Neurostimulation Versus Therapy for Problems With Emotions

Neurostimulation Enhanced Cognitive Restructuring for Transdiagnostic Emotional Dysregulation: A Component Analysis

The primary goal of this clinical trial is to evaluate the unique neural and behavioral effects of a one-session training combining cognitive restructuring (CR), an emotion regulation skill, with excitatory repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (dlPFC). The secondary aim is to identify key changes in the emotion regulation neural network following the combined intervention versus each of the components alone. The third aim is to explore personalized biomarkers for response to emotion regulation training.

Participants will participate in brain imaging while undergoing an emotional regulation task. Participants will be randomly assigned to CR training or to psychoeducation about emotions. Participants will be reminded of recent stressors and will undergo real or sham high frequency rTMS, targeted using fMRI (functional MRI) results. Participants who learned CR will practice this skill during rTMS in a one-time session. Following this training, participants will undergo another fMRI and an exit interview to assess for immediate neural and behavioral changes. Measures of emotion regulation will be assessed at a one week and a one month follow up visit.

Study Overview

• Status: Not yet recruiting
• Conditions: Mood Disorders; Obsessive-Compulsive Disorder; Anxiety Disorders; OCD; Stress Disorder; Emotional Distress; Emotion Regulation; Eating Disorders; Emotion Dysregulation; Emotional Dysfunction; Emotional Impulsivity; Emotional Instability; Impulse Control Disorder; Emotional Maladjustment
• Intervention / Treatment: Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS); Behavioral: Cognitive Restructuring; Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS); Behavioral: Emotional Awareness training

Detailed Description

Emotional dysregulation constitutes a serious public health problem and novel approaches are needed to effectively address it transdiagnostically. Despite rapid advancements in affective and cognitive neuroscience, there have been few attempts to translate basic findings into novel interventions. In addition, the relevance of different nodes in the emotion regulation network to psychopathology and to successful reduction of emotional arousal is not yet fully understood. Noninvasive neurostimulation, such as repetitive transcranial magnetic stimulation (rTMS), is a powerful tool with which dysfunction can be alleviated temporarily, by modulating neural activation. Therefore, the objective of the current study is to examine immediate neural and behavioral changes following neuromodulation enhanced emotion regulation training for transdiagnostic adults who report difficulties calming down when upset. The central hypothesis is that neurostimulation enhances the acquisition of emotion regulation skills and leads to remediated neural function in the emotion regulation network. The investigators' long-term goal is to develop novel interventions that harness neuroscientific findings to advance behavioral treatments.

The primary aim of this project is to evaluate the unique neural and behavioral effects of a one-session training combining cognitive restructuring (CR), an emotion regulation skill, with excitatory rTMS over the dorsolateral prefrontal cortex (dlPFC). The secondary aim is to identify key changes in the emotion regulation neural network following the combined intervention versus each of the components alone. The third aim is to explore personalized biomarkers for response to emotion regulation training. To achieve these aims, 240 rTMS naïve, community adults who meet criteria for affective or stress DSM-5 disorders (excluding if co-occurring anorexia, alcohol and substance use, bipolar I, or psychotic disorders) and who self-report high emotional dysregulation and low use of CR will participate in brain imaging while undergoing an emotional regulation task. Both structural (anatomical and DTI) and functional MRI (fMRI) images will be collected. Participants will be randomly assigned to CR training (groups 1 & 2) or to psychoeducation about emotions (group 3; aimed to control for nonspecific factors). Participants will be reminded of recent autobiographical stressors and will undergo real (groups 1 & 3) or sham (group 2) high frequency rTMS, targeted using fMRI results. Participants who learned CR will practice this skill during rTMS in a one-time session, and physiological arousal will be monitored throughout the emotion induction and regulation practice. Following this training, 1 week later, participants will undergo another functional scan to assess for immediate neural and behavioral changes. Bio-behavioral measures of emotion regulation will be assessed at this one week visit. The 1-month follow up will occur 1 month after the one week follow-up visit. At this final follow-up visit, participants will also complete an exit interview that assesses acceptability and expectancies as well as the Brief-Treatment History Inventory (THI) to check for any changes. As part of the exit interview with the study doctor or another study team member, participants will be told if they were randomized to either active or sham stimulation and opportunities for questions will be allowed. One final set of bio-behavioral measures of emotion regulation will be completed as well. If successful, the investigators' line of research will provide key mechanistic information to develop a novel transdiagnostic treatment for affective and stress disorders.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andrada D Neacsiu, PhD; Phone Number: 9196846714; Email: [email protected]
• Study Contact Backup: Name: Lisalynn D Kelley, CCRP; Phone Number: 9196846701; Email: [email protected]

