Modulation of Frontoparietal Dynamics Underlying Adolescent Working Memory Deficits

The objective of this project is to examine the contributing roles of the PPC and PFC in WM processes and relatedly, develop optimal targets for modulating WM-related neural oscillations. Patient Arm: In a 2x2 factorial double-blind design, we will randomize a sample of adolescents (13-18 years) with WM deficits to intermittent theta burst stimulation (iTBS) at the left dorsolateral prefrontal cortex (DLPFC) or inferior parietal lobule (IPL), based on each participant's structural brain MRI. Control Arm: A sample of healthy young adults (18-25 years) will receive an individualized theta-gamma parameters protocol of iTBS to the left DLPFC. Participants in both arms will complete an active iTBS session and a sham iTBS session. The primary outcome will be theta-gamma coupling during WM demands, as measured via electroencephalography (EEG) during a Sternberg spatial WM task (SWMT) immediately before and after iTBS. The central hypothesis is that the PFC and PPC regions have complimentary roles in executing WM processes. Further, iTBS can modulate theta-gamma coupling in these regions to improve behavioral performance. Our central hypothesis is formulated based on our preliminary data on the critical role of theta-gamma coupling in WM processes. To attain the overall objectives, the following specific aims will be pursued:

Aim 1: Examine the effect of iTBS to the PPC on the encoding stage of WM. Hypothesis: Compared to sham and DLPFC conditions, iTBS to the IPL will increase theta-gamma coupling during encoding. Modulation of theta-gamma coupling will correlate with improved behavioral performance.

Aim 2: Examine the effect of iTBS to the PFC on the maintenance stage of WM. Hypothesis: Compared to sham and IPL conditions, iTBS to the DLPFC will increase theta-gamma coupling during maintenance. Modulation of theta-gamma coupling will correlate with improved behavioral performance.

Aim 3: Examine the feasibility and preliminary effect of individualized iTBS to the PFC. Hypothesis: It will be feasible to utilize peak theta-gamma coupling during the SWMT to identify optimal iTBS parameters. Individualized iTBS will increase theta-gamma coupling during WM demands and improve behavioral performance.

Exploratory Aim: Identify the neocortical circuitry underlying oscillatory modulation. Computational modeling designed for neural interpretation of EEG will translate obtained recordings into cellular/circuit-level activity delineating the neural mechanism of the observed modulation. Hypothesis: pyramidal-interneuron mechanisms within the PPC/PFC will underlie the theta/gamma oscillatory modulation.

Patient Arm: We will enroll a sample of adolescents (age 13-18 years) with working memory deficits and ADHD. Participation in this study will not require any adjustments to their clinical care. There are no costs to this study (participants compensated) and there are no expected long-term benefits to the participants. Participants will be compensated for each session. Participants can withdraw from the study at any time.

Inclusion criteria

• Ability to provide assent and have parent provide parental permission
• English fluency of the participant and the legal guardian/parent
• 13-18 years
• 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.

Healthy Control Arm: We will target a sample of healthy, young adults. Inclusion Criteria

• Ability to provide consent
• English fluency of the participant
• 18-25 years
• Never diagnosed or meets current criteria for a psychiatric disorder, as measured by self-report of prior diagnoses and formal completion of the diagnostic interview.

Exclusion criteria

For patient and healthy control participants

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 MRI or TMS might result in increased risk of side effects or complications. Common 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. These account for the majority of the exclusion criteria listed below:

• 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, braces or fillings)
• Non-removable makeup or piercings
• 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)
• Chronic treatment with prescription medications that decrease cortical seizure threshold, not including psychostimulant medication if deemed to be medically safe as part of the medical review process.
• Active psychosis or mania
• Current suicidal intent
• Current pregnancy
• Significant visual, hearing or speech impairment
• Current wards of the state