Modulating Inhibitory Control Networks in Gambling Disorder With Theta Burst Stimulation (TMS-GD)

In this project the investigators propose a randomized double-blind placebo-controlled design in which 40 patients with GD will receive active or sham cTBS to the pre-SMA for 2 weeks. The investigators will combine TMS, multimodal structural and functional MRI and behavioral measures in order to identify circuit-level mechanisms of action and therapeutic targets (connectivity changes that explain clinical improvement) and assess the efficacy of TMS in modulating inhibitory control and symptom severity in this population.

Study Overview

• Status: Unknown
• Conditions: Gambling Disorder
• Intervention / Treatment: Device: Transcranial Magnetic stimulation

Detailed Description

SPECIFIC AIMS The appropriate interplay of cognitive and reward systems is essential for adaptive human behavior, allowing a homeostatic balance between immediate basic pleasures and long-term planned rewards. Deficits in inhibitory control from cortical cognitive systems over subcortical reward circuits is a key pathophysiological feature of addictive behavior that has not been studied satisfactorily in gambling disorder (GD). The clinical phenotype of this population is characterized by unsuccessful efforts to reduce or stop gambling despite negative outcomes, suggestive of faulty inhibitory control of gambling impulses that sustain the chronicity and comorbidities of this clinical syndrome. Deficits in behavioral and cognitive control constitute a symptom dimension associated with diminished response inhibition in experimental tasks such as the Stop Signal Task (SST). The pre-supplementary motor area (pre-SMA) is a key node of the cognitive control network responsible for response inhibition. Pre-SMA activation has been associated to response inhibition performance in fMRI studies using the SST and recent evidence also suggests that its activity represents a motivational signal for movement. In fact, pre-SMA seems to have a dominant role in bridging the delay between expected reward and specific actions rather than determining whether an action is made. Although the pathophysiology of GD is not well understood, studies have shown altered brain activity in prefrontal regions (including pre-SMA) of GD patients during response inhibition tasks in addition to functional connectivity abnormalities of SMA during rest. These circuit-level abnormalities represent a potential therapeutic target that could be modulated by brain stimulation therapies such as transcranial magnetic stimulation (TMS). Theta burst stimulation (TBS), is a particularly brief and effective form of TMS that can be inhibitory (continuous or cTBS) or excitatory (intermittent or iTBS). Although pre-SMA has been successfully targeted with traditional TMS and TBS for impulse-control disorders like OCD, this approach has never been tested for GD in therapeutic or mechanistic studies. Despite the significant morbidity and mortality of GD, there is a dramatic shortage of effective treatment options for these patients, partly due to the lack of valid pathophysiological models for target discovery and experimental therapeutics. In this project the investigators propose a randomized double-blind placebo-controlled design in which 40 patients with GD will receive active or sham cTBS to the pre-SMA for 2 weeks. The investigators will combine TMS, multimodal structural and functional MRI and behavioral measures in order to identify circuit-level mechanisms of action and therapeutic targets (connectivity changes that explain clinical improvement) and assess the efficacy of TMS in modulating inhibitory control and symptom severity in this population.

Aim 1 (ACUTE MECHANISM OF ACTION): To assess circuit-level effects of a single session of cTBS to the pre-SMA in GD patients. Hypothesis 1.1: cTBS will lead to increase in functional connectivity between cortical inhibitory nodes (pre-SMA) and reward subcortical structures (Nucleus Accumbens, NAc), and these changes will correlate with improvement in reaction time in SST. Hypothesis 1.2: cTBS will not lead to acute changes in FA, RD or AD in the mesocorticolimbic pathway. Hypothesis 1.3: cTBS will lead to increased cognitive control network and decreased NAc activation during SST. Exploratory analyses will test the predictive value of acute circuit changes for clinical improvement after 2 weeks and 1 month follow up.

