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Resting state functional connectivity of the ventral tegmental area and avolition in subjects with schizophrenia
Clinical and translational [2] Cervilla, J.A., 2016. Protocol and methodology of Study epidemiological mental health in Andalusia: PISMA-ep. Rev Psiquiatr Salud Ment. [3] Bromet, E., Andrade, L.H., Hwang, I., Sampson, N. A., Alonso, J., de Girolamo, G., et al., 2011. Crossnational epidemiology of DSM-IV major depressive episode. BMC Med. 9, 90. P.3.020 Resting state functional connectivity of the ventral tegmental area and avolition in subjects with schizophrenia G.M. Giordano1*, M. Stanziano2, A. Mucci1, M. Papa2, S. Galderisi1. 1University of Naples SUN, Department of Psychiatry- Largo Madonna delle Grazie- 80138, Naples, Italy; 2University of Naples SUN, Laboratory of Neuronal Networks- Department of Mental and Physical Health and Preventive Medicine- Via Luciano Armanni 5- 80138, Naples, Italy Background: Avolition is a core symptom of schizophrenia, is associated to poor functional outcome and there are no effective treatments [1]. Avolition represents a multifaceted construct, which might be related to abnormalities of reward prediction or valuation, effort computation, encoding of action-outcome contingency and decision-making processes. All these aspects are related to mesocorticolimbic and corticostriatal circuits [2] that receive input, modulate or inhibit two classes of dopaminergic neurons. The first one encodes motivational value (desirability of stimuli) and is located in the ventromedial substantia nigra pars compacta (SNc) and ventro-tegmental area (VTA) with projection to nucleus accumbens shell (NAs), ventral prefrontal cortex and dorsal striatum; the second one, encoding motivational salience (arousal elicited by the stimulus), is located in dorsolateral SNc, medial VTA and projects to the dorsolateral prefrontal cortex, nucleus accumbens core (NAc) and dorsal striatum [3]. Important nodes of both circuits are the insula and the anterior cingulate cortex. The VTA has the highest number of both populations of DA neurons. Purpose: In the light of these observations, the aim of the present study was to investigate resting-state functional connectivity (RS-FC) in the motivational circuits in schizophrenia patients and its relationships with real-life motivation and avolition. Method: Resting state functional magnetic resonance connectivity (RS-FC) was investigated in 22 healthy controls (HC) and in 26 schizophrenia patients (SCZ) treated with second generation antipsychotics only (SGAs) and divided in high (HA = 13) and low avolition
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(LA = 13) subgroups. Brain Voyager QX 2.6.3 (Brain Innovation BV, Maastricht, The Netherlands) and ANCOVA (age as a covariate) were used for imaging analyses. The volume-of-interest (VOI) of VTA was derived from a previous study [4]. We used the Quality of Life Scale and the Schedule for the Deficit Syndrome to assess respectively real-life motivation and avolition. Pearson’s r coefficients were used to investigate associations of RS-FC with motivation and avolition scores. Results: HA patients, in comparison to LA patients and HC, showed significantly reduced VTA RS-FC (all p values < 0.001) with the right ventrolateral prefrontal cortex (R VLPFC), right posterior insula (R pINS) and right lateral occipital cortex (R LOC). The RS-FC of these regions was positively correlated with motivation in the whole sample (all p values < 0.001) and negatively correlated to avolition scores in schizophrenia patients (R VLPFC p = 0.002; R pINS p < 0.001; R LOC p = 0.006). Conclusion: Our findings demonstrate that avolition in schizophrenia is linked to dysfunctional connecivity between VTA and R pINS, R VLPFC, R LOC. As recently demonstrated in rodents [5] the selective dysconnection of the insular cortex from the NAc impairs the retrieval of outcome values of instrumental actions to motivate behavior. Our findings of the relationships of VTA-insula hypoconnectivity and motivational deficits support the translational value of this rodent model of avolition. The further investigation of the molecular modulators of this connectivity is critical to foster development of new treatments for avolition in schizophrenia. Reference(s) [1] Galderisi, S., Merlotti, E., Mucci, A., 2015. Neurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci, 265, 543–58. [2] Barch, D.M., Dowd, E.C., 2010. Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions. Schizophr Bull, 36, 919–34. [3] Bromberg-Martin, E.S., Matsumoto, M., Hikosaka, O., 2010. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron, 68, 815–34. [4] Kahn, I., Shohamy, D., 2013. Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans. Hippocampus, 23, 187–92. [5] Parkes, S.L., Bradfield, L.A., Balleine, B.W., 2015. Interaction of insular cortex and ventral striatum mediates the effect of incentive memory on choice between goal-directed actions. J Neurosci, 35, 6464–71.
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(LA = 13) subgroups. Brain Voyager QX 2.6.3 (Brain Innovation BV, Maastricht, The Netherlands) and ANCOVA (age as a covariate) were used for imaging analyses. The volume-of-interest (VOI) of VTA was derived from a previous study [4]. We used the Quality of Life Scale and the Schedule for the Deficit Syndrome to assess respectively real-life motivation and avolition. Pearson’s r coefficients were used to investigate associations of RS-FC with motivation and avolition scores. Results: HA patients, in comparison to LA patients and HC, showed significantly reduced VTA RS-FC (all p values < 0.001) with the right ventrolateral prefrontal cortex (R VLPFC), right posterior insula (R pINS) and right lateral occipital cortex (R LOC). The RS-FC of these regions was positively correlated with motivation in the whole sample (all p values < 0.001) and negatively correlated to avolition scores in schizophrenia patients (R VLPFC p = 0.002; R pINS p < 0.001; R LOC p = 0.006). Conclusion: Our findings demonstrate that avolition in schizophrenia is linked to dysfunctional connecivity between VTA and R pINS, R VLPFC, R LOC. As recently demonstrated in rodents [5] the selective dysconnection of the insular cortex from the NAc impairs the retrieval of outcome values of instrumental actions to motivate behavior. Our findings of the relationships of VTA-insula hypoconnectivity and motivational deficits support the translational value of this rodent model of avolition. The further investigation of the molecular modulators of this connectivity is critical to foster development of new treatments for avolition in schizophrenia. Reference(s) [1] Galderisi, S., Merlotti, E., Mucci, A., 2015. Neurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci, 265, 543–58. [2] Barch, D.M., Dowd, E.C., 2010. Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions. Schizophr Bull, 36, 919–34. [3] Bromberg-Martin, E.S., Matsumoto, M., Hikosaka, O., 2010. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron, 68, 815–34. [4] Kahn, I., Shohamy, D., 2013. Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans. Hippocampus, 23, 187–92. [5] Parkes, S.L., Bradfield, L.A., Balleine, B.W., 2015. Interaction of insular cortex and ventral striatum mediates the effect of incentive memory on choice between goal-directed actions. J Neurosci, 35, 6464–71.