Gambling Disorder Clinical Trial
Official title:
Modulating Inhibitory Control Networks in Gambling Disorder With Theta Burst Stimulation
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.
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.
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