Neural Correlates of Sensory Phenomena in Tourette Syndrome

The most pervasive sensory manifestation of TS is sensory over-responsivity (SOR). SOR is defined as excessive behavioral response to commonplace environmental stimuli. SOR is an integral but poorly understood facet of the TS phenotype, one intertwined with core elements of the disorder and worse QOL. This proposal seeks to clarify the mechanistic bases of SOR in TS. Adults with with TS will be recruited 1) to complete a standardized clinical symptom assessment battery and 2) to undergo electroencephalogram (EEG), autonomic, and audio-visual monitoring during tactile and auditory stimuli paradigms, as well as at rest.

Study Overview

• Status: Recruiting
• Conditions: Hypersensitivity; Tourette Syndrome; Tics; Sensory Disorders
• Intervention / Treatment: Diagnostic test: Electroencephalogram (EEG) testing procedure; Diagnostic test: Autonomic function testing procedure

Detailed Description

Tourette syndrome (TS) is a multifaceted disorder that affects 0.6-1% of the global population. Across the lifespan, individuals with TS suffer worse quality of life (QOL) than the general population. While tics are the defining feature of TS, it is the widespread psychiatric and sensory symptoms that exert greater impact on QOL: more than 85% of individuals with TS are diagnosed with a psychiatric disorder, and 90% experience distressing sensory symptoms. The latest TS disease models and practice guidelines account for common psychiatric symptoms, but sensory symptoms remain under-recognized and under-studied. Progress in understanding and treating TS requires deepening insight into the disorder's sensory dimension.

The most pervasive sensory manifestation of TS is sensory over-responsivity (SOR). SOR is defined as excessive behavioral response to commonplace environmental stimuli. SOR is associated with avoidant behavior and functional impairment. More than 50% of children and 80% of adults with TS report SOR. Across age groups, SOR is positively correlated with severity of tics and psychiatric symptoms and negatively correlated with QOL. Thus, SOR is an integral facet of the TS phenotype, one intertwined with core elements of the disorder and worse QOL. This proposal seeks to clarify the mechanistic bases of SOR in TS (Aims 1 and 2).

Enhanced understanding of SOR's neurobiological basis is crucial to a more complete knowledge of TS pathophysiology. Two neurophysiologic mechanisms are implicated in SOR: sensory gating impairment and autonomic hyperarousal. Sensory gating is the physiologic process whereby redundant environmental stimuli are filtered out in the early stages of perception. Impairment of sensory gating gives rise to altered sensory perception. Autonomic hyperarousal is a state of excessive sympathetic tone and/or reduced parasympathetic tone, which hampers behavioral adaptation to sensory input. In TS, multiple lines of evidence suggest both sensory gating and autonomic function are impaired. However, prior investigations have suffered from methodologic limitations and have not examined the link between neurophysiologic dysfunction and sensory symptoms.

Aim 1. Identify an electroencephalographic (EEG) signature of SOR in TS. Hypotheses: (1a) relative to healthy controls, TS adults exhibit impaired sensory gating; (1b) extent of impaired sensory gating in TS correlates with degree of SOR. We will recruit 60 TS adults and 60 age- and sex-matched healthy controls to complete rating scales for SOR, psychiatric symptoms, and tics. Subjects will then be monitored on dense-array scalp EEG during sequential auditory and tactile sensory gating paradigms.

Aim 2. Identify an autonomic signature of SOR in TS. Hypotheses: (2a) relative to healthy controls, TS adults exhibit autonomic hyperarousal in response to non-aversive sensory stimuli; (2b) extent of autonomic hyperarousal correlates with SOR severity in TS. Heart rate and electrodermal activity will be monitored during the Aim 1 sensory gating paradigms and during a 10-minute rest period. Heart rate variability and electrodermal activity will serve as indices of parasympathetic and sympathetic activity, respectively.

Impact: Results will clarify the extent of sensory gating impairment in TS, the nature of autonomic dysfunction in TS, and the clinical correlates of neurophysiologic dysfunction in TS.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: David A Isaacs, MD; Phone Number: 615-875-7394; Email: david.a.isaacs@vumc.org
• Study Contact Backup: Name: Michelle R Eckland, BS; Phone Number: 615-875-7394; Email: michelle.r.eckland.1@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232-5400
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Michelle R Eckland, BS; Phone Number: 615-875-7394; Email: michelle.r.eckland.1@vumc.org
      • Principal Investigator: David A Isaacs, MD
      • Sub-Investigator: Heather Riordan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The two groups of participants will include:

1. adult with Tourette syndrome or other chronic tic disorder
2. healthy controls

Description

Inclusion criteria for TS arm:

• Diagnosis of Tourette syndrome or other chronic tic disorder
• ≥ 18 years of age
• Ability to complete survey instruments
• English fluency (given that all scales are validated in English)

Exclusion criteria for TS arm:

- Known diagnosis of autism spectrum disorder, developmental delay, cerebral palsy, other significant neurologic disease, schizophrenia, or psychotic disorders will be excluded, in order to lessen potentially confounding factors.

(Note: Patients with OCD, ADHD, anxiety, and/or depression will be permitted, given that these diagnoses are widely prevalent in the adult TS population.)

