AnxietyNCT02573246
Neuromodulation Enhanced Cognitive Restructuring: A Proof of Concept Study
A study testing Cognitive Restructuring and rTMS in people with Anxiety and Depression, run by Duke University at 1 site in United States.
Trial summary
Psychological treatments are effective, but take a long time and can be burdensome. Therefore, avenues to optimize behavioral treatments are needed. Despite important advancements, neuroscience has had a limited effect on psychotherapy development. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Anxiety, Depression, Personality Disorders
- What is being tested?
- Cognitive Restructuring and rTMS
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 148 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2016to 17 Feb 2020
- 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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Has difficulty thinking differently in emotional situations
- Meets diagnostic criteria for a current DSM-5 depressive, anxiety, obsessive-compulsive, somatic, personality, eating, or trauma and stress-related disorders (including in partial remission): major depressive disorder, persistent depressive disorder, panic disorder, agoraphobia, social anxiety disorder, specific phobia, generalized anxiety disorder, obsessive-compulsive disorder, trichotillomania, excoriation disorder, hoarding disorder, body dysmorphic disorder, other specified, or unspecified obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, adjustment disorders, somatic symptom disorder, conversion disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, borderline personality disorder, narcissistic personality disorder, histrionic personality disorder, antisocial personality disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder, personality disorder unspecified, depressive disorder unspecified, anxiety disorder unspecified.
- Willing and able to participate in the intervention and all required study visits, stay on the same dose of psychiatric medication (if any) throughout the study, not participate in cognitive-behavioral therapy throughout their participation in the study.
- Has cellphone that can be used during the ambulatory assessment portion of the study.
Who cannot join
- Current or recent (within the past 6 months) substance dependence disorder(excluding nicotine and caffeine)
- Current serious medical illness, including migraine headaches. '
- Currently on psychotropic medications with dosage unchanged for less than four weeks prior to study entry OR plan to make changes in medication within 2 months after starting the study
- History of seizure except those therapeutically induced by electroconvulsive therapy (ECT), 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).
- Diagnosed with the following conditions: psychotic disorder, any DSM disorder secondary to a general medical condition, or substance-induced, Bipolar I disorder (current or lifetime), life-threatening anorexia or any other disorder requiring immediate hospitalization, high-risk for suicidal behavior, including current suicidal ideation with a method and plan or hospitalization for suicidal behavior within 1yr before the study.
- Currently engaged or planning to engage in other treatment during the course of the study (including behavior therapy, or other types of individual, family, or group psychotherapy/counseling).
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- Is diagnosed with a clinically defined neurological disorder including, but not limited to: any condition likely to be associated with increased intracranial pressure; space occupying brain lesion; history of stroke, transient ischemic attack within two years; cerebral aneurysm; dementia; Parkinson's disease; Huntington's disease; Multiple sclerosis.
- Has increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure (such as after large infarctions or trauma), or currently taking medication that lowers the seizure threshold (e.g Wellbutrin, Adderall, Clozaril).
- Has any of the following treatment histories: TMS treatment at any point in their lifetime; use of any investigational drug or device within 4 weeks of the screening.
- Subjects with cochlear implants
- Women who are pregnant or breast feeding
- Chronic absence of shelter or impending jail that would make consistent participation in the study difficult
- Cannot easily come to Duke several times for the study procedures
- Does not have a mobile phone or is unwilling to use mobile phone for ambulatory assessment
- Does not speak/understand English enough to benefit from the psychotherapeutic intervention
- Intellectual disability
- For imaging arm of the study, participants must also be able to tolerate an MRI, thus must be eligible based on the MRI safety screening form.
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Medical Center-Civitan Bldg
Durham, North Carolina, 27710
About this study
Psychological treatments are effective, but take a long time and can be burdensome. Therefore, avenues to optimize behavioral treatments are needed. Despite important advancements, neuroscience has had a limited effect on psychotherapy development. Therefore, one paradigm shift would be to develop neuroscience informed behavioral treatments.
The investigators identified from the literature a problem that affects several mental disorders (emotion dysregulation) and a neural circuit that underlies this important concern. They found that this circuit is dysfunctional in those with psychopathology but can be changed with treatment. The goal is in one session to train this brain network to operate more efficiently and to test the short and long term effects of this intervention. The investigators plan to engage this brain network using a traditional psychotherapy strategy (cognitive restructuring) and to enhance learning using repetitive transcranial magnetic stimulation (rTMS), a neuromodulation technique through which magnetic stimulation enhances the electrical activity in brain areas close to the scalp.
