Brain State-dependent Stimulation to Improve Movement

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool to non-invasively modulate brain circuits, brain plasticity, and behavior. This proposal will test the hypothesis that controlling behavioral state during focal multi-day rTMS of a brain region involved in grasping movements will enhance the functional specificity of the neuromodulation action among distributed brain regions involved in voluntary motor control and concomitantly improve manual dexterity. Results from this study will be used to optimize rTMS therapy for individuals with neuromotor impairments by controlling behavioral state to improve the efficacy of rTMS treatment.

Healthy volunteers that qualify for this study will have motor skill assessments and basic neuromotor testing (using neurophysiology with TMS and functional Magnetic Resonance Imaging (fMRI) scans). Participants will be asked to come in for up to nine sessions that include 1 screening session, 5 consecutive daily rTMS sessions and 3 assessment sessions with resting-state and task-based fMRI, neurophysiology with TMS, and hand motor tasks over the course of 3-4 weeks.

This study will examine a particular type of rTMS, known as theta burst stimulation (TBS), which has been shown to induce longer lasting effects than other forms of rTMS, making TBS an important tool for therapeutic applications. While TBS provides relatively focal stimulation, effects on the brain occur through interconnected networks in ways that are poorly understood. Moreover, stimulation is highly state-dependent, and the use of rTMS in most therapeutic settings, such as the treatment of motor impairments, leaves behavioral state uncontrolled. Augmenting rTMS therapy by inducing specific behavioral states is an attractive idea for improving therapeutic rTMS, but the relevant knowledge base is sparse. To address this critical gap, this exploratory R21 proposal will examine the effects of TBS and behavioral state on brain and motor behavior. The investigators will test the broad hypothesis that when TBS is applied during a controlled behavior state, motor function will be facilitated, compared to stimulation when behavioral state is uncontrolled. The investigators will focus on the posterior parietal cortex (PPC), and associated parietofrontal circuits, which subserve skilled grasp control, an ability known to be impaired in stroke, traumatic brain injury, and other motor disorders. The investigators will collect functional magnetic resonance imaging (fMRI), neurophysiological measures with TMS, and behavioral measures in all subjects for three different interventions.

In Aim 1, the investigators will show improvement in action performance by manipulating the behavioral state during PPC stimulation.

In Aim 2, the investigators will demonstrate modulation of neurophysiological aftereffects of PPC stimulation on motor output by manipulating behavioral state.

In Aim 3, the investigators will assess the relationship between brain connectivity, plasticity and behavior in response to the behavioral state during brain stimulation.

Impact: Results will provide insights into the effects of rTMS and behavioral state on the brain and behavior. This knowledge will lay a mechanistic foundation for future studies to show how controlling behavioral state during rTMS can improve therapeutic efficacy in neurological disorders.

Eligibility Criteria:
Inclusion Criteria:

* Women of child bearing age cannot be pregnant or trying to become pregnant
* Ability to tolerate small, enclosed spaces without anxiety
* Ability and willingness to give informed consent to participate
* No history of neurological disorder
* Right handed
* English speaking

Exclusion Criteria:

* Are left-handed
* Are younger than 18 or older than 50 years old
* Women who are pregnant, suspect they are pregnant, or are attempting to become pregnant
* Have metal anywhere in the head, excluding the mouth
* Have a pacemaker, deep brain stimulator, vagus nerve stimulator or any other medically implanted device
* Have cochlear hearing implants
* Are taking GABAergic, NDMA-receptor antagonist, or other drug known to influence neural receptors
* Have any of the below conditions that would put participants at increased risk of having a seizure: a personal or family history of seizure/epilepsy, taking prescription drugs that lower the threshold for seizures, recent history of excessive alcohol consumption, history of alcohol addiction/dependence, recent history of recreational drug use, history of drug addiction/dependence
* Have been diagnosed with any of the following: a stroke, brain hemorrhage, brain tumor, encephalitis, multiple sclerosis, Parkinson's disease or Alzheimer's disease, depression in the past 6 months, attention deficit disorder, schizophrenia, manic depressive (bipolar) disorder, normal pressure hydrocephalus or increased intra-cranial pressure, diabetes requiring insulin treatment, any serious heart disorder or liver disease
* Have had a migraine in the past month
* MRI specific exclusion criteria: Any relevant history of open-heart surgery, artificial heart valve, brain aneurysm surgery, braces or extensive dental work, cataract surgery or lens implant, or artificial limb or joint. History of foreign metallic object in the body such as bullets, BB's, pellets, shrapnel, or metalwork fragments. Claustrophobia, have uncontrollable shaking, or cannot lie still for one hour.