Electrophysiological Probes And Treatments In Neurobehavioral Disorders

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

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 have reproduced this effect in two cohorts and shown that the effects on connectivity are restricted to the targeted network. In a Bayesian-adaptive trial, we have also examined the number of days of treatment required to produce a lasting effect. Because there is evidence from imaging and behavioral experiments that the episodic memory network competes with procedural learning network, we also looked for effects on regions connected with a relevant region of the striatum. We found that enhancement of connectivity in the episodic memory network also increases connectivity between the hippocampus and striatum in a way which could reduce its availability for procedural learning. Confirming this suspicion we also found an inverse correlation between episodic memory network connectivity enhancement and procedural memory performance after stimulation. This is the first direct, causal, evidence of the relationship between the two networks and is of basic and clinical interest. In work directed at revealing further details of how TMS of the episodic memory network improves memory performance, we looked at individual differences in the organization of white matter pathways from the stimulation site in the inferior parietal cortex to network sites with the greatest change in connectivity across studies. Although the target site was chosen for maximal connectivity to the hippocampus in each individual, participants with the strongest white matter connectivity from the stimulation site to the precuneus, a cortical area involved in episodic memory, had the largest effects on network connectivity and memory performance. We also used individual differences in fractional anisotropy among candidate pathways from the parietal stimulation site to the hippocampal seed to find the oligosynaptic route by which the effect propagates. Fractional anisotropy in the parietal-parahippocampal pathway and several pathways via other regions of the medial temporal lobe predicted the changes in hippocampal functional connectivity produced by parietal TMS. Fractional anisotropy in these pathways was also related to changes in episodic, but not procedural, memory. In other work, we found that enhancement of hippocampal connectivity by TMS increases the connectivity of the hippocampal network and caudate nucleus and that this effect is likely mediated via the precuneus and/or the ventrolateral thalamus. Moreover, this increase in connectivity between the episodic memory network and nodes of the procedural memory network was associated with a proportional decrease in procedural memory performance after parietal TMS. This mechanism could account for the classical observation of functional antagonism between memory systems under laboratory conditions. Modulation of the visual attentional network There are simple and reliable ways of inducing quantifiable changes in behavior, including adaptation to prism goggles that shift vision a few degrees to either side. We are studying the basis of this phenomenon with functional MRI and using TMS to intervene in the same neural pathways and attempt to produce the same imaging and behavior changes. This work is aimed at a getting a better understanding and developing new treatments for the syndrome of hemispatial neglect after right hemisphere damage. Adaptation to vision-shifting prisms (PA) alters spatial cognition according to the direction of visual displacement by temporarily modifying sensorimotor mapping. Right-shifting prisms (right PA) improve neglect of left visual field in patients, possibly by decreasing activity in the left hemisphere and increasing it in the right. Left PA shifts attention rightward in healthy individuals by an opposite mechanism. However, functional imaging studies of PA are inconsistent, perhaps because of differing activation tasks. Recently, we measured resting-state functional connectivity in healthy individuals before and after PA. When contrasted, right versus left PA decreased RSFC in the spatial navigation network defined by the right posterior parietal cortex (PPC), hippocampus, and cerebellum. Within-PA-direction comparisons showed that right PA increased resting state functional connectivity in subregions of the PPCs and between the PPCs and the right middle frontal gyrus and left PA decreased RSFC between these regions. Both right and left PA decreased RSFC between the PPCs and bilateral temporal areas. In summary, right PA increases connectivity in the right frontoparietal network and left PA produces essentially opposite effects. Furthermore, right, compared with left, PA modulates resting state functional connectivity in the right hemisphere navigation network. Hemispatial neglect is thought to result from disruption of interhemispheric equilibrium. Right hemisphere lesions deactivate the right frontoparietal network and hyperactivate the left via release from interhemispheric inhibition. Support for this theory comes from TMS studies in healthy subjects, in whom right PPC inhibition causes neglect-like, rightward, visuospatial bias. Concurrent TMS and fMRI after right PPC TMS show task-dependent changes but may have failed to identify effects of stimulation in areas not directly activated by the specific task, providing an incomplete picture. We used resting-state functional connectivity after inhibitory TMS over the right PPC to look for changes in the networks underlying visuospatial attention. In a crossover experiment in healthy individuals, we delivered continuous theta burst TMS to the right PPC and vertex (control). We hypothesized that PPC stimulation would cause a rightward visuospatial bias, decrease PPC connectivity with frontal areas, and increase PPC connectivity with the attentional network in the left hemisphere. We also expected that individual differences in fractional anisotropy (FA) in white matter connections between the PPCs would account for variability in TMS-induced RSFC changes. As expected, TMS over the right PPC caused a rightward shift in line bisection judgment and increased RSFC between the right PPC and the left superior temporal gyrus. This effect was inversely related to fractional anisotropy, a measure of white matter organization, in the posterior corpus callosum. Local inhibition of the right PPC reshapes connectivity in the attentional network and depends on interhemispheric connections.