AMPLIFI: Adaptive Modulation of Plasticity Through Lactate and Fitness Interventions

The AMPLIFI study is a mechanistic clinical trial designed to investigate the neurophysiological effects of acute aerobic exercise on cortical plasticity and motor learning in older adults and individuals with chronic stroke. Participants are randomized into one of three groups: (1) moderate-to-high intensity aerobic exercise at lactate threshold, (2) moderate intensity aerobic exercise, (3) low-intensity aerobic exercise, or (4) education-only control.

The primary outcome measure is cortical inhibition, assessed using transcranial magnetic stimulation (TMS) measures including short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF). Secondary outcomes include performance on upper extremity motor tasks, measures of verbal and executive function, and blood lactate levels.

Participants complete three sessions over 2-3 weeks, including baseline assessments, VO2 max testing, multiple blood draws, and cognitive and motor testing. The exercise intervention is delivered via stationary cycling at intensities tailored using individual VO2 max data and lactate monitoring. Genetic and biochemical assays will be performed on blood samples to explore associations between metabolic and neural response.

This study will clarify how lactate-related exercise intensity impacts cortical inhibition and whether those effects support improvements in motor learning. Findings may help define the mechanisms by which exercise promotes neuroplasticity and support individualized rehabilitation strategies for aging and post-stroke populations.

• High intensity cycling (Behavioral), also known as HIIT: Participants cycle on a stationary ergometer at an intensity prescribed to reach their lactate threshold, guided by VO2 max results and lactate sampling. The session lasts approximately 20 minutes and is preceded and followed by TMS assessments and a structured motor learning task. This condition is designed to evaluate the effect of exercise-induced metabolic stress on cortical inhibition and motor learning.
• Low-intensity cycling (Behavioral), also known as MICT: Participants perform 20 minutes of cycling at a light workload below their lactate threshold. Exercise intensity is individualized using heart rate and perceived exertion (Borg RPE scale), avoiding significant metabolic activation. TMS and motor learning are assessed pre- and post-exercise. This condition serves as an active comparator to assess the impact of exercise intensity.
• Health education session (Behavioral), also known as Education: Participants receive a 20-minute session of health education content (e.g., wellness, healthy aging). No exercise is performed. Participants undergo TMS and motor learning testing before and after the session. This condition is used to control for attention and cognitive engagement without physical activity.
• Moderate Intensity Aerobic Exercise (Behavioral): Participants cycle on a stationary ergometer at an intensity prescribed to surround, but not exceed their lactate threshold, guided by VO2 max results and lactate sampling. The session lasts approximately 20 minutes and is preceded and followed by TMS assessments and a structured motor learning task. This condition is designed to evaluate the effect of moderate exercise-induced metabolic stress on cortical inhibition and motor learning.

Primary outcomes

• Motor Learning Performance (12-Digit Serial Reaction Time Task) [Baseline, Day 2, Day 3, Day 4, and Day 5]: Motor learning is assessed using the 12-digit Serial Reaction Time Task (SRTT), a computer-based measure of implicit motor sequence learning. Participants respond to visual cues by pressing buttons in a fixed or random sequence. Learning is quantified by changes in reaction time and accuracy across structured and unstructured trials. A learning index is derived by comparing performance between patterned (learning) and random sequences.

Secondary outcomes

• Change in Long-Interval Intracortical Inhibition (LICI) [Baseline, Day 5]: LICI is measured using a 100 ms interstimulus interval to assess GABA_B-mediated inhibition. Recorded before and after each intervention session.
• Change in Intracortical Facilitation (ICF) [Baseline, Day 5]: ICF is assessed using paired-pulse TMS with a 10-15 ms interstimulus interval to evaluate cortical excitability.
• Change in Blood Lactate Concentration [Day 2, Day 3, Day 4]: Measured via fingerstick blood samples pre-, mid-, and post-exercise.
• Change in Executive Function (D-KEFS Verbal Fluency and Stroop Tests) [Day 1 and Day 5]: Executive function neuropsychological tests.

Sex: All, ages: 18 Years to 85 Years, accepts healthy volunteers

Inclusion Criteria:

For All Participants:

* Able to provide informed consent
* Right-handed (for TMS consistency)
* English-speaking
* Clearance for moderate-intensity aerobic exercise
* Able to safely sit and pedal a stationary cycle ergometer
* No contraindications to TMS (e.g., no metal in skull, pacemakers, or seizure history)

Younger Adults (18-35):

* No history of neurological or psychiatric conditions
* Not currently on medications that affect the central nervous system

Older Adults (60-85):

* No diagnosis of dementia
* Independent in activities of daily living
* No stroke history

Stroke Survivors (40-85):

* At least 6 months post-stroke (chronic phase)
* Medically stable and cleared for aerobic exercise
* Able to engage in motor learning task (with or without hemiparetic adaptations)

Exclusion Criteria:

* History of epilepsy or seizures
* Current substance abuse or uncontrolled psychiatric disorder
* Severe cardiovascular disease or unstable medical condition
* Pregnancy
* Contraindications to TMS or exercise testing (e.g., implanted neurostimulators, severe hypertension)
* Participation in another interventional trial within the past 30 days

• Keith McGregor, PhD, Principal investigator, Keith McGregor