Exploring the Role of Neuroactive Steroids in Tourette Syndrome (NS in TS)

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by motor and phonic tics. The studies proposed in this application will explore the endocrine mechanisms underlying two of the least well-understood biological characteristics of TS, namely its marked male predominance and stress susceptibility. In particular, our exploratory studies will characterize the steroid profile in TS-affected boys and girls to identify novel potential biomarkers and therapeutic targets for this disorder.

Study Overview

• Status: Not yet recruiting
• Conditions: Tourette Syndrome in Children
• Intervention / Treatment: Behavioral: Tic suppression task

Detailed Description

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by motor and phonic tics. Available treatment strategies remain unsatisfactory, due to limited knowledge of the biological foundations of this disorder. The studies proposed in this application will explore the mechanisms underlying two of the least well-understood biological characteristics of TS, namely its marked male predominance and stress susceptibility. Studies from the investigators suggest that these features of TS are contributed by neuroactive steroids, a family of mediators implicated in sex and stress regulation.

The typical age of onset of TS is 6-7 years, coinciding with adrenarche, a phase of adrenal maturation characterized by an upsurge in adrenal neuroactive steroids, such as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In preliminary studies, the investigators found that DHEA exacerbated tic-like responses in animal models of TS. Interestingly, the dose of DHEA needed to elicit TS-like responses in females is higher than those needed in males, possibly pointing to a mechanism of sex differences in TS.

Stress reduces the ability of TS patients to suppress tics, but the underlying mechanisms remain unknown. Studies in animal models indicate that this process may be due to the elevation of the neuroactive steroid allopregnanolone (AP) in the prefrontal cortex. By inhibiting the ability of the prefrontal cortex to suppress tics, AP promotes tic execution. In a pilot study, the investigators found that tic suppression, a well-known stressful task in TS patients, increases AP salivary levels. Furthermore, in another proof-of-concept study, the investigators found that inhibiting AP synthesis led to a reduction in tic severity and facilitated voluntary control of tics in stressful situations.

These findings lead to the hypothesis that TS patients exhibit alterations of the composition of their neuroactive steroid profiles, including: 1) an increase in baseline DHEA(S) levels in male TS patients, in correlation with life-time severity; and 2) an exaggerated elevation in AP in response to acute stress.

The two Aims of this proposal will test this hypothesis by: 1) comparing the baseline urinary steroidomic profile of TS-affected boys and girls with non-affected sex- and age-matched controls; and 2) charting the dynamic alterations in steroidomic salivary profiles in response to tic suppression. These studies will advance understanding of the endocrine mechanisms in TS and lead to the identification of potential biomarkers for the severity of tics and comorbid symptoms. In the long run, the results of these studies may open the way for the development of new therapies for TS that may reduce tic severity and increase patients' responsiveness to behavioral interventions.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marco Bortolato, MD PhD; Phone Number: 8015873352; Email: marco.bortolato@utah.edu
• Study Contact Backup: Name: Michael Himle, PhD; Phone Number: 8015817529; Email: michael.himle@utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
      • Contact: Michael Himle, PhD; Phone Number: 801-581-7529; Email: michael.himle@utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 12 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnostic criteria of TS for cases (and lack of any tic disorders for controls)
• Age between 8 and 12 years old (this age range is to ensure that TS participants can perform the tic suppression task)
• confirmation of sexual development by parent and/or self-reported Tanner stage of pubic hair development.

Exclusion Criteria:

• major psychiatric disorders such as a psychotic disorder, autism spectrum disorder, conduct disorder, and substance use disorder;
• other neurological disorders;
• clinically significant endocrinological disorders;
• use of therapies that can modify hormonal profile;
• pharmacotherapies that may change stress sensitivity, such as antidepressants and anxiolytics.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tic suppression; Children with tics will undergo a tic suppression experimental paradigm.

Behavioral: Tic suppression task; Tic Suppression Task (TST, administered to Tourette syndrome participants only): At the beginning of the task, the child participant will be seated alone in front of a computer monitor with a countdown timer visible on the screen. For the first 10 minutes (baseline condition) they will be asked to tic freely and not to try to suppress their tics. For the second 10 minutes children will be asked to suppress their tics and will receive points for successful suppression. Participants will then be asked to sit alone in the room and tic freely for an additional 10-minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Salivary allopregnanolone concentrations	Change of concentrations of salivary allopregnanolone, as measured by chromatography/ mass spectrometry. All concentrations will be expressed in pg/ml.	Through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tic frequency	Direct observation	Through study completion, an average of 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of salivary concentrations of other neuroactive steroids	Changes in concentrations of pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenediol, progesterone, androstenedione, testosterone, dihydroprogesterone, dihydrotestosterone, isoallopregnanolone, pregnanolone, epipregnanolone, 3-alpha androstanediol, androsterone, epiandrosterone, etiocholanolone, and cortisol as measured by chromatography/ mass spectrometry. All concentrations will be expressed in pg/ml.	Through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Albert Einstein College of Medicine; University of Miami
• Investigators: Principal Investigator: Marco Bortolato, MD PhD, University of Utah

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2022
• Primary Completion (Anticipated): March 31, 2024
• Study Completion (Anticipated): March 31, 2024

Study Registration Dates

• First Submitted: February 24, 2022
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 16, 2022

Study Record Updates

• Last Update Posted (Actual): March 16, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Tic Disorders; Syndrome; Tourette Syndrome
• Other Study ID Numbers: 00150143

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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