The study team proposed two studies to examine this novel approach, In one of the studies 83 participants were enrolled and 47 eligible participants were divided into 3 groups. All participants were trained in emotion regulation by first being asked to remember an event where they experienced a negative emotion and then being instructed either to think differently about the event, or to wait. Participants simultaneously underwent either active (left or right side of brain) or sham rTMS. In a second study 65 participants were enrolled, and 31 were assigned to either active left or sham rTMS guided using neuroimaging results. Across both studies, the investigators measured regulation in the lab and during a-week long naturalistic assessment. Participants in the second study returned for a follow up neuroimaging visit at the end of this week. Participants returned for a one moth follow up assessment and to rate feasibility, acceptability, and provide feedback. This proof of concept set of studies demonstrated feasibility and preliminary efficacy for this approach, which opens new frontiers for neuroscience informed treatment development.
Read the detailed description
Despite significant advancements in psychiatric research, the majority of adults with mental health disorders do not benefit from current evidence-based treatments, especially if they have difficulties managing negative emotions. One solution to this unmet clinical need is to take a neuroscience-informed approach to treatment development in order to radically change patient care. Despite an explosion of research on the neurobiological underpinnings of emotion, emotion regulation, and psychopathology, there have been few attempts to use such findings to advance behavioral treatments. Neuroscience-informed treatment development could optimize psychotherapy gains and reduce burden on therapists and clients. Therefore, we propose to build a fundamentally novel approach to treating difficulties managing negative emotions (or emotion dysregulation) that builds on the strength of current therapies, but that also accelerates and enhances gains.
Adults with several different psychiatric disorders have difficulty managing negative emotions, a problem that has been traced back to impairments in the fronto-limbic brain circuitry. In healthy samples this neural network is activated in response to tasks requiring regulation of emotional arousal and disrupting this circuit leads to psychiatric symptoms. In psychiatric samples, this circuit is underperforming as evidenced by (1) hyperactivity in the amygdala (the brain structure that signals emotional arousal), (2) slow return to baseline after amygdala activation, (3) hypoactivity in frontal regions (responsible for regulation), and (3) insufficient cross-talk between these regions when patients experience negative emotional arousal. Evidence-based cognitive-behavioral psychotherapy and neurostimulation are two different interventions that can remediate function in impaired brain circuits. Both interventions have evidence of success in changing the fronto-limbic network but also need improvement. Therefore, the investigators plan to combine magnetic brain stimulation and cognitive restructuring (an evidence-based behavioral treatment for difficulties managing emotions) in a one-session intervention.
The investigators recruited participants for two studies. In one study, 83 transdiagnostic adults (i.e., who meet criteria for any DSM 5 disorder) who engage in cognitive restructuring with low frequency as measured by an established questionnaire were enrolled and 47 were randomly assigned to either active (left or right) or sham repetitive transcranial magnetic stimulation (rTMS). In a second study, 65 transdiagnostic adult participants with high emotional dysregulation were enrolled, and 31 were randomly assigned to active left or sham rTMS guided using neuroimaging analyses. All included participants practiced reducing negative emotions (induced with standardized autobiographical stressors) using cognitive restructuring while undergoing high frequency or sham rTMS to the right or left dorsolateral prefrontal cortex. Standardized, established procedures were used to teach cognitive restructuring, to generate personalized stressors, to induce negative emotional arousal, and to implement the one session of rTMS. Immediate effects were evaluated using measures of emotional arousal and regulation during the intervention and for one week afterwards using 8 daily automated mobile phone calls. Long-term effects in emotion regulation, functional and psychiatric impairment were examined at 1-week and 1-month follow-up interviews.
Participants in the imaging portion of the study underwent an MRI before the intervention day. This imaging session included training in the emotion regulation task to be performed in the scanner, including practice in reappraisal and distraction; a memory cue assessment to rehearse cuing of memories; a mock scan if necessary, MRI safety screening confirmation, structural (Diffusion tensor imaging and anatomical) and functional MRI (fMRI) images will be collected. During the fMRI scan, participants completed the emotional regulation task where they were asked to recall an emotional memory from the Emotional Memory selection tasks and then be cued to reappraise, distract or allow negative emotions. At the end of the trials, participants rated their current emotional state. At the one week follow up, in addition to the tasks described above, they returned to complete a second MRI after 1 week where they were reoriented to the emotion regulation task, had structural and functional MRI images collected with the emotion regulation task occurring during the fMRI portion.
