Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers

Not Applicable

Completed

Conditions: Traumatic Brain Injury

Interventions: Device: Repetitive Transcranial Magnetic Stimulation

Registration Number: NCT04972786

Lead Sponsor: University of New Mexico

Brief Summary: 21 healthy control participants will be recruited. On Day 1 they will complete reward-guided decision making tasks and questionnaires followed by a functional magnetic resonance imaging (fMRI) scan. On Days 2 and 3 they will receive repetitive transcranial magnetic stimulation (rTMS) targeting a specific part of the brain called the dorsal anterior cingulate cortex (dACC) or sham stimulation, and will then repeat a subset of the same decision making tasks and fMRI sequences. If brain stimulation modifies decision making and dACC activity, it could represent a novel way of treating patients with neural circuit deficits that impede motivated behavior. Of particular relevance to the current trial, this rTMS study will run in parallel with a study of apathy (i.e., diminished motivation) in patients with traumatic brain injury (TBI), with the goal of eventually leading to a patient-centered trial of rTMS treatment for this disruptive neuropsychiatric symptom.

Detailed Description: TBI is a common and impairing acquired neurological disorder caused by a concussive event to the head. Psychiatric disorders associated with impaired decision making-in particular: apathy, or diminished motivated behavior-are common post-injury in TBI. Despite the critical importance of diagnosing and characterizing psychiatric problems such as apathy in TBI, very little is known about the neuropathologies underlying apathy in this patient group.

Reinforcement learning (RL)-i.e. the process of learning the reward value of stimuli and actions-represents a fundamental cross-species construct underlying motivated decision making. Further, aberrant reward processing has been strongly implicated in symptoms of apathy in the field of computational psychiatry. Despite extensive evidence that brain injuries can lead to maladaptive motivated decision making, the specific RL aberrations that might underlie this phenomenon, and their association with psychiatric sequelae remain unclear. Therefore, extant work has failed to provide insight into the computational mechanisms underlying maladaptive decision making in patients with TBI, and such work will be critical to build a better understanding of the neuropathologies that underlie apathy in TBI. This gap in current knowledge is being targeted by a related study from which healthy controls will be recruited for the current rTMS trial.

However, even if we gain a better understanding of the RL neural mechanisms that cause aberrant motivated behavior and psychiatric sequelae in TBI, translating this into an actionable target for clinical intervention remains unclear. Psychological interventions including Cognitive-Behavioral Therapy (CBT) and Motivational Interviewing (MI) have been investigated for treating symptoms of TBI. However, the potential benefit of both CBT and MI is limited in TBI, as they both rely heavily on high-level cognitive abilities-e.g. selective attention, executive control, and metacognition/insight-that are commonly impaired in this population. In addition to psychotherapies, two categories of pharmacotherapy have been investigated to reduce psychiatric sequelae in TBI: selective serotonin reuptake inhibitors (SSRIs) and dopamine agonists. A randomized controlled trial of SSRIs for TBI failed to demonstrate reductions in patient neuropsychiatric symptoms after a 10-week intervention. Multiple pilot studies (Ns=10-11) of dopamine agonists for TBI have been conducted, demonstrating preliminary support that they may reduce apathy. Yet, a recent meta-analysis suggested a high degree of unreliability in the literature on dopamine agonism in TBI. Dopamine agonists also carry the risk of significant side effects including increased apathy or maladaptive impulsivity. Unreliability and maladaptive side effects of dopaminergic medications are likely driven by their lack of circuit-specificity: They modulate dopaminergic tone throughout the brain, rather than within a dedicated neural circuit underlying a specific symptom profile. Therefore, a more effective approach to treating apathy in TBI may involve both i) avoiding therapies that rely on high-level cognition, and ii) establishing circuit-specific approaches for ameliorating patient apathy. Precise fMRI-guided rTMS represents one possible approach. The current project aims to test the efficacy of fMRI-guided TMS to RL neural circuits anchored in dorsal anterior cingulate cortex (dACC) on motivated decision making in healthy controls. Ultimately, the hope is that this approach might represent a first step towards a potential clinical intervention for TBI patients with clinical apathy.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

12 or more years of education
ability to provide informed consent independently

Exclusion Criteria

Non-fluency in English
Prior history of seizure
contraindications to MRI (metal in the body)
history of substance abuse (excluding moderate alcohol/cannabis usage)
medical diagnosis of psychosis or mania

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sham rTMS	Repetitive Transcranial Magnetic Stimulation	Participants will receive sham rTMS for 10-20 minutes.
Active rTMS	Repetitive Transcranial Magnetic Stimulation	Participants will receive active rTMS for 10-20 minutes.

Primary Outcome Measures

Name	Time	Method
dACC BOLD Signal (After Sham rTMS Session)	30 minutes post-rTMS	Encoding of trial-by-trial immediate expected value (IEV) in dorsal anterior cingulate cortex (dACC) region-of-interest that was targeted with rTMS. Expressed in units of BOLD % signal change. This primary outcome reflects IEV encoding in this region immediately after sham rTMS.
Immediate Expected Value (IEV; After Sham rTMS Visit)	30 minutes post-rTMS	A normative computational model (POMDP) is run to fit behavioral performance on a 3-armed bandit reinforcement learning task. Weighting of immediate expected value (IEV) on this model can be generated for each subject, indicating the degree to which they relied on immediate value to drive their decisions. This between-subjects IEV parameter reflects a standardized coefficient from a multinomial logistic regression (softmax) model. Higher values indicate a greater tendency to rely on IEV when making choices.
dACC BOLD Signal (After Active rTMS Session)	30 minutes post-rTMS	Encoding of trial-by-trial immediate expected value (IEV) in dorsal anterior cingulate cortex (dACC) region-of-interest that was targeted with rTMS. Expressed in units of BOLD % signal change. This primary outcome reflects IEV encoding in this region immediately after active rTMS.
Effort-Based Discounting (After Sham rTMS)	30 minutes post-rTMS	Participants make a series of effort - value tradeoff decisions on our Effort-Based Decision-Making task. Values reflect a standardized coefficient of the random subject-level intercept from a hierarchical logistic regression model fit with an interaction term, between effort and value, to index "effort-based discounting" of reward (i.e., the degree to which increases in effort level change the motivational salience of reward value on decisions). Higher values indicate a greater tendency to de-value rewards based on increasing effort level.
Immediate Expected Value (IEV; After Active rTMS Visit)	30 minutes post-rTMS	A normative computational model (POMDP) is run to fit behavioral performance on a 3-armed bandit reinforcement learning task. Weighting of immediate expected value (IEV) on this model can be generated for each subject, indicating the degree to which they relied on immediate value to drive their decisions. This between-subjects IEV parameter reflects a standardized coefficient from a multinomial logistic regression (softmax) model. Higher values indicate a greater tendency to rely on IEV when making choices.
Effort-Based Discounting (After Active rTMS)	30 minutes post-rTMS	Participants make a series of effort - value tradeoff decisions on our Effort-Based Decision-Making task. Values reflect a standardized coefficient of the random subject-level intercept from a hierarchical logistic regression model fit with an interaction term, between effort and value, to index "effort-based discounting" of reward (i.e., the degree to which increases in effort level change the motivational salience of reward value on decisions). Higher values indicate a greater tendency to de-value rewards based on increasing effort level.