Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers

Study Overview
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Brief Summary
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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
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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.

Official Title
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Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Sham versus active rTMS to dACC
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham rTMS<br>Participants will receive sham rTMS for 10-20 minutes. | Device: Repetitive Transcranial Magnetic Stimulation<br>* TMS pulses will be delivered through an air-cooled coil in either a figure-eight or double-cone shape, with the latter being particularly useful for targeting deeper structures such as dACC. The first phase of the TMS protocol will involve a standardized motor-thresholding procedure, wherein peripheral responses evoked by single TMS pulses are recorded via an electromyographic recording device. In this phase, the TMS coil's stimulation intensity is titrated to a level that is comfortable yet effective at reliably exciting neuronal populations orthogonal to the coil (50% motor-evoked potentials ≥50 microvolts; typical duration≈20-40 mins). Then repetitive TMS (rTMS) will be administered to a pre-determined cortical target based on the individual's pre-TMS fMRI scan using a Localite Neuronavigation system (duration≈10-20 mins). The rTMS protocol will involve the delivery of a train of TMS pulses over a cortical target prior to performance of behavioral tasks during a post-rTMS fMRI scan.<br>|
| Active Comparator: Active rTMS<br>Participants will receive active rTMS for 10-20 minutes. | Device: Repetitive Transcranial Magnetic Stimulation<br>* TMS pulses will be delivered through an air-cooled coil in either a figure-eight or double-cone shape, with the latter being particularly useful for targeting deeper structures such as dACC. The first phase of the TMS protocol will involve a standardized motor-thresholding procedure, wherein peripheral responses evoked by single TMS pulses are recorded via an electromyographic recording device. In this phase, the TMS coil's stimulation intensity is titrated to a level that is comfortable yet effective at reliably exciting neuronal populations orthogonal to the coil (50% motor-evoked potentials ≥50 microvolts; typical duration≈20-40 mins). Then repetitive TMS (rTMS) will be administered to a pre-determined cortical target based on the individual's pre-TMS fMRI scan using a Localite Neuronavigation system (duration≈10-20 mins). The rTMS protocol will involve the delivery of a train of TMS pulses over a cortical target prior to performance of behavioral tasks during a post-rTMS fMRI scan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in task-related brain network activity centered around the dACC as measured by fMRI following rTMS. | dACC encodes both the value and amount of effort required to perform a given decision. Both value and effort computations will be probed during fMRI before and after rTMS application to dACC. It is hypothesized that rTMS will modulate the BOLD response at dACC during both tasks. Further, it is hypothesized that brain regions known to be functionally connected to dACC (e.g. ventromedial prefrontal regions, subcortical circuits e.g. ventral striatum) may also demonstrate modulated neural recruitment post-rTMS. | 30 minutes post-rTMS | 
| Changes in reliance on immediate expected value to guide decisions during a 3-armed Bandit reinforcement learning task. | Given that dACC encodes information about the immediate expected value (IEV) of potential options, rTMS to dACC is expected to modulate reliance on IEV during 3-armed Bandit task performance. This will be assayed using a well-validated partially observable Markov decision process (POMDP) method for modelling normative performance on this task. | 30 minutes post-rTMS | 
| Shifts in the effort-reward tradeoff. | The degree to which participants discount potential rewards based on the amount of physical effort required to obtain them will be modulated by rTMS to dACC. | 30 minutes post-rTMS |