The proposed study aims to evaluate safety and efficacy of combined dextroamphetamine (Dexedrine) and transcranial direct current stimulation (tDCS) with melodic intonation therapy (MIT) for treatment of aphasia after stroke. The target population is patients with chronic speech deficits due to a left hemisphere non-hemorrhagic stroke. Findings from this proposed project will help in the design of future larger studies.The safety phase will use cross-over, placebo controlled and single-blinded design. 10 participants with post stroke chronic non-fluent aphasia will undergo two experiments. To study the safety and effect of combined dextroamphetamine, tDCS and MIT therapy the study will use a parallel-groups, randomized, sham and placebo controlled, and double-blinded design in which 48 participants with post stroke chronic non-fluent aphasia will be randomly assigned to receive either 1) dextroamphetamine therapy with active stimulation, 2) placebo medication with active stimulation, 3) dextroamphetamine therapy with sham stimulation or 4) placebo medication with sham stimulation for the same duration.

Two phases were planned for this study, as described below. The safety phase of the study was completed; however, due to limited funding, the efficacy phase was never started (that is, the efficacy phase was terminated).

SAFETY PHASE: The safety phase will use cross-over, placebo controlled and single-blinded design. 10 participants with post stroke chronic non-fluent aphasia will undergo two experiments. In the experiment 1, the subjects will receive 10 mg dextroamphetamine, 1.5 mA anodal tDCS to right inferior frontal gyrus (right Broca's area), and melodic intonation therapy. The two experiments of one time intervention will be separated by 1 week of washout and when the subjects come back for experiment 2, any later side effects will be evaluated. In the experiment 2, the subjects will receive placebo medication with anodal tDCS to right IFG (Broca's area) and melodic intonation therapy. During the experiments, thirty minutes before stimulation, participants in the active drug experiment (n=10) will take 10 mg dextroamphetamine per oral -experiment 1- and participants in the placebo drug experiment will take placebo pill per oral -experiment 2-. During the 20 minute stimulation phase, the participants (n=10) will receive anodal tDCS (1.5 mA) on ipsilesional right inferior frontal gyrus (Broca's area). All participants will simultaneously receive melodic intonation therapy for duration of an hour during and after 20 minutes of stimulation.

EFFICACY PHASE: To study the safety and effect of combined dextroamphetamine, tDCS and MIT therapy the study will use a parallel-groups, randomized, sham and placebo controlled, and double-blinded design in which 48 participants with post stroke chronic non-fluent aphasia will be randomly assigned to receive either 1) dextroamphetamine therapy with active stimulation, 2) placebo medication with active stimulation, 3) dextroamphetamine therapy with sham stimulation or 4) placebo medication with sham stimulation for the same duration. The subjects from the previous step of the study will be asked to participate to this step. Thirty minutes before stimulation participants in the active drug groups, group 1 (n=12) and group 3 (n=12) will take dextroamphetamine 10 mg per oral and participants in the placebo groups, group 2 (n=12) and group 4 (n=12) will take placebo pill per oral. During the 20 minute stimulation phase, the participants in the active stimulation groups, groups 1 (n=12) and 2 (n=12) will receive anodal tDCS (1.5 mA) on right inferior frontal gyrus (Broca's area), and participants in the sham control groups, group 3 (n=12) and group 4 (n=12) will receive sham stimulation. All participants will simultaneously receive melodic intonation therapy for duration of an hour during and after 20 minutes of stimulation. Treatment will be administered at an intensity of 5 sessions per week for 2 weeks.

Inclusion Criteria:

• Age above 18
• Native English proficiency;
• Nonfluent speech;
• Premorbid right handedness;
• Non-hemorrhagic left hemispheric stroke at least 6 months prior to the investigation.
• No contraindications for MRI (only subjects who will undergo MRI scan).

Exclusion Criteria:

• Hypersensitivity or idiosyncrasy to dextroamphetamine or to other sympathomimetic agents;
• Pregnant or trying to become pregnant;
• Active alcohol abuse, illicit drug use or drug abuse or significant mental illness;
• Subjects receiving alpha adrenergic antagonists or agonists;
• Any history of epilepsy;
• Any condition that would prevent the subject from giving voluntary informed consent;
• An implanted brain stimulator;
• Aneurysm clip or other metal in the brain;
• Enrolled or plans to enroll in an interventional trial during this study;
• Scalp wounds or infections;
• Previous stroke with residual deficits (TIAs not a reason for exclusion);
• A concurrent progressive neurologic disorder, acute coronary syndrome, severe heart disease (NYHA Classification > 3), or other major medical condition;
• Advanced atherosclerosis, Unstable cardiac dysrhythmia or uncontrolled hypertension (>160/100 mm Hg), or untreated hyperthyroidism;
• Diagnosis of glaucoma
• During or within 14 days following the administration of monoamine oxidase inhibitors;
• Subjects requiring palliative care;
• Terminal medical condition such as AIDS or cancer;
• Subjects unable to comprehend or follow verbal commands;
• Based on PI's or local physician's assessment patient unable to tolerate the trial procedure due to medical condition;

The safety phase of the study was completed; however, the efficacy phase was not started.