Distinct Mechanisms of Cognitive Behavioral Therapy Effects in Youth With Migraine

Pediatric migraine is a prevalent disorder that results in significant pain and disability
for children and adolescents. Little is known about the distinct brain changes that occur in
youth with migraine when they receive cognitive behavioral therapy, which is known to
decrease headache days for these patients. Pediatric medical and behavioral clinicians can
use mechanistic insights from this study to provide patients and families with a stronger
rationale for treatment, thereby decreasing stigma and increasing confidence in and
commitment to the care plan.

This project will study migraine, which affects > 6 million youth in the U.S. Cochrane
reviews show that psychological therapies for pediatric headache result in better outcomes
than control conditions (56% improved vs. 22% in 714 participants), and our CBT+Amitriptyline
Study found that 66% of youth with chronic migraine had a ≥ 50% reduction in headache days
compared to 36% in an education control+Amitriptyline (AMI) group. Despite this evidence
base, the neural mechanisms supporting the efficacy of CBT for pain remain poorly understood.
The lack of mechanistic understanding is a barrier to treatment utilization, particularly
given the time, effort, and expense for pediatric migraine patients to receive CBT vs.
conventional pharmacological therapy (which in a national trial reduced headache days similar
to placebo pill: AMI 52% of participants improved; Placebo 61%). Pilot data from the
investigators demonstrate that: CBT induces changes in brain connectivity/activation, and QST
at baseline predicts reduced migraines at 8 weeks.

Inclusion Criteria:

- Diagnosis: Migraine with or without aura or chronic migraine that meets the
International Classification of Headache Disorders, 3rd Edition (beta) (ICHD-3b)
criteria

- Frequency: Headache frequency based upon prospective headache diary of 28 days must be
≥ 8 and ≤ 28

- PedMIDAS: PedMIDAS Disability Score > 10, indicating at least mild disruption in daily
activities and < 140, indicating extreme disability that may require more
comprehensive, multi-component therapy

- English speaking: able to complete interviews and questionnaires in English

Exclusion Criteria:

- Continuous migraine defined as an unrelenting headache for a 28 day period

- Weight less than 30 kg or greater than 120 kg, or weight/size incompatible with MRI
scanner

- Must agree not to take non-specific acute medication, such as NSAIDS (e.g.,
ibuprofen), more than 3 times per week, or migraine specific acute medications, such
as triptans, more than 6 times per month

- No current prophylactic anti-migraine medication within a period equivalent to < 5
half-lives of that medication before entering the screening phase, and agree to not
begin a migraine prevention medication during the study period

- Current use of the following medications/products: opioids, antipsychotics,
antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol,
nutraceuticals

- Known history of allergic reaction or anaphylaxis to amitriptyline

- Abnormal findings on ECG at baseline, particularly lengthening of the QT interval ≥
450 msec

- Orthodontic braces, metallic or electronic implants, or other metal objects in the
body which obscure or interfere with the MRI, or pose a risk from heating, movement,
or malfunction in the MRI environment

- Claustrophobia

- Youth who are pregnant, or those who are sexually active and not using a medically
accepted form of contraception (barrier or hormonal methods)

- Diagnosis of epilepsy or other neurological diseases

- Inability to learn how to swallow pills using behavioral techniques (if indicated)

- Present psychiatric disease as defined by DSM IV (e.g. psychosis, bipolar disorder,
major depression, generalized anxiety disorder), alcohol or drug dependence, or
documented developmental delays or impairments (e.g., autism, cerebral palsy, ADHD, or
mental retardation) that, in the opinion of the investigator, would interfere with
adherence to study requirements or safe participation in the study