• Use of anti-seizure medications, stimulants, or other psychotropic medications known to alter EEG signal
• Recreational substance use within past 30 days

Inclusion criteria for healthy control arm:

• ≥ 18 years of age AND age within 5 years of a participant in the TS arm of same biological sex (for purposes of age- and sex-matching)
• Ability to complete survey instruments
• English fluency (given that all scales are validated in English)

Exclusion criteria for healthy control arm:

• Any neurologic or psychiatric diagnoses
• History of tics
• Use of any psychotropic medications within the past 30 days
• Recreational substance use within past 30 days

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tourette Syndrome; Adults (>18 years of age) with diagnosis of Tourette syndrome	Diagnostic test: Electroencephalogram (EEG) testing procedure; EEG testing procedure, comprised of somatosensory and auditory event-related potential paradigms, as well as resting state EEG; Diagnostic test: Autonomic function testing procedure; Autonomic function testing procedure, comprised of electrodes to determine heart rate variability and electrodermal activity (EDA)
Healthy Control; Adults who are generally healthy with no known neurologic or psychiatric diagnoses	Diagnostic test: Electroencephalogram (EEG) testing procedure; EEG testing procedure, comprised of somatosensory and auditory event-related potential paradigms, as well as resting state EEG; Diagnostic test: Autonomic function testing procedure; Autonomic function testing procedure, comprised of electrodes to determine heart rate variability and electrodermal activity (EDA)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Network oscillations in response to sensory stimuli	Neural activity captured on EEG can be spectrally decomposed into various frequency constituencies. Neural activity in the gamma frequency range, so-called gamma band oscillations (GBOs), are associated with sensory processing and integration and are postulated to underlie sensory phenomena in TS.	Baseline
Heart rate variability	Change beat-to-beat variability in heart rate	Baseline
Electrodermal activity in response to sensory stimuli	Sweat response changes within 1-3 seconds of non-aversive sensory stimulus	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Premonitory Urge to Tic Scale (PUTS)	Validated self-report questionnaire comprised of 9 items assessing character and severity of premonitory urges. Scale range: 9 (least affected) - 36 (most affected)	Within 1 week of baseline
Yale Global Tic Severity Scale (YGTSS)	Validated, gold-standard clinician-administered tic assessment scale, comprised of 11 items. Scale range: 0 (best) - 100 (worst)	Within 1 week of baseline
Dimensional Obsessive Compulsive Scale (DOCS)	Validated self-report questionnaire assessing severity of obsessive and compulsive symptoms, comprised of 20 items. Scale range 0 (least affected) - 80 (most affected)	Within 1 week of baseline
Adult ADHD Self-Report Screening Scale	Validated self-report scale, developed since release of Diagnostic and Statistical Manual-V, comprised of 6 items. Scale range 0 (least affected) - 24 (most affected)	Within 1 week of baseline
Generalized Anxiety Disorder 7 (GAD-7)	Validated self-report scale assessing presence and extent of anxiety, comprised of 7 items. Scale range 0 (least affected) - 21 (most affected)	Within 1 week of baseline
Patient Health Questionnaire 9 (PHQ-9)	Validated self-report scale assessing presence and extent of depression, comprised of 9 items. Scale range 0 (least affected) - 27 (most affected)	Within 1 week of baseline
Sensory Gating Inventory (SGI)	Validated self-report questionnaire assessing sensory hypo- or hyper-sensitivity, comprised of 36 items. The 4 sub-scales include Perceptual Modulation, Distractability, Over-Inclusion, and Fatigue and Stress Vulnerability. Total scale range 0 (least affected) - 180 (most affected)	Within 1 week of baseline
Sensory Perception Quotient (SPQ)	Validated self-report questionnaire assessing sensory hypo- or hyper-sensitivity, comprised of 35 items. Scale range 0 (highest sensory sensitivity) - 105 (lowest sensory sensitivity).	Within 1 week of baseline
Gilles de la Tourette Syndrome - Quality of Life Scale (GTS-QOL)	Validated self-report questionnaire assessing health-related quality of life for patients with Tourette syndrome, comprised of 27 items. Scale range 0 (best quality of life) - 108 (worst quality of life)	Within 1 week of baseline
Patient Reported Outcomes Measurement Information System (PROMIS) Sleep-Related Impairment	Validated self-report questionnaire to measures sleep-related impairments, consisting of 8 items. Scale range 0 - 100 (t-score scaled with lower values indicating less impairment).	Within 1 week of baseline
Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2)	Validated self-report questionnaire assessing interoceptive sensibility, comprised of 37 items. Each scale item is a statement to which respondents must select "never" (0) to "always" (5) on a six-point Likert scale. No total MAIA-2 score exists. Rather, individual scale items belong to one of eight MAIA-2 subscales. For each subscale, higher score signifies more of that construct.	Within 1 week of baseline
Body Perception Questionnaire - Short Form (BPQ-SF)	Validated self-report questionnaire assessing interoceptive sensibility, comprised of 46 items total, divided into 3 sections: Body Awareness (raw total score 26-130), Supradiaphragmatic Reactivity (raw total score 15-69), and Subdiaphragmatic Reactivity (raw total score 6-28). Raw scores are converted to T-scores. Higher raw and T-scores indicate greater maladaptive body awareness.	Within 1 week of baseline

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2021
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neurologic Manifestations; Disease; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Tic Disorders; Hypersensitivity; Syndrome; Tourette Syndrome; Sensation Disorders
• Other Study ID Numbers: NCoSPTS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified clinical variables, EEG data, and autonomic data metrics may be shared with other researchers.
• IPD Sharing Time Frame: The above information will be available for sharing within 6 months of publication.
• IPD Sharing Access Criteria: Researchers wishing to access the above information should contact the investigative team and provide: 1) hypothesis-driven scientific question for which the data will be analyzed and 2) proposed methods for responsibly analyzing the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No