Neuromodulation Enhanced Cognitive Restructuring: A Proof of Concept Study

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 propose to recruit 65 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 and to randomly assign them to either real or sham repetitive
transcranial magnetic stimulation (rTMS). All included participants will practice 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 will be used to teach cognitive
restructuring, to generate personalized stressors, to induce negative emotional arousal, and
to implement the one session of rTMS. Immediate effects will be 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 will be examined at 1-week and 1-month follow-up interviews. The
investigators hypothesize that rTMS will enhance cognitive restructuring by yielding a
quicker reduction in emotional arousal when compared to sham TMS, and will lead to more
frequent use of the cognitive restructuring in the natural environment. If successful, this
study may be the first in a series of investigations using innovative paradigms to optimize
treatment for psychiatric disorders and it could lead to the next generation of
neuroscience-informed behavioral interventions.

An additional 40 participants will be recruited for the study using identical
inclusion/exclusion criteria as the main portion of the study, however, if their score on the
emotion regulation questionnaire is above the low frequency, a group of participants who meet
for medium to high frequency on the scale will be allowed to participate in this arm if the
also score high on the difficulties with emotion regulation scale and meet all other
inclusion/exclusion criteria as well as can undergo an MRI. Participants in the imaging
portion of the study will undergo an MRI before the intervention day. This imaging session
will include 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 will complete the emotional regulation task where they
will be 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 will rate their current emotional state. Participants in the imaging portion of
the study will be randomized to sham or left dorsal lateral prefrontal cortex stimulation
only. After undergoing the intervention visit, they will then return to complete a second MRI
after 1 week where they will reoriented to the emotion regulation task, have structural and
functional MRI images collected with the emotion regulation task occurring during the fMRI
portion.

They will also complete the online questionnaires as the other groups and then will return to
the clinic within 30days for the final follow-up visit.

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.