The investigators hypothesized that rTMS would enhance cognitive restructuring by yielding a quicker reduction in emotional arousal when compared to sham TMS, and would lead to more frequent use of the cognitive restructuring in the natural environment. This set of studies is intended to launch a series of investigations using innovative paradigms to optimize treatments for psychiatric disorders and it could lead to the next generation of neuroscience-informed behavioral interventions.
- Conditions
- Anxiety, Depression, Personality Disorders, Trauma and Stress-related Disorders, Somatic Disorders, Obsessive Compulsive Disorders
- Being tested
- Cognitive Restructuring, rTMS, Sham rTMS
- Keywords
- neurostimulation, cognitive restructuring, TMS, emotion regulation, MRI, Emotional Memory Task, Reappraisal, Distraction
- Medical subject headings
- Anxiety Disorders, Depression, Personality Disorders, Trauma and Stressor Related Disorders, Compulsive Personality Disorder, Feeding and Eating Disorders, Emotional Regulation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cognitive RestructuringBehavioural
Cognitive restructuring is a cognitive behavioral intervention through which 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.
rTMSDevice
rTMS is a neurostimulation intervention where the participant receives 15 minutes of high frequency (10 HZ) transcranial magnetic stimulation pulses
Sham rTMSDevice
Sham rTMS is a placebo intervention aimed to mimic the effects of repetitive transcranial magnetic stimulation with no known direct benefit for the participant.
| Study group | Role | What they receive |
|---|---|---|
| Cognitive Restructuring+rTMS (left) | Experimental | Participants in this arm will be administered the neuromodulation enhanced cognitive restructuring intervention over the left side of the brain and will partake in short term and long term follow up testing. Receives: Behavioral: Cognitive Restructuring; Device: rTMS |
| Cognitive Restructuring + sham rTMS | Sham comparator | Participants in this arm will receive cognitive restructuring alone as an active intervention and will partake in short term and long term follow up testing. Receives: Behavioral: Cognitive Restructuring; Device: Sham rTMS |
| Cognitive Restructuring+rTMS (right) | Experimental | Participants in this arm will be administered the neuromodulation enhanced cognitive restructuring intervention over the right side of the brain and will partake in short term and long term follow up testing. Receives: Behavioral: Cognitive Restructuring; Device: rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Return to Heart Rate Baseline During the Regulation Period During Training
The estimated marginal mean of the difference in length of time that it takes participants to reduce emotional arousal after three emotional inductions when they use Cognitive Restructuring (CR) with or without the enhancing effects of transcranial magnetic stimulation (TMS). Psychophysiological measurements were collected continuously using the BIOPAC MP-150. For each baseline, heart rate (HR) was averaged from the last 240s. Time to return to one's HR baseline was defined as the amount of time (e.g., number of seconds) it took from the beginning of regulation for the continuously monitored HR to reach a value that was lower than the average pre-stimulus baseline HR. Lower numbers indicate quicker regulation (desirable outcome). A baseline value for regulation duration was computed as the time it took during habituation for the person to return to HR baseline. Number of seconds was transformed with a logarithmic function for analyses to achieve normality.
Measured: 1 week after intake
Time to Return to Heart Rate Baseline During the Regulation Period at Follow up
The investigators will examine difference in length of time that it takes participants to reduce emotional arousal (as measured with physiological indicators) after an emotional induction when they use CR. This measure, was collected at the 1 month follow up assessment. Only one stressor-regulation period was presented at follow up. The number of seconds it took for participants to return to the pre-stimulus baseline during the regulation period was transformed with a log function for normality. Lower numbers indicate quicker regulation, a desirable outcome.
Measured: 1 month
Physiological Emotion Regulation
The investigators will record heart rate continuously throughout the intervention and then extract high frequency heart rate variability (an index of emotion regulation) from the regulation periods. Continuously recorded HR was divided into 120 s bins, and HF-HRV was extracted from cleaned raw ECG from each bin. Baseline HF-HRV was measured at the beginning of the experiment and right before each autobiographical stressor presentation. The treatment condition (active left, active right, or sham), baselines, the experimental condition (regulation 1, 2, and 3), and the time within each experimental condition (0 to 4 for each 120 s segment within that period) were used to predict HF-HRV. Higher HF-HRV indicates enhanced regulation, a desirable outcome. To make interpretation easier, the raw HF-HRV score was multiplied with 1000000. To achieve normality, this multiplied score was transformed with a logarithmic function.
