Traumatic Brain InjuryNCT04972786
Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers
A study testing Repetitive Transcranial Magnetic Stimulation in people with Traumatic Brain Injury, run by University of New Mexico at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Traumatic Brain Injury
- What is being tested?
- Repetitive Transcranial Magnetic Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Aug 2021to 21 Jun 2023
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 12 or more years of education
- ability to provide informed consent independently
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of New Mexico Domenici Hall
Albuquerque, New Mexico, 87131
About this study
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.
Read the 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.
- Conditions
- Traumatic Brain Injury
- Being tested
- Repetitive Transcranial Magnetic Stimulation
- Medical subject headings
- Brain Injuries, Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repetitive Transcranial Magnetic StimulationDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Sham rTMS | Sham comparator | Participants will receive sham rTMS for 10-20 minutes. Receives: Device: Repetitive Transcranial Magnetic Stimulation |
| Active rTMS | Active comparator | Participants will receive active rTMS for 10-20 minutes. Receives: Device: Repetitive Transcranial Magnetic Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
dACC BOLD Signal (After Active rTMS Session)
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.
Measured: 30 minutes post-rTMS
Immediate Expected Value (IEV; After Active rTMS Visit)
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.
Measured: 30 minutes post-rTMS
Effort-Based Discounting (After Active 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.
Measured: 30 minutes post-rTMS
dACC BOLD Signal (After Sham rTMS Session)
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.
Measured: 30 minutes post-rTMS
Immediate Expected Value (IEV; After Sham rTMS Visit)
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.
Measured: 30 minutes post-rTMS
Effort-Based Discounting (After Sham 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.
Measured: 30 minutes post-rTMS
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2021
- Study start1 Aug 2021
- Primary completion21 Jun 2023
- Study completion21 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Sham versus active rTMS to dACC
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of New Mexico
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jeremy Hogeveen, University of New Mexico
- Investigators
- Jeremy Hogeveen, PhD, Principal investigator, University of New Mexico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04972786
- Sponsor's protocol ID
- 20-623
- Status last verified
- Jun 2024
- First submitted
- 13 Jul 2021
- Last updated
- 16 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Noninvasive Modulation of Motivational Brain Regions in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT04972786
- Acronym / sponsor ID
- 20-623
- Conditions
- Traumatic Brain Injury
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- University of New MexicoUniversity, hospital or other
- Study start
- 1 Aug 2021 (actual)
- Primary completion
- 21 Jun 2023 (actual)
- Study completion
- 21 Jun 2023 (actual)
- First posted
- 22 Jul 2021 (actual)
- Results
- Posted 16 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Sham versus active rTMS to dACC
| Arm | Type | Receives |
|---|---|---|
| Sham rTMS | Sham comparator | Device: Repetitive Transcranial Magnetic StimulationParticipants will receive sham rTMS for 10-20 minutes. |
| Active rTMS | Active comparator | Device: Repetitive Transcranial Magnetic StimulationParticipants will receive active rTMS for 10-20 minutes. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- 12 or more years of education
- ability to provide informed consent independently
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repetitive Transcranial Magnetic StimulationTMS 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. | Device | Active rTMS, Sham rTMS |
Primary outcome
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.
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.
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.
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.
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.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeremy Hogeveen, PhD principal investigator
University of New Mexico
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Repetitive Transcranial Magnetic Stimulation in people with Traumatic Brain Injury, run by University of New Mexico at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
dACC BOLD Signal (After Active rTMS Session) (time frame: 30 minutes post-rTMS). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2024.