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
      • CONTACT: Andrada D Neacsiu, PhD; Phone Number: 919-684-6714; Email: [email protected]
      • PRINCIPAL_INVESTIGATOR: Andrada D Neacsiu, PhD
      • SUB_INVESTIGATOR: Tommy Fu, MD
      • SUB_INVESTIGATOR: Kevin LaBar, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 18 to 55
• elevated overall score on Difficulties with Emotion Regulation Scale (DERS total score >=90)
• has been in the same type of psychotherapy (including none) for the last 4 weeks/1mo (*except for current CBT) and is willing to stay on the same regimen throughout the study.
• low self-reported use of cognitive restructuring (ERQ restructuring subscale average score < 4.7)
• meets criteria for at least one mood (including Bipolar II w/o current hypomania), anxiety, stressor, OCD, Impulse Control, ADHD, or eating DSM-5 disorder (except exclusionary diagnoses such as severe anorexia). Note: Both current or partial remission of the disorder will be ok for inclusion into the study.
• verbal agreement to maintain dose of prescribed psychotropic medication (if any) constant throughout the study, provided they are stable on it for the past 4 weeks (except exclusion medication and except if there is a medical emergency requiring changes in medication).
• Naïve to rTMS

Exclusion Criteria:

• current hypomania (Note: Bipolar II w/o current hypomanic episode is ok for inclusion)
• meets diagnostic criteria for current or history of psychotic disorder, or psychotic features,
• meets diagnostic criteria for Bipolar I disorder
• meets diagnostic criteria on SCID5 for current alcohol or substance use disorder (moderate and high severity) or meets past history of severe alcohol use disorder
• unable to read, blind, or deaf, or unwilling to give consent
• non-English speaker,
• verbal IQ < 90 on the North American Adult Reading Test (NART).
• current uncontrolled anorexia or other condition requiring hospitalization
• high risk for suicide defined as either having attempted suicide in past 6 months or reporting current suicidal ideation that includes a method, plan, or intent to die
• current serious medical illness, including current severe migraine headaches
• started/changed psychotropic medications in the prior 4 weeks, or plans to change medication during the study
• history of seizure except those therapeutically induced by ECT (childhood febrile seizures are acceptable and these subjects may be included in the study), history of epilepsy in self or first degree relatives, stroke, brain surgery, head injury, cranial metal implants, known structural brain lesion, devices that may be affected by TMS (pacemaker, medication pump, cochlear implant, implanted brain stimulator)
• conditions associated with increased intracranial pressure, space occupying brain lesion, transient ischemic attack, cerebral aneurysm, dementia, Parkinson's or Huntington's disease, multiple sclerosis
• on medications that reduce seizure threshold (e.g., stimulants, Wellbutrin, Clozaril, Provigil)
• use of investigational drug or devices within 4 weeks of screening
• cochlear implants
• Pregnancy
• metal in body that would exclude them from the MRI scan; severe claustrophobia
• is a prisoner or in police custody at time of screening, or has pending court case jeopardizing the participation in the study
• has had TMS in their lifetime
• has had CBT in the past 4 weeks or plans to start therapy during the study
• weighs over 300 pounds (could not fit in MRI scanner)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cognitive Restructuring + Active Repetitive Transcranial Magnetic Stimulation (rTMS); Group 1 (G1)- 80 eligible participants will receive training in Cognitive Restructuring (CR). These participants will use CR while receiving active rTMS over their individual dlPFC target and will partake in short term and long term follow up testing.	Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS); excitatory rTMS over the right dlPFC; Other Names: Active rTMS; Behavioral: Cognitive Restructuring; Cognitive restructuring is a cognitive behavioral intervention throughwhich participants learn how to think differently about stressful events in order to feel less emotional arousal. Specifically, participants learn how to distance themselves from the situation, think of the memory as just a memory, or focus on alternative explanations or facets of the situation that are less emotionally upsetting.; Other Names: CR
SHAM_COMPARATOR: Cognitive Restructuring + Sham rTMS; Group 2 (G2) - 80 eligible participants will receive training in CR alone as an active intervention. These participants will use CR while receiving sham rTMS over their individual dlPFC target and will partake in short term and long term follow up testing.	Behavioral: Cognitive Restructuring; Cognitive restructuring is a cognitive behavioral intervention throughwhich participants learn how to think differently about stressful events in order to feel less emotional arousal. Specifically, participants learn how to distance themselves from the situation, think of the memory as just a memory, or focus on alternative explanations or facets of the situation that are less emotionally upsetting.; Other Names: CR; Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS); sham rTMS over the right dlPFC; Other Names: Sham rTMS