Measured: 1 week after study start
Changes in Activation in the Neural Emotion Regulation Network
For groups 4 \&5, the investigators collected functional imaging data while participants engaged in an emotion regulation task. We examined the BOLD response change in the contrast between down-regulating negative emotions and feeling negative emotions a week after intervention controlling for the maximum change in this contrast at intake. Specifically we examined changes in activation in the dorsolateral prefrontal cortex (dlPFC), ventrolateral PFC (vlPFC), ventromedial PFC (vmPFC), the amygdala and insula. Data were first preprocessed with fMRIprep and MRIQC. At the first level, functional data were analyzed as individual runs, using a general linear model (GLM) in which trial events were convolved with a double-gamma hemodynamic response function. The [Restructure- Feel_negative] contrast was then used to generate Level 2 analysis, in which BOLD activity for each of the four runs were combined using a fixed-effect model. Higher numbers indicate more activation (desired outcome).
Measured: 1 week
Secondary outcomes (5)
Acceptability, as Measured by Qualitative Exit Interview
The investigators will examine how acceptable participants find the intervention. A previously developed in-house interview (A. D. Neacsiu, Luber, et al., 2018) was administered at the 1-month follow up, and it included Likert-type questions about feasibility, acceptability, and overall satisfaction rated on a scale from 0 (not at all) to 9 (extremely; secondary outcomes).
Measured: 1 month
Feasibility, as Measured by Qualitative Exit Interview
The investigators will examine how feasible the proposed intervention is. A previously developed in-house interview (A. D. Neacsiu, Luber, et al., 2018) was administered at the 1-month follow up, and it included Likert-type questions about feasibility, acceptability, and overall satisfaction rated on a scale from 0 (not at all) to 9 (extremely; secondary outcomes).
Measured: 1 month
Change in General Psychological Distress, as Measured by the Outcome Questionaire -45
The investigators will examine change in general psychological distress after the intervention. The Outcome Questionnaire-45 (OQ-45) is a 45-item self-report measure used to track severity of psychopathology throughout treatment. It consists of subscales that identify three types of problems that lead to general stress: psychological symptoms, interpersonal conflicts, and problems with social roles. Items are rated on a Likert scale ranging from 0 (never) to 4 (almost always). We computed the total score (ranging from 0 to 180) from data collected at intake, at 1 week after the intervention, and at 1 month after the intervention. Higher score indicate higher psychopathological distress than lower scores. The estimated marginal means from the growth model comparing differences between conditions are presented in the table below.
Measured: 1 week and 1 month
Change in Daily General Emotional Distress
The investigators will examine change in emotional distress after the intervention as measured by daily mobile phone ratings 8 times/day for 7 days of subjective units of distress; SUDS). The 8 ratings/day will then be averaged into a mean/day. This daily SUDS mean (range 0-9) will be entered in analyses. Higher SUDS indicates more distress.
Measured: 1 week
Change in Emotion Dysregulation and Functional Impairment
The investigators will examine changes in the reappraisal scale of the Emotion Regulation Questionnaire (ERQ; range 1-7), in the total score from the Difficulties with Emotion Regulation Scale (DERS; range 36-180), and in the total score from the work and social adjustment functional impairment scale (WSAS; range 0-40) from before to after the one time intervention. Higher ERQ-Reappraisal scores indicate more use of cognitive restructuring (a favorable outcome). Lower DERS total score and lower WSAS average score indicate lower overall emotional dysregulation and lower impairment in functioning, which are desirable outcomes. Outcomes were analyzed using HLM models and the data presented below represents the estimate marginal means for each condition for the growth in each outcome controlling for baseline.
Measured: 1 week and 1 month after the intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Oct 2015 (estimated)
- Study startMar 2016
- Primary completion17 Feb 2020
- Study completion17 Feb 2020
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.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for AnxietyStudies of the same condition, open and under way.
- More trials run by Duke UniversityThe sponsor's other registered studies.
- 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants were assigned to one of 2 studies (main and supplement) that ran concurrently. 83 participants were enrolled in the main study, and 65 in the supplement.
