rTMS and EF Training for Working Memory Deficits in Adolescent Psychopathology

Study Overview
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Brief Summary
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Executive functioning (EF) deficits are a core, transdiagnostic feature of psychopathology and one of the strongest predictors of clinical and functional outcomes, yet there remains a dearth of treatments available for EF deficits. EF is a collection of cognitive control processes that includes working memory (i.e., maintain/manipulate data not perceptually present), inhibition (i.e., inhibit/control of attention, thoughts, behaviors) and flexibility (i.e., shift flexibly between tasks/sets). These EF subdomains are subserved by a network (i.e., cognitive control network) of frontal (e.g., dorsolateral prefrontal cortex [DLPFC]), parietal and subcortical regions, with hypoactivation in such regions often underlying EF deficits. There is a recent call in psychiatry to develop experimental therapeutics that target anomalous neural systems underlying symptomology. Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic, non-invasive method of cortical excitability modulation. High frequency rTMS to the left DPLFC has an activating effect on the cognitive control network, with initial research in adults finding a subsequent enhancing effect on working memory, inhibition, and flexibility. rTMS represents a very promising potential tool to target EF deficits in psychopathology.

Official Title
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rTMS and Executive Functioning Training for Working Memory Deficits in Adolescent Psychopathology

Conditions
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ADHD With Working Memory Deficits

Intervention / Treatment
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* Device: Magstim Super Rapid2 stimulator, 10 Hz condition
* Device: Magstim Super Rapid2 stimulator, Sham condition
* Device: Magstim Super Rapid2 stimulator, iTBS condition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide assent and have parent provide parental permission English fluency 13-17 years List Sorting Test (NIH Toolbox) performance: Greater than 1.0 standard deviation (SD) below normative mean Parent rating on BRIEF-2 Working Memory: Greater than 1.0 SD above normative mean IQ > 80 Clinical diagnosis of attention deficit hyperactivity disorder (ADHD): predominantly inattentive type, predominantly hyperactive/impulsive type, combined type, or unspecified type. Diagnostic criteria will be confirmed with NICHQ Vanderbilt Assessment Scales-Parent. Exclusion Criteria: Participants will be screened to exclude individuals with neurological or medical conditions that might confound the results, as well as to exclude participants in whom rTMS might result in increased risk of side effects or complications. Common TMS contraindications include metallic hardware in the body, cardiac pacemaker, patients with an implanted medication pumps or an intracardiac line, or prescription of medications known to lower seizure threshold. This accounts for the majority of the exclusion criteria listed: Intracranial pathology from a known genetic disorder (e.g., NF1, tuberous sclerosis) or from acquired neurologic disease (e.g. stroke, tumor), cerebral palsy, history of severe head injury, or significant dysmorphology History of fainting spells of unknown or undetermined etiology that might constitute seizures History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy Any progressive (e.g., neurodegenerative) neurological disorder Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.) Contraindicated metal implants in the head, brain or spinal cord (excluding dental implants or fillings) Pacemaker Implanted medication pump Vagal nerve stimulator Deep brain stimulator TENS unit (unless removed completely for the study) Ventriculo-peritoneal shunt Signs of increased intracranial pressure Intracranial lesion (including incidental finding on MRI) History of head injury resulting in prolonged loss of consciousness Substance abuse or dependence within past six months (i.e., DSM-5 substance use disorder criteria met) Chronic treatment with prescription medications that decrease cortical seizure threshold

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 Hz rTMS<br> | Device: Magstim Super Rapid2 stimulator, 10 Hz condition<br>* 10 Hz (2,000 pulses) at left DLPFC<br>|
| Sham Comparator: Sham rTMS<br> | Device: Magstim Super Rapid2 stimulator, Sham condition<br>* sham<br>|
| Experimental: iTBS rTMS<br> | Device: Magstim Super Rapid2 stimulator, iTBS condition<br>* 50 Hz, iTBS (600 pulses) at left DLPFC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compared to sham condition, activation of the left DLPFC prior to EF training will temporarily increase working memory performance as measured by the Sternberg Spatial Working Memory Test | The SWMT is a performance-based neuropsychological test of working memory | Task performance will be measured immediately prior to and following the active and sham rTMS/EF training sessions. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compared to sham condition, activation of the left DLPFC prior to EF training will temporarily increase fronto-parietal gamma power and theta-gamma coupling during working memory demands. |  | EEG will be measured during SWMT immediately prior to and following the active and sham rTMS/EF training sessions. |