Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
New Mexico
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Albuquerque, New Mexico, United States, 87131
- University of New Mexico Domenici Hall
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Sham Comparator: Sham rTMS
Participants will receive sham rTMS for 10-20 minutes.
|
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.
|
|
Active Comparator: Active rTMS
Participants will receive active rTMS for 10-20 minutes.
|
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
dACC BOLD Signal (After Active rTMS Session)
Time Frame: 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.
|
30 minutes post-rTMS
|
|
Immediate Expected Value (IEV; After Active rTMS Visit)
Time Frame: 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.
|
30 minutes post-rTMS
|
|
Effort-Based Discounting (After Active rTMS)
Time Frame: 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.
|
30 minutes post-rTMS
|
|
dACC BOLD Signal (After Sham rTMS Session)
Time Frame: 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.
|
30 minutes post-rTMS
|
|
Immediate Expected Value (IEV; After Sham rTMS Visit)
Time Frame: 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.
|
30 minutes post-rTMS
|
|
Effort-Based Discounting (After Sham rTMS)
Time Frame: 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.
|
30 minutes post-rTMS
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Jeremy Hogeveen, PhD, University of New Mexico
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 20-623
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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