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 148 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke University
- Sponsor type
- University, hospital or other
- Collaborators
- Brain & Behavior Research Foundation
- Responsible party
- Sponsor
- Investigators
- Andrada D Neacsiu, PhD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02573246
- Sponsor's protocol ID
- Pro00066383
- Status last verified
- May 2021
- First submitted
- 8 Oct 2015
- Last updated
- 16 Jul 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Gross, J. J. Handbook of Emotion Regulation, Second Edition. (The Guilford Press, 2013).
Neacsiu AD, Eberle JW, Kramer R, Wiesmann T, Linehan MM. Dialectical behavior therapy skills for transdiagnostic emotion dysregulation: a pilot randomized controlled trial. Behav Res Ther. 2014 Aug;59:40-51. doi: 10.1016/j.brat.2014.05.005. Epub 2014 May 27.
PubMed 24974307Kazdin AE, Blase SL. Rebooting Psychotherapy Research and Practice to Reduce the Burden of Mental Illness. Perspect Psychol Sci. 2011 Jan;6(1):21-37. doi: 10.1177/1745691610393527. Epub 2011 Feb 3.
PubMed 26162113Luber B, Steffener J, Tucker A, Habeck C, Peterchev AV, Deng ZD, Basner RC, Stern Y, Lisanby SH. Extended remediation of sleep deprived-induced working memory deficits using fMRI-guided transcranial magnetic stimulation. Sleep. 2013 Jun 1;36(6):857-71. doi: 10.5665/sleep.2712.
PubMed 23729929Feeser M, Prehn K, Kazzer P, Mungee A, Bajbouj M. Transcranial direct current stimulation enhances cognitive control during emotion regulation. Brain Stimul. 2014 Jan-Feb;7(1):105-12. doi: 10.1016/j.brs.2013.08.006. Epub 2013 Sep 21.
PubMed 24095257Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry. 1987 Nov;44(11):970-5. doi: 10.1001/archpsyc.1987.01800230050009.
PubMed 3675137
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neuromodulation Enhanced Cognitive Restructuring: A Proof of Concept Study
- ClinicalTrials.gov ID
- NCT02573246
- Acronym / sponsor ID
- Pro00066383
- Conditions
- Anxiety, Depression, Personality Disorders, Trauma and Stress-related Disorders, Somatic Disorders, Obsessive Compulsive Disorders
- Keywords
- neurostimulation, cognitive restructuring, TMS, emotion regulation, MRI, Emotional Memory Task, Reappraisal, Distraction
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 148 participants (actual)
- Lead sponsor
- Duke UniversityUniversity, hospital or other
- Collaborators
- Brain & Behavior Research Foundation
- Study start
- Mar 2016 (actual)
- Primary completion
- 17 Feb 2020 (actual)
- Study completion
- 17 Feb 2020 (actual)
- First posted
- 9 Oct 2015 (estimated)
- Results
- Posted 10 May 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Psychological treatments are effective, but take a long time and can be burdensome. Therefore, avenues to optimize behavioral treatments are needed. Despite important advancements, neuroscience has had a limited effect on psychotherapy development. Therefore, one paradigm shift would be to develop neuroscience informed behavioral treatments.
The investigators identified from the literature a problem that affects several mental disorders (emotion dysregulation) and a neural circuit that underlies this important concern. They found that this circuit is dysfunctional in those with psychopathology but can be changed with treatment. The goal is in one session to train this brain network to operate more efficiently and to test the short and long term effects of this intervention. The investigators plan to engage this brain network using a traditional psychotherapy strategy (cognitive restructuring) and to enhance learning using repetitive transcranial magnetic stimulation (rTMS), a neuromodulation technique through which magnetic stimulation enhances the electrical activity in brain areas close to the scalp.
The study team proposed two studies to examine this novel approach, In one of the studies 83 participants were enrolled and 47 eligible participants were divided into 3 groups. All participants were trained in emotion regulation by first being asked to remember an event where they experienced a negative emotion and then being instructed either to think differently about the event, or to wait. Participants simultaneously underwent either active (left or right side of brain) or sham rTMS. In a second study 65 participants were enrolled, and 31 were assigned to either active left or sham rTMS guided using neuroimaging results. Across both studies, the investigators measured regulation in the lab and during a-week long naturalistic assessment. Participants in the second study returned for a follow up neuroimaging visit at the end of this week. Participants returned for a one moth follow up assessment and to rate feasibility, acceptability, and provide feedback. This proof of concept set of studies demonstrated feasibility and preliminary efficacy for this approach, which opens new frontiers for neuroscience informed treatment development.
