Electrophysiological Probes And Treatments In Neurobehavioral Disorders

National Institute Of Neurological Disorders And Stroke

Investigators

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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. We have begun 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). The state-dependency of the effects of TMS on memory performance and biomarkers of cognitive processing by has important implications for the use of neuromodulation in cognitive paradigms. INVESTIGATION OF THE UNPLEASANTNESS OF PAIN AND PHYSICAL EFFORT The experience of pain can be quantified on two partially independent, dimensions: a sensory-discriminative dimension (intensity) and an emotional dimension (unpleasantness or, in economic terms, the utility or desirability of escape from or avoidance of that pain. In this sense, pain is like other punishing events, such monetary loss. Sources of acute pain, e.g., athletic injury and dental procedures, may have similar intensity, yet vary in unpleasantness. Additionally, chronic and acute pain from the same source may have different emotional impact. While pain perception necessarily relies on ascending spinothalamic and thalamocortical pathways and somatosensory cortical areas, functional imaging shows pain related activity in many brain areas and networks. Chronic pain, particularly, engages cortical regions involved in cognitive-emotional processing. The assignment reward and punishment value value to events involves a network, including the orbitofrontal (OFC), ventromedial prefrontal, and anterior cingulate cortical areas, and ventral striatum, collectively known as the subjective value network (SVN). Experimental studies of pain as a punishment or modulator of reward implicate these areas [7-9]. Subjective value is updated continuously in reaction to external and internal states and competing drives. This may account for the varying unpleasantness of pain over time and across motivational, cognitive, and emotional states. Neural activity in the OFC increases proportionally with subjective reward value and decreases with punishment cost. In general, the lateral OFC is activated by punishment, whereas the medial OFC (mOFC) tends to activate in response to reward. This makes the OFC a tempting target for neuromodulation to reduce the unpleasantness of chronic pain, where interventions aimed at sensory systems and pain intensity may be less successful due to refractory physiological changes, e.g., central sensitization. We are currently preparing a pilot trial of MS targeted to reduce the burden of pain in chronic pain patients. Stimulation aimed at increasing network connectivity and activation will be directed to a region of the inferior parietal cortex with maximum connectivity with the medial OFC in each individual. The primary outcome is feasibility and tolerability, but we will also measure changes in an ecological momentary assessment for chronic pain and fMRI. In addition to assigning negative value to pain, the SVN appears to regulate the unpleasantness of physical effort and the willingness to exert it, experienced on the dimension of vigor and fatigue. 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. We are interested in whether noninvasive neuromodulation targeted to SVN, might affect willingness to exert effort for a particular reward. Our first study in this area 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.