ACTIVE_COMPARATOR: Emotional Awareness Training + Active Repetitive Transcranial Magnetic Stimulation (rTMS); Group 3 (G3) - 80 eligible participants will receive emotional awareness training that includes the same amount of time and interaction with the experimenter. These participants will receive active rTMS over their individual dlPFC target and will partake in short term and long term follow up testing.	Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS); excitatory rTMS over the right dlPFC; Other Names: Active rTMS; Behavioral: Emotional Awareness training; Emotional awareness training will be conducted that includes the same amount of time and interaction with the experimenter; Other Names: Psychoeducation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
High frequency Heart Rate Variability (HF-HRV) during regulation blocks during the neurostimulation day,	Calculation of physiological data High frequency HRV (HF-HRV) during regulation blocks during the neurostimulation day, controlling for baseline HF-HRV	Within a month of the initial assessment
Time to return to Heart Rate (HR) baseline measured during regulation period	During the 3 runs of the negative mood induction task of neurostimulation, calculating the time it takes to return baseline HR will be calculated during each of the 3 regulation periods.	Within a month of the initial assessment
Percent signal change in vlPFC for the [restructure-flow_negative] contrast	the percent change in the signal in the ventral lateral Prefrontal Cortex (vlPFC) from pre-post neuroimaging	baseline Neuroimaging Scan vs post Neuroimaging scan (1 week follow-up post neurostimulation)
Difference in dorsolateral prefrontal cortex (dlPFC)-left_amygdala connectivity during [restructure - flow_negative]	Using Generalized Psychophysiological Interaction (gPPI) analysis the difference in dlPFC-left amygdala connectivity pre-post neuromaging	baseline Neuroimaging Scan, post Neuroimaging Scan (1 week follow-up post neurostimulation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Subjective units of distress (SUDS)	Subjective units of distress measured after baseline, stressor and every two minutes during regulation, including at the end of regulation during the neurostimulation day. This will be calculated with each of the 3 stressors.	Neurostimulation visit (which will occur within a month of the initial assessment) - pre/post stressor task
Difficulties in Emotion Regulation Scale (DERS) self-report change	Change in self-reported DERS will be investigated immediately after the followup neuroimaging session and one month after training. DERS inclusion for study is a score of 90 or higher. Min-Max score ranges from 36-180 (with higher scores signifying more difficulties with emotion regulation)	Baseline DERS, 1 week follow-up after neurostimulation, 1 month follow-up
Emotion Regulation Questionnaire (ERQ) self-report change	Change in Self-reported use of Cognitive Restructuring (CR) as measured with the Emotion Regulation Questionnaire (ERQ) one week and one month after training. We will also examine pre-post changes in ERQ-Reappraisal scale using a similar growth model approach, accounting for severity of psychopathology and baseline. The ERQ is a 10-item scale designed to measure respondents' tendency to regulate their emotions in two ways: (1) Cognitive Reappraisal (6 scale items) and (2) Expressive Suppression (4 scale items). Scores for the 2 scales are reported the average score of the total items in that scale. The lower the average score on the reappraisal scale the more problems with regulating emotions.	Baseline ERQ, 1 week follow-up after neurostimulation, 1 month follow-up
Percent signal change in dlPFC for the [restructure - flow_negative] contrast	the percent change in the signal in the dlPFC from pre-post neuroimaging	baseline Neuroimaging scan, post Neuroimaging Scan (1 week follow-up neurostimulation)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HF-HRV during regulation block at one week follow-up and one month after training	Change in HF-HRV mean during regulation block of stressor task at neurostimulation visit at one week follow-up and one month follow-up	Neurostimulation day (which will occur within a month of the initial assessment), one week follow-up, 1 month follow-up
Time to return to HR baseline measured during regulation period at one week after training, and one month after.	time it takes to return baseline HR will be calculated during the behavioral stressor computer task at one week follow-up and one month follow-up	Neurostimulation day (which will occur within a month of the initial assessment), one week follow-up, 1 month follow-up
Percent signal change in the left insula for the [restructure -flow_negative contrast	the percent change in the signal in the left insula in pre-post neuroimaging	baseline Neuroimaging scan, post Neuroimaging Scan (1 week follow-up neurostimulation)
Insula connectivity with the ventral medial prefrontal cortex (vmPFC) and dlPFC	change in insula connectivity with the vmPFC and dlPFC in pre-post neuroimaging	baseline Neuroimaging scan, post Neuroimaging Scan (1 week follow-up neurostimulation)
Percent signal change in Orbitofrontal cortex (OFC) for the [restructure -flow_negative contrast	the percent change in the signal in the OFC in pre-post neuroimaging	baseline Neuroimaging scan, post Neuroimaging Scan (1 week follow-up neurostimulation)
Percent signal change in the temporoparietal junction (TPJ) for the [restructure -flow_negative contrast	the percent change in the signal in the TPJ in pre-post neuroimaging	baseline Neuroimaging scan, post Neuroimaging Scan (1 week follow-up neurostimulation)