Detailed description
Despite significant advancements in psychiatric research, the majority of adults with mental health disorders do not benefit from current evidence-based treatments, especially if they have difficulties managing negative emotions. One solution to this unmet clinical need is to take a neuroscience-informed approach to treatment development in order to radically change patient care. Despite an explosion of research on the neurobiological underpinnings of emotion, emotion regulation, and psychopathology, there have been few attempts to use such findings to advance behavioral treatments. Neuroscience-informed treatment development could optimize psychotherapy gains and reduce burden on therapists and clients. Therefore, we propose to build a fundamentally novel approach to treating difficulties managing negative emotions (or emotion dysregulation) that builds on the strength of current therapies, but that also accelerates and enhances gains.
Adults with several different psychiatric disorders have difficulty managing negative emotions, a problem that has been traced back to impairments in the fronto-limbic brain circuitry. In healthy samples this neural network is activated in response to tasks requiring regulation of emotional arousal and disrupting this circuit leads to psychiatric symptoms. In psychiatric samples, this circuit is underperforming as evidenced by (1) hyperactivity in the amygdala (the brain structure that signals emotional arousal), (2) slow return to baseline after amygdala activation, (3) hypoactivity in frontal regions (responsible for regulation), and (3) insufficient cross-talk between these regions when patients experience negative emotional arousal. Evidence-based cognitive-behavioral psychotherapy and neurostimulation are two different interventions that can remediate function in impaired brain circuits. Both interventions have evidence of success in changing the fronto-limbic network but also need improvement. Therefore, the investigators plan to combine magnetic brain stimulation and cognitive restructuring (an evidence-based behavioral treatment for difficulties managing emotions) in a one-session intervention.
The investigators recruited participants for two studies. In one study, 83 transdiagnostic adults (i.e., who meet criteria for any DSM 5 disorder) who engage in cognitive restructuring with low frequency as measured by an established questionnaire were enrolled and 47 were randomly assigned to either active (left or right) or sham repetitive transcranial magnetic stimulation (rTMS). In a second study, 65 transdiagnostic adult participants with high emotional dysregulation were enrolled, and 31 were randomly assigned to active left or sham rTMS guided using neuroimaging analyses. All included participants practiced reducing negative emotions (induced with standardized autobiographical stressors) using cognitive restructuring while undergoing high frequency or sham rTMS to the right or left dorsolateral prefrontal cortex. Standardized, established procedures were used to teach cognitive restructuring, to generate personalized stressors, to induce negative emotional arousal, and to implement the one session of rTMS. Immediate effects were evaluated using measures of emotional arousal and regulation during the intervention and for one week afterwards using 8 daily automated mobile phone calls. Long-term effects in emotion regulation, functional and psychiatric impairment were examined at 1-week and 1-month follow-up interviews.
Participants in the imaging portion of the study underwent an MRI before the intervention day. This imaging session included training in the emotion regulation task to be performed in the scanner, including practice in reappraisal and distraction; a memory cue assessment to rehearse cuing of memories; a mock scan if necessary, MRI safety screening confirmation, structural (Diffusion tensor imaging and anatomical) and functional MRI (fMRI) images will be collected. During the fMRI scan, participants completed the emotional regulation task where they were asked to recall an emotional memory from the Emotional Memory selection tasks and then be cued to reappraise, distract or allow negative emotions. At the end of the trials, participants rated their current emotional state. At the one week follow up, in addition to the tasks described above, they returned to complete a second MRI after 1 week where they were reoriented to the emotion regulation task, had structural and functional MRI images collected with the emotion regulation task occurring during the fMRI portion.
The investigators hypothesized that rTMS would enhance cognitive restructuring by yielding a quicker reduction in emotional arousal when compared to sham TMS, and would lead to more frequent use of the cognitive restructuring in the natural environment. This set of studies is intended to launch a series of investigations using innovative paradigms to optimize treatments for psychiatric disorders and it could lead to the next generation of neuroscience-informed behavioral interventions.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 3
- Model description
- Participants were assigned to one of 2 studies (main and supplement) that ran concurrently. 83 participants were enrolled in the main study, and 65 in the supplement.
