Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia

Richter, Anja; Petrović, Aleksandra; Diekhof, Esther K.; Trost, Sarah; Wolter, Sarah; Gruber, Oliver

doi:10.1016/j.jpsychires.2015.09.005

Cited by 20 publications

(17 citation statements)

References 44 publications

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“…First, we demonstrated that activation in a priori brain regions of the mesolimbic system, namely the VS and VTA was significantly modulated by experimental context (Table 2), replicating previous findings (Diekhof and Gruber, 2010; Diekhof et al, 2012; Richter et al, 2015).…”

Section: Resultssupporting

confidence: 87%

“…The findings presented above, however, revealed a reduced negative VS-avPFC-coupling in subjects with high adversity load when compared to those with low during reward rejection, indicating not only a disturbed bottom-up mechanism but also an impaired top-down control of the mesolimbic system by prefrontal brain regions. Using the DRD paradigm, pathophysiological changes