Electrophysiological Probes And Treatments In Neurobehavioral Disorders

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Modulation of memory networks: Human memory is composed of two, largely segregated, systems, the episodic system, which records explicit, verbalizable, records of experience, e.g., what you had for breakfast or the route from home to work, and the procedural system, which gradually builds motor and cognitive skills and habits through repetition and rewarded or punished experience. The episodic system is centered in the hippocampus and includes a network of cortical sites, while the procedural system is a system of parallel loops involving the cortex, basal ganglia, and thalamus, with important modulatory input from the midbrain dopamine nuclei. We and others have shown that transcranial magnetic stimulation (TMS) delivered to the inferior parietal cortex, an accessible node in the episodic memory network, causes a significant increase in resting state functional connectivity in the entire network and clinically relevant improvement in visual learning in healthy individuals. Stimulation is targeted to the individual subject's area with densest functional connectivity with a seed region in the hippocampus. We reproduced this effect in two cohorts and shown that the effects on connectivity are restricted to the targeted network. Using the effects of TMS, we have also explored effects of episodic memory activation on the procedural network, explaining previously described aspects of their interaction. We have also used individual differences in white matter fractional anisotropy to find the pathways by which the activity responsible for these effects reaches medial temporal lobe structures from the parietal cortex. This year, we began analysis of a study using event-related and resting state electroencephalography (EEG) to see how single TMS trains, delivered to the posterior parietal cortex, online, during a memory task, affect brain activity and performance associated with the encoding and recall of information. The control condition was identical TMS, delivered to the vertex. One aim of the study was to investigate how TMS modulates EEG neural measures of successful memory and the association of this modulation with behavioral performance. During encoding, TMS delivered to the posterior parietal lobe and targeted to the episodic memory network increased the late positive posterior ERP (400-600ms in posteromedial electrodes) and significantly decreased the stimulus-evoked theta/alpha (4-13Hz) power for stimuli that were later remembered. Both of these EEG signatures were associated with successful recall of encoded information in previous work. During during rest after encoding and TMS, network-targeted stimulation significantly decreased the stimulus-evoked theta/alpha (4-13Hz) power. During retrieval of previously presented stimuli, network-targeted TMS, increased the late positive posterior ERP (400-600ms in posteromedial electrodes) for correctly recalled stimuli, relative to incorrect trials. The other main aim of this study was to examine how memory task state influences susceptibility to TMS effects on the network and determine the optimal neural state for improving memory. Network-targeted TMS, delivered synchronously with encoding of information, relative to delivery prior to trial onset, improved memory for encoded stimuli. TMS under these conditions also increased the late positive posterior ERP (400-600ms in the posteromedial electrodes). Investigation of the unpleasantness of physical effort I have a long-standing interest in role of the reward system, not just in learning, where we have done several studies, but in the regulation of behavior. In particular, I am interested in the theory that the valuation placed on action governs the willingness to exert mental and physical effort. Distortions in the estimation of the rewarding or punishing value of goals and actions may play a role in disorders of impaired effort production and excessive fatigue, e.g., Parkinson disease, where the reward system is known to be affected, and chronic fatigue syndrome/myalgic encephalomyelitis, where the mechanism is unknown. Another question of interest is whether neuromodulation targeted to the subjective valuation system (SVN), which assigns rewarding and punishing values to actions, goals, and objects in the environment, might affect willingness to exert effort. Our first study in this project is a fMRI experiment to compare activation of the SVN (ventromedial prefrontal cortex, ventral striatum, posterior cingulate), related to the rated unpleasantness of painful thermal stimulation (an established paradigm) effort (grip force). Our hypothesis is that the SVN will be activated proportionally to the rated unpleasantness of both pain and effort. If this hypothesis is borne out, we will proceed to a TMS experiment targeting the subjective valuation network and looking for changes in functional connectivity and activation in response to effort, as well as an exploratory behavioral outcome.