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: PRINCIPAL_INVESTIGATOR: Andrada D Neacsiu, PhD, Duke University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): April 15, 2023
• Primary Completion (ANTICIPATED): May 31, 2027
• Study Completion (ANTICIPATED): July 1, 2027

Study Registration Dates

• First Submitted: January 12, 2023
• First Submitted That Met QC Criteria: January 25, 2023
• First Posted (ACTUAL): February 3, 2023

Study Record Updates

• Last Update Posted (ACTUAL): February 3, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Neuromodulation; neuroimaging; TMS; Emotion regulation; Emotion Dysregulation; Neurostimulation; cognitive restructuring; Distress Intolerance; regulation skills
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Obsessive-Compulsive Disorder; Anxiety Disorders; Feeding and Eating Disorders; Mood Disorders; Impulsive Behavior; Disruptive, Impulse Control, and Conduct Disorders
• Other Study ID Numbers: Pro00111390; 1R01MH129302-01A1 (OTHER_GRANT: National Institute of Mental Health (NIMH))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data from this study will be submitted to the National Institute of Mental Health Data Archive (NDA) at the National Institutes of Health (NIH). NDA is a large database where deidentified study data from many NIH studies are stored and managed. NDA is run by the National Institute of Mental Health (NIMH) that allows researchers studying mental illness and brain science to collect and share deidentified information with each other. When the study team sends the data to the NIMH, they will do this through a password secure system where participants are identified by a specific GUID which is a unique # representing 1 specific person in the nation.

NIMH will also report to Congress and on its website about the different studies using NDA data. Participants can decide that they do not want to share their information to NDA.

• IPD Sharing Time Frame: Either on a rolling basis over the life of the grant/project per NDA's sharing calendar. Otherwise, within 6 months of completing participant data collection or very soon after publication of primary aims.

IPD Sharing Access Criteria

Users with NDA credentials must submit Data Access Requests for one NDA Permission Group at a time. Each DAR requires an NDA Data Use Certification (DUC) signed by the lead recipient and an authorized Signing Official from the recipient's research institution. All recipients on a Data Access Request/Data Use Certification must be affiliated with the lead recipient's research institution. If the Lead Recipient on a DUC changes institutions, they may identify another Recipient on the DUC as a replacement.

Data Access Requests for a given NDA Permission Group are reviewed by one NIH-staffed Data Access Committee (DAC).

Detailed information about NDA permission groups is maintained at https://nda.nih.gov/nda/about-us.html.

When approved to access, teams have access to query and download all data available using the NDA Query Tool and NDA download tools.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No