Common neuronal mechanisms underlying tics and hyperactivity

Israelashvili, Michal; Yael, Dorin; Vinner, Esther; Belelovsky, Katya; Bar‐Gad, Izhar

doi:10.1016/j.cortex.2020.02.010

Cited by 12 publications

(11 citation statements)

References 85 publications

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“…During the quiet waking state, within each session, changes in the LFP signal appeared as stereotypic deflections with a typical temporal structure (Figures 2A and 2B, correlation coefficient: 0.97 G 0.02, mean G SD) and with stable magnitude values (Figure 2D, CV of magnitude: 0.24 G 0.10, mean G SD). These deflections, termed ''LFP spikes,'' were previously described in the acute tic expression model subsequent to bicuculline injections in primates and rats, and were highly correlated with individual motor tics (McCairn et al, 2009;Israelashvili and Bar-Gad, 2015). Similar results were observed for prolonged periods in our previous study, which described the chronic model (Vinner et al, 2017).…”

Section: Macro-level Neural Correlates Are Dissociated From Tic Expression During Sleepsupporting

confidence: 81%

“…LFP recordings performed during deep brain stimulation implantation surgeries in patients with TS have revealed tonic and phasic changes in BG output associated with tic expression (Zhuang et al, 2009;Israelashvili et al, 2017;Zhu et al, 2019). Extracellular recordings in animal models inducing motor tics have led to a better understanding of the relationship between the properties of neural correlates and tic expression throughout the cortico-BG pathway (Muramatsu et al, 1990;McCairn et al, 2009McCairn et al, , 2016Israelashvili and Bar-Gad, 2015;Klaus and Plenz, 2016). Macro-scale neural correlates, which manifest as deflections of the LFP signal (''LFP spikes''), were shown to be highly correlated with the expression of individual motor tics.…”

Section: Discussionmentioning

confidence: 99%

“…The similarity of tic expression in the experimental model led us to the behavioral hypothesis that the tics would undergo the same modulation observed in patients with TS during the sleep-wake cycle. In the experimental model, the timing of a single tic and the body part in which it will be expressed are modulated via cortical input (Israelashvili and Bar-Gad, 2015) and striatal somatotopic organization (Bronfeld et al, 2013b), respectively, thus enabling a controlled study of tic modulation. The BG have also been implicated in sleep-wake regulation (Vetrivelan et al, 2010;Lazarus et al, 2012Lazarus et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of tic generation from tic expression during the sleep-wake cycle

et al. 2021

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Motor tics, the hallmark of Tourette syndrome (TS), are modulated by different behavioral and environmental factors. A major modulating factor is the sleepwake cycle in which tics are attenuated to a large extent during sleep. This study demonstrates a similar reduction in tic expression during sleep in an animal model of chronic tic disorders and investigates the underlying neural mechanism. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABA A antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a state-dependent dissociation between motor tic expression and their macro-level neural correlates (''LFP spikes'') during the sleep-wake cycle. Local field potential (LFP) spikes, which are highly correlated with tic expression during wakefulness, persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was time-locked to the LFP spikes during wakefulness, but this locking decreased significantly during sleep. These results suggest that whereas LFP spikes encode motor tic generation and feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in patients with TS during sleep and potentially during other behavioral states.

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Section: Macro-level Neural Correlates Are Dissociated From Tic Expression During Sleepsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dissociation of tic generation from tic expression during the sleep-wake cycle

et al. 2021

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“…Therefore, the rescue of locomotor and social novelty behavior by the chemogenetic manipulation suggests that these behaviors depend on tonic prefrontal inhibition, but do not require precise temporal regulation of this inhibition 43,44 . In line with this notion, the schizophrenia-relevant behavioral deficit such as hyperactivity was also found in other pharmacological models of disinhibition in the forebrain regions [45][46][47][48] .…”

Section: Discussionsupporting

confidence: 67%

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition

Wang

Zhao

et al. 2021

Nat Commun

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Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Nav1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Nav currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.

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“…Nevertheless, the clinical overlap and co-morbidity across neurodevelopmental conditions, suggests that people with Tourette Syndrome are more likely to manifest joint hypermobility compared to the general population. For example, there are high comorbidity rates of both ADHD and autism with TS, with estimates ranging from 60-80% for ADHD and 6.5-50% for autism (Cavanna et al, 2009) Interestingly, this neurodevelopmental triad also share a common involvement of fronto-striatal systems in respective symptomology(Rapanelli et al, 2017, Israelashvili et al, 2020) Comorbidity aside, even those with a single diagnosis of TS may be more predisposed to joint hypermobility than the general population given the links between autonomic dysfunction, premonitory urge sensations, and tics (Rae et al, 2019, Hawksley et al, 2015)…”

Section: Introductionmentioning

confidence: 99%

Increased rate of joint hypermobility in autism and related neurodevelopmental conditions is linked to dysautonomia and pain

Jll

Iodice

Cl³

et al. 2020

Preprint

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Objective: Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social and emotional functioning. Vulnerability to chronic physical symptoms, including fatigue and pain, are also recognised. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts vulnerability to psychological symptoms alongside recognised physical symptoms. Here, we tested for increased rates of joint hypermobility, autonomic dysfunction and pain in 109 adults with neurodevelopmental diagnoses. Method: Rates of generalized joint laxity in those individuals with neurodevelopmental conditions were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a neurotypical control group. Results: Adults with neurodevelopmental diagnoses manifest elevated rates of joint hypermobility (50%) compared to the general population rate of 20% and a matched control population of 10%. Odds ratio for hypermobility in individuals with neurodevelopmental diagnoses, compared to the general population was 4.51 (95%CI 2.17-9.37), with greater odds in females rather than males. Neurodevelopmental patients reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than controls Conclusions: In adults with neurodevelopmental conditions, there is a strong link between the expression of joint hypermobility, autonomic dysfunction and pain, more so than in healthy controls. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties including comorbid stress-sensitive physical symptoms.

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Common neuronal mechanisms underlying tics and hyperactivity

Cited by 12 publications

References 85 publications

Dissociation of tic generation from tic expression during the sleep-wake cycle

Dissociation of tic generation from tic expression during the sleep-wake cycle

Overexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition

Increased rate of joint hypermobility in autism and related neurodevelopmental conditions is linked to dysautonomia and pain

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