| Arm | Type | Receives |
|---|---|---|
| Cognitive Restructuring+rTMS (left) | Experimental | Behavioral: Cognitive Restructuring, Device: rTMSParticipants in this arm will be administered the neuromodulation enhanced cognitive restructuring intervention over the left side of the brain and will partake in short term and long term follow up testing. |
| Cognitive Restructuring + sham rTMS | Sham comparator | Behavioral: Cognitive Restructuring, Device: Sham rTMSParticipants in this arm will receive cognitive restructuring alone as an active intervention and will partake in short term and long term follow up testing. |
| Cognitive Restructuring+rTMS (right) | Experimental | Behavioral: Cognitive Restructuring, Device: rTMSParticipants in this arm will be administered the neuromodulation enhanced cognitive restructuring intervention over the right side of the brain and will partake in short term and long term follow up testing. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Has difficulty thinking differently in emotional situations
- Meets diagnostic criteria for a current DSM-5 depressive, anxiety, obsessive-compulsive, somatic, personality, eating, or trauma and stress-related disorders (including in partial remission): major depressive disorder, persistent depressive disorder, panic disorder, agoraphobia, social anxiety disorder, specific phobia, generalized anxiety disorder, obsessive-compulsive disorder, trichotillomania, excoriation disorder, hoarding disorder, body dysmorphic disorder, other specified, or unspecified obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, adjustment disorders, somatic symptom disorder, conversion disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, borderline personality disorder, narcissistic personality disorder, histrionic personality disorder, antisocial personality disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder, personality disorder unspecified, depressive disorder unspecified, anxiety disorder unspecified.
- Willing and able to participate in the intervention and all required study visits, stay on the same dose of psychiatric medication (if any) throughout the study, not participate in cognitive-behavioral therapy throughout their participation in the study.
- Has cellphone that can be used during the ambulatory assessment portion of the study.
Key exclusion criteria (17 listed)
- Current or recent (within the past 6 months) substance dependence disorder(excluding nicotine and caffeine)
- Current serious medical illness, including migraine headaches. '
- Currently on psychotropic medications with dosage unchanged for less than four weeks prior to study entry OR plan to make changes in medication within 2 months after starting the study
- History of seizure except those therapeutically induced by electroconvulsive therapy (ECT), 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).
- Diagnosed with the following conditions: psychotic disorder, any DSM disorder secondary to a general medical condition, or substance-induced, Bipolar I disorder (current or lifetime), life-threatening anorexia or any other disorder requiring immediate hospitalization, high-risk for suicidal behavior, including current suicidal ideation with a method and plan or hospitalization for suicidal behavior within 1yr before the study.
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 |
|---|---|---|
| Cognitive RestructuringCognitive restructuring is a cognitive behavioral intervention through which 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. | Behavioural | Cognitive Restructuring + sham rTMS, Cognitive Restructuring+rTMS (left), Cognitive Restructuring+rTMS (right) |
| rTMSrTMS is a neurostimulation intervention where the participant receives 15 minutes of high frequency (10 HZ) transcranial magnetic stimulation pulses | Device | Cognitive Restructuring+rTMS (left), Cognitive Restructuring+rTMS (right) |
| Sham rTMSSham rTMS is a placebo intervention aimed to mimic the effects of repetitive transcranial magnetic stimulation with no known direct benefit for the participant. | Device | Cognitive Restructuring + sham rTMS |
Primary outcome
Time to Return to Heart Rate Baseline During the Regulation Period During Training
Time frame: 1 week after intake
The estimated marginal mean of the difference in length of time that it takes participants to reduce emotional arousal after three emotional inductions when they use Cognitive Restructuring (CR) with or without the enhancing effects of transcranial magnetic stimulation (TMS). Psychophysiological measurements were collected continuously using the BIOPAC MP-150. For each baseline, heart rate (HR) was averaged from the last 240s. Time to return to one's HR baseline was defined as the amount of time (e.g., number of seconds) it took from the beginning of regulation for the continuously monitored HR to reach a value that was lower than the average pre-stimulus baseline HR. Lower numbers indicate quicker regulation (desirable outcome). A baseline value for regulation duration was computed as the time it took during habituation for the person to return to HR baseline. Number of seconds was transformed with a logarithmic function for analyses to achieve normality.
Time to Return to Heart Rate Baseline During the Regulation Period at Follow up
Time frame: 1 month
The investigators will examine difference in length of time that it takes participants to reduce emotional arousal (as measured with physiological indicators) after an emotional induction when they use CR. This measure, was collected at the 1 month follow up assessment. Only one stressor-regulation period was presented at follow up. The number of seconds it took for participants to return to the pre-stimulus baseline during the regulation period was transformed with a log function for normality. Lower numbers indicate quicker regulation, a desirable outcome.
