Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for memory and thinking problems due to epilepsy. In this study, participants will be assigned randomly (i.e., by flip of a coin), to a group that takes MPH and a group that takes a placebo (sugar pill). Participants will not know the group to which they have been assigned. Tests of attention and memory will be completed before taking the study pills and at Week 8. All participants will then have the option of taking MPH for the next two months, and attention and memory will be tested again at Week 16. The study will determine whether methylphenidate is helpful for the treatment of attention and memory problems in adults with epilepsy, and whether the medication is safe and beneficial when taken over an extended time period.

The proposed study is a randomized, double-blind trial of MPH vs. placebo in subjects with epilepsy and impaired attention. In the blinded phase, subjects will receive placebo or MPH (titrated to 20mg twice daily) for 8 weeks. Subjects will then receive open-label MPH for 8 weeks (titrated to 20mg twice daily). Cognitive tests will be performed at baseline, Week 8 (the end of the double-blind period), and at Week 16 (the end of the open-label period).

The primary aim is to evaluate the efficacy of MPH for the treatment of attentional dysfunction in subjects with epilepsy. It is expected that subjects will have improved attention when taking MPH compared to placebo, measured by the Conner's Continuous Performance Test (CPT). The effects of MPH on other cognitive functions that rely in part on attention, including a composite measure of memory (MCG Paragraph Test), psychomotor speed (Symbol Digit Modalities Test), and divided attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test), will be ascertained. Improved performance when taking MPH compared to placebo is expected. Finally, the study will establish the effect of MPH on overall quality of life. It is hypothesized that there will be improvement in self-reported quality of life with MPH, but no change with placebo, as assessed by the Quality of Life in Epilepsy Patient Inventory.

We will evaluate the safety of MPH compared to placebo with respect to seizure frequency. Secondary analyses will determine continued efficacy over an open-label period. To control for practice effects, cognitive performance will be compared to healthy subjects and epilepsy patients without cognitive complaints, who will complete the repeated cognitive measures but remain untreated for the duration of the trial.

Inclusion Criteria:

1. SUBJECTS WITH EPILEPSY

   Participants will include adult subjects with focal-onset epilepsy, based on clinical history, imaging studies and ictal and/or interictal EEG interpreted by a clinical epileptologist. Seizures may be symptomatic, idiopathic, traumatic, or non- traumatic in etiology. Subjects must have self-reported cognitive dysfunction. Subjects must also meet the following eligibility criteria:

   • Age 18 years of age or older;
   • Capacity to provide informed consent;
   • Ability to live independently and complete activities of daily living;
   • Stable seizure frequency at the time of enrollment, such that the subject's treating physician does not believe a change in ASM regimen to be warranted during the trial (ASMs should remain unchanged during the 16 weeks of participation unless absolutely required clinically due an unanticipated change in seizure frequency or severity);
   • Fluency in written and spoken English.

2. CONTROLS *DO NOT UNDERGO ANY DRUG OR PLACEBO INTERVENTION Two additional subject groups will be included, to control for effects of repeated testing in the open-label extension phase: healthy subjects and epilepsy patients without cognitive complaints, who will not receive the study drug at any point during the study. Epilepsy patients without cognitive deficits must otherwise meet all of the above criteria.

Healthy controls must meet the following inclusion criteria:

• Age 18 years or older;
• Capacity to provide informed consent;
• Ability to live independently and complete activities of daily living;
• Fluency in written and spoken English.

Exclusion Criteria:

SUBJECTS WITH EPILEPSY

Subjects with epilepsy with or without cognitive complaints will be excluded from participation for:

• Psychogenic, non-epileptic spells
• Delirium in the past year
• Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable neoplasm with no plans for resection will not be cause for exclusion.
• A history of alcohol or illicit drug abuse;
• Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or focal-onset seizures with impaired awareness within 24 hours of neuropsychological testing;
• Status epilepticus in the past year;
• Neurosurgery within the past 6 months;
• Active suicidal plan/intent in the past 6 months, a history of suicide attempt in the last 2 years, more than 1 lifetime suicide attempt, and/or current high-risk suicide flag in the medical record;
• Psychotic disorders
• Severe anxiety (>26 on the Beck Anxiety Inventory [BAI]) and impulse control disorders;
• Untreated sleep disorders;
• Use of narcotic or other sedating medications within 6 hours of testing (i.e., diphenhydramine);
• Concurrent severe major medical illness (i.e., cancer requiring chemotherapy or resection)
• Prior transient ischemic attack (TIA) or stroke

Subjects with epilepsy will also be excluded for a diagnosis of dementia (i.e., Alzheimer's disease). Subjects with epilepsy and cognitive complaints must have a MoCA score of 18 or greater. Subjects with epilepsy and no cognitive complaints must have a MoCA score of 26 or greater.

Subjects with epilepsy and cognitive complaints must meet additional exclusion criteria, to minimize risks of MPH:

• Current pregnancy or pregnancy planned during the trial
• Breastfeeding
• Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or MAOI use within 14 days of beginning the trial;
• Structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or coronary artery disease (including a history of myocardial infarction, cardiac stent placement, coronary artery bypass graft surgery, or angina);
• Bipolar disorders;
• Concurrent use of medications for erectile dysfunction (e.g., tadalafil, sildenafil);
• Use of medications that may lower seizure threshold (e.g., tramadol, bupropion) or induce psychosis (i.e., varenicline);
• Known allergy or intolerance to MPH;
• Uncontrolled hypertension;

HEALTHY CONTROLS

Healthy controls will be excluded based on the following criteria:

• History of seizures, epilepsy, or psychogenic, non-epileptic spells;
• Diagnosis of dementia (i.e., Alzheimer's disease), MoCA score of <26;
• Delirium in the past year;
• Other progressive neurologic illness (i.e., malignant brain tumor);
• Prior moderate or severe traumatic brain injury (TBI);
• Mild TBI within the past 6 months;
• A history of alcohol or illicit drug abuse;
• Active suicidal plan/intent in the past 6 months, a history of suicide attempt in the last 2 years, more than 1 lifetime suicide attempt, and/or current high-risk suicide flag in the medical record;
• Psychotic, severe anxiety (BAI >26), or impulse control disorders;
• Untreated sleep disorders;
• Use of narcotic or other sedating medications within 6 hours of testing;
• Ongoing major neurological or medical illness (i.e., cancer requiring chemotherapy or resection);
• Prior TIA or stroke;

An anonymized data set may be shared upon written request to the PI and available no later than one year following publication. The data will be shared pending a written agreement 1) prohibiting the recipient from identification or re-identification of the data and forbidding any attempts to do so, and 2) allowing scientific use only. The data set will be provided via encrypted VA email.

Data will be made available no later than one year following publication. Data will be available for at least 6 years following completion of the study.

The data will be shared pending a written agreement 1) prohibiting the recipient from identification or re-identification of the data and forbidding any attempts to do so, and 2) allowing scientific use only.

Double-blind, placebo-controlled study. A designated unblinded study team member will perform the randomization and provide group assignment to the local Research Pharmacies. The unblinded study team member and Research Pharmacies will hold the randomization key, while all other individuals are blinded to study group assignment.