Aim 2 (CHRONIC MECHANISM OF ACTION): To assess circuit-level effects of 10 session of cTBS to the pre-SMA in GD patients Hypothesis 2.1: cTBS will lead to increases in functional connectivity between preSMA and NAc, and these will correlate with behavioral and clinical improvement. Hypothesis 2.2: cTBS will lead to increased FA and decreased RD and AD in the mesocorticolimbic pathway, and these will correlate with clinical improvement. Hypothesis 2.3: cTBS will lead to further increased cognitive control network and decreased NAc activation during SST, and these will correlate with clinical improvement.

Aim 3 (BEHAVIORAL/CLINICAL): To determine the behavioral and clinical changes of cTBS to the preSMA in GD. Hypothesis 3.1: A single session of cTBS will lead to improvement in reaction time in the SST, but not in symptom severity measured with clinical scales. Hypothesis 3.2: 10 sessions of cTBS will lead to improvement in reaction time in the behavioral inhibition task, in addition to a reduction in clinical severity (including craving/urges) as measured by clinical scales.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Florence, Italy, 50100
    • Recruiting
    • CNSOnlus, Institute of Neuroscience

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. DSM-5 diagnosis of Gambling Disorder
2. Age between 18 and 65 years

Exclusion Criteria:

1. any additional current psychiatric comorbidity, except for nicotine addiction;
2. a lifetime DSM-5 diagnosis of schizophrenia or other psychotic syndromes, substance dependence or substance abuse, including alcohol, bipolar I or II disorder, mental disorder due to a general medical condition;
3. serious suicide risk;
4. illness duration less than two years;
5. hospitalization in the last 6 months;
6. the inability to receive TMS because of metallic implants, or history of seizures (personal or family history of seizure in first degree relatives);
7. any major medical disease;
8. pregnancy or nursing of an infant;
9. the inability or refusal to provide written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Active cTBS treatment; Active cTBS will be administered with a Magventure MagPro Stimulator R30 using a butterfly coil. TBS consists of bursts of 3 pulses separated by 20ms (i.e. 50 Hz), with each triplet being repeated every 200 ms (i.e. 5 Hz). Stimulus intensities will be set at 80% of AMT. The investigators will use 2 trains of 600 pulses each separated by 1 minute (a total of 1200 pulses).	Device: Transcranial Magnetic stimulation; Neuromodulation tool
SHAM_COMPARATOR: Sham cTBS treatment; Sham cTBS will be administered with a Magventure MagPro Stimulator R30 using a butterfly sham coil. The same active cTBS configuration will be used.	Device: Transcranial Magnetic stimulation; Neuromodulation tool

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cTBS effects on gambling symptoms change	cTBS effects on gabling symptoms severity assessed through the PG-Y-BOCS (Yale-Brown Obsessive-Compulsive Scale modified for Pathological Gambling). Range from: 0-40 (higher values=worse symptoms)	Baseline - Day 10 (after 10 cTBS sessions) - after 1 month follow-up
cTBS effects on gambling symptoms change	cTBS effects on gabling symptoms severity assessed through the GUQ (Gambling Urges Questionnaire). Range from: 0-60 (higher values=worse symptoms)	Baseline - Day 10 (after 10 cTBS sessions) - after 1 month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute mechanism of action	Functional MRI assessment	Day 1
Chronic mechanism of action	Functional MRI assessment	Day 10

Collaborators and Investigators

• Sponsor: CNS Onlus

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 20, 2018
• Primary Completion (ANTICIPATED): December 1, 2019
• Study Completion (ANTICIPATED): December 1, 2019

Study Registration Dates

• First Submitted: September 6, 2018
• First Submitted That Met QC Criteria: September 11, 2018
• First Posted (ACTUAL): September 13, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2018
• Last Update Submitted That Met QC Criteria: September 11, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; Gambling Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disruptive, Impulse Control, and Conduct Disorders; Disease; Gambling
• Other Study ID Numbers: TMS-GD

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: Yes
• product manufactured in and exported from the U.S.: Yes