Clinical trial NCT02573246: Neuromodulation Enhanced Cognitive Restructuring: A Proof of Concept Study
Official title: Neuromodulation Enhanced Cognitive Restructuring: A Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Anxiety
Depression
Personality Disorders
Trauma and Stress-related Disorders
Somatic Disorders
Obsessive Compulsive Disorders
Eating Disorders
Difficulties With Cognitive Emotion Regulation
Keywords: neurostimulation
cognitive restructuring
TMS
emotion regulation
MRI
Emotional Memory Task
Reappraisal
Distraction
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Brain & Behavior Research Foundation
First posted: 2015-10-09
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

1. Has difficulty thinking differently in emotional situations
2. 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.
3. 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.
4. Has cellphone that can be used during the ambulatory assessment portion of the study.

Exclusion Criteria:

1. Current or recent (within the past 6 months) substance dependence disorder(excluding nicotine and caffeine)
2. Current serious medical illness, including migraine headaches. '
3. 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
4. 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).
5. 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.
6. 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).
7. 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.
8. 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).
9. 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.
10. Subjects with cochlear implants
11. Women who are pregnant or breast feeding
12. Chronic absence of shelter or impending jail that would make consistent participation in the study difficult
13. Cannot easily come to Duke several times for the study procedures
14. Does not have a mobile phone or is unwilling to use mobile phone for ambulatory assessment
15. Does not speak/understand English enough to benefit from the psychotherapeutic intervention
16. 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.

Primary outcomes:
measure: Time to Return to Heart Rate Baseline During the Regulation Period During Training
timeFrame: 1 week after intake
measure: Time to Return to Heart Rate Baseline During the Regulation Period at Follow up
timeFrame: 1 month
measure: Physiological Emotion Regulation
timeFrame: 1 week after study start
measure: Changes in Activation in the Neural Emotion Regulation Network
timeFrame: 1 week
Secondary outcomes:
measure: Acceptability, as Measured by Qualitative Exit Interview
timeFrame: 1 month
measure: Feasibility, as Measured by Qualitative Exit Interview
timeFrame: 1 month
measure: Change in General Psychological Distress, as Measured by the Outcome Questionaire -45
timeFrame: 1 week and 1 month
measure: Change in Daily General Emotional Distress
timeFrame: 1 week
measure: Change in Emotion Dysregulation and Functional Impairment
timeFrame: 1 week and 1 month after the intervention
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center-Civitan Bldg
state: North Carolina
Study officials:
affiliation: Duke University
name: Andrada D Neacsiu, PhD
role: PRINCIPAL_INVESTIGATOR
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