity to a region within the anterior striatum (putamen) was specific to tic-inducing lesions when compared with control lesions. Connectivity between deep brain stimulation electrodes and the lesion network map was predictive of tic improvement, regardless of the deep brain stimulation target. Taken together, our results reveal a common brain network involved in tic generation which shows potential as a therapeutic target for neuromodulation.

Lesion network mapping for symptom localization: recent developments and future directions

“…Lesions causing cervical dystonia are connected to the cerebellum and sensory cortex, converging with connectivity with the optimal globus pallidus DBS electrode location connectivity in patients with idiopathic generalized or cervical dystonia [23]. Similarly, Ganos, Al-Fatly et al [5 ▪ ] recently showed that connectivity between DBS sites and a network connected to lesions causing tics significantly predicted clinical improvement in patients. In depression, therapeutic brain stimulation (both invasive and noninvasive) and brain lesions converged on common circuits [28 ▪ ].…”

“…Similarly, LNM has recently been applied to other long-standing neurological mysteries, including motor/vocal tics, blindsight, and pathological laughter and crying, characterized by inappropriate outbursts of laughter and/or weeping [5 ▪ ,13,22 ▪ ]. In each of these conditions, prior neuroimaging studies have provided heterogeneous results and causal lesions are scattered throughout many different regions in the brain, leaving the neural substrate unknown.…”

“…Therefore, if LNM is to be relevant to symptoms in these populations, it must be demonstrated that primary and lesion-induced symptoms involve dysfunction of the same brain networks. Although LNM directly only applies to symptoms caused by lesions, recent work in cervical dystonia [23], tics [5 ▪ ], and mania [24] have shown that networks identified through brain lesions are also abnormal in idiopathic patients with the same disorder. In cervical dystonia, Corp et al [23] showed that the cerebellar and somatosensory regions identified by LNM showed abnormal rs-fMRI connectivity in an independent dataset of idiopathic cervical dystonia patients.…”

“…Similarly, although a growing body of literature suggests that LNM can help to identify therapeutic targets [5 ▪ ,19,23,28 ▪ ], these studies have relied solely on retrospective patient data. It is important to take the next step and conduct prospective trials to investigate the efficacy of directly targeting LNM identified networks.…”

“…Lesion-based studies have advanced from individual cases to controlled data-driven whole brain analyses with sophisticated computational neuroimaging tools [2,3]. However, lesions causing similar symptoms often occur in heterogeneous brain locations with little overlap, leaving localization unclear [4 ▪ ,5 ▪ ]. One of the reasons for the lack of overlap is that lesions can also have a functional effect on remote but connected brain regions through disconnection or diaschisis, complicating efforts at lesion-based symptom localization [6,7].…”