Physiological Emotion Regulation
Time frame: 1 week after study start
The investigators will record heart rate continuously throughout the intervention and then extract high frequency heart rate variability (an index of emotion regulation) from the regulation periods. Continuously recorded HR was divided into 120 s bins, and HF-HRV was extracted from cleaned raw ECG from each bin. Baseline HF-HRV was measured at the beginning of the experiment and right before each autobiographical stressor presentation. The treatment condition (active left, active right, or sham), baselines, the experimental condition (regulation 1, 2, and 3), and the time within each experimental condition (0 to 4 for each 120 s segment within that period) were used to predict HF-HRV. Higher HF-HRV indicates enhanced regulation, a desirable outcome. To make interpretation easier, the raw HF-HRV score was multiplied with 1000000. To achieve normality, this multiplied score was transformed with a logarithmic function.
Changes in Activation in the Neural Emotion Regulation Network
Time frame: 1 week
For groups 4 \&5, the investigators collected functional imaging data while participants engaged in an emotion regulation task. We examined the BOLD response change in the contrast between down-regulating negative emotions and feeling negative emotions a week after intervention controlling for the maximum change in this contrast at intake. Specifically we examined changes in activation in the dorsolateral prefrontal cortex (dlPFC), ventrolateral PFC (vlPFC), ventromedial PFC (vmPFC), the amygdala and insula. Data were first preprocessed with fMRIprep and MRIQC. At the first level, functional data were analyzed as individual runs, using a general linear model (GLM) in which trial events were convolved with a double-gamma hemodynamic response function. The [Restructure- Feel_negative] contrast was then used to generate Level 2 analysis, in which BOLD activity for each of the four runs were combined using a fixed-effect model. Higher numbers indicate more activation (desired outcome).
5 secondary outcomes
Acceptability, as Measured by Qualitative Exit Interview
Time frame: 1 month
Feasibility, as Measured by Qualitative Exit Interview
Time frame: 1 month
Change in General Psychological Distress, as Measured by the Outcome Questionaire -45
Time frame: 1 week and 1 month
Change in Daily General Emotional Distress
Time frame: 1 week
Change in Emotion Dysregulation and Functional Impairment
Time frame: 1 week and 1 month after the intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jul 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- BackgroundGross, J. J. Handbook of Emotion Regulation, Second Edition. (The Guilford Press, 2013).
- Background: PubMed 24974307Neacsiu AD, Eberle JW, Kramer R, Wiesmann T, Linehan MM. Dialectical behavior therapy skills for transdiagnostic emotion dysregulation: a pilot randomized controlled trial. Behav Res Ther. 2014 Aug;59:40-51. doi: 10.1016/j.brat.2014.05.005. Epub 2014 May 27.
- Background: PubMed 26162113Kazdin AE, Blase SL. Rebooting Psychotherapy Research and Practice to Reduce the Burden of Mental Illness. Perspect Psychol Sci. 2011 Jan;6(1):21-37. doi: 10.1177/1745691610393527. Epub 2011 Feb 3.
- Background: PubMed 23729929Luber B, Steffener J, Tucker A, Habeck C, Peterchev AV, Deng ZD, Basner RC, Stern Y, Lisanby SH. Extended remediation of sleep deprived-induced working memory deficits using fMRI-guided transcranial magnetic stimulation. Sleep. 2013 Jun 1;36(6):857-71. doi: 10.5665/sleep.2712.
- Background: PubMed 24095257Feeser M, Prehn K, Kazzer P, Mungee A, Bajbouj M. Transcranial direct current stimulation enhances cognitive control during emotion regulation. Brain Stimul. 2014 Jan-Feb;7(1):105-12. doi: 10.1016/j.brs.2013.08.006. Epub 2013 Sep 21.
- Background: PubMed 3675137Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry. 1987 Nov;44(11):970-5. doi: 10.1001/archpsyc.1987.01800230050009.
- Individual participant dataSharing planned: No
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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.
Andrada D Neacsiu, PhD principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cognitive Restructuring and rTMS in people with Anxiety and Depression, run by Duke University 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 4 inclusion and 17 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 2021. 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 10 May 2021). 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?
Time to Return to Heart Rate Baseline During the Regulation Period During Training (time frame: 1 week after intake). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02573246, which also lists 6 linked publications.
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 2021.