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      Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man

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          Significance

          We reveal prominent delta oscillations in the nucleus accumbens preceding food reward in mice and use them to guide responsive neurostimulation to suppress binge-like behavior. Similar electrographic signatures are observed in human nucleus accumbens during reward anticipation as well, suggesting their translational potential in the development of a treatment for loss of impulse control in obesity and perhaps additional brain disorders.

          Abstract

          Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

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          Most cited references18

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          FMRI visualization of brain activity during a monetary incentive delay task.

          Comparative studies have implicated striatal and mesial forebrain circuitry in the generation of autonomic, endocrine, and behavioral responses for incentives. Using blood oxygen level-dependent functional magnetic resonance imaging, we sought to visualize functional activation of these regions in 12 normal volunteers as they anticipated and responded for monetary incentives. Both individual and group analyses of time-series data revealed significant activation of striatal and mesial forebrain structures (including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving both monetary rewards and punishments. In addition to these areas, during trials involving punishment, group analysis revealed activation foci in the anterior cingulate and thalamus. These results corroborate comparative studies which implicate striatal and mesial forebrain circuitry in the elaboration of incentive-driven behavior. This report also introduces a new paradigm for probing the functional integrity of this circuitry in humans.
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            Dopamine operates as a subsecond modulator of food seeking.

            The dopamine projection to the nucleus accumbens has been implicated in behaviors directed toward the acquisition and consumption of natural rewards. The neurochemical studies that established this link made time-averaged measurements over minutes, and so the precise temporal relationship between dopamine changes and these behaviors is not known. To resolve this, we sampled dopamine every 100 msec using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the nucleus accumbens of rats trained to press a lever for sucrose. Cues that signal the opportunity to respond for sucrose evoked dopamine release (67 +/- 20 nm) with short latency (0.2 +/- 0.1 sec onset). When the same cues were presented to rats naive to the cue-sucrose pairing, similar dopamine signals were not observed. Thus, cue-evoked increases in dopamine in trained rats reflected a learned association between the cues and sucrose availability. Lever presses for sucrose occurred at the peak of the dopamine surges. After lever presses, and while sucrose was delivered and consumed, no further increases in dopamine were detected. Rather, dopamine returned to baseline levels. Together, the results strongly implicate subsecond dopamine signaling in the nucleus accumbens as a real-time modulator of food-seeking behavior.
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              Neuronal activity in monkey ventral striatum related to the expectation of reward.

              Projections from cortical and subcortical limbic structures to the basal ganglia are predominantly directed to the ventral striatum. The present study investigated how the expectation of external events with behavioral significance is reflected in the activity of ventral striatal neurons. A total of 420 neurons were studied in macaque monkeys performing in a delayed go-no-go task. Lights of different colors instructed the animal to do an arm-reaching movement or refrain from moving, respectively, when a trigger light was illuminated a few seconds later. Task performance was reinforced by liquid reward in both situations. A total of 60 ventral striatal neurons showed sustained increases of activity before the occurrence of individual task events. In 43 of these neurons, activations specifically preceded the delivery of reward, independent of the movement or no-movement reaction. In a series of additional tests, these activations were time locked to the subsequent reward, disappeared within a few trials when reward was omitted, and were temporally unrelated to mouth movements. Changes in the appetitive value of the reward liquid modified the magnitude of activations, suggesting a possible relationship to the hedonic properties of the expected event. Activations also occurred when reward was delivered in a predictable manner outside of any behavioral task. These data suggest that neurons in the ventral striatum are activated during states of expectation of individual environmental events that are predictable to the subject through its past experience. The prevalence of activations related to the expectation of reward suggests that ventral striatal neurons have access to central representations of reward and thereby participate in the processing of information underlying the motivational control of goal-directed behavior.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                2 January 2018
                18 December 2017
                18 December 2017
                : 115
                : 1
                : 192-197
                Affiliations
                [1] aDepartment of Neurosurgery, Stanford University , Stanford, CA 94305;
                [2] bDepartment of Neurology and Neurological Sciences, Stanford University , Stanford, CA 94305;
                [3] cDepartment of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305;
                [4] dDepartment of Radiology, Stanford University , Stanford, CA 94305;
                [5] eNancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305;
                [6] fDepartment of Psychology, Stanford University , Stanford, CA 94305
                Author notes
                2To whom correspondence may be addressed. Email: malenka@ 123456stanford.edu or chalpern@ 123456stanford.edu .

                Contributed by Robert C. Malenka, November 5, 2017 (sent for review July 11, 2017; reviewed by Andre G. Machado and Sameer A. Sheth)

                Author contributions: H.W., B. Knutson, R.C.M., and C.H.H. designed research; H.W., K.J.M., N.R.W., V.K.R., B. Knutson, and C.H.H. performed research; H.W., K.J.M., Z.B., V.K.R., K.E.L., B. Kakusa, M.D.S., M.W., D.J.C., B.K.R., H.B.-S., B. Knutson, and C.H.H. analyzed data; and H.W., K.J.M., R.C.M., and C.H.H. wrote the paper.

                Reviewers: A.G.M., Cleveland Clinic Foundation; and S.A.S., Columbia University.

                1H.W. and K.J.M. contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-6687-6422
                Article
                201712214
                10.1073/pnas.1712214114
                5776799
                29255043
                56d72990-4c4e-4033-b2cd-5c078bfb5a41
                Copyright © 2017 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 6
                Funding
                Funded by: Stanford Neurosciences Institute
                Award ID: NA
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: K12NS080223
                Funded by: Brain and Behavior Research Foundation (BBRF) 100000874
                Award ID: NA
                Categories
                Biological Sciences
                Neuroscience

                deep brain stimulation,nucleus accumbens,delta band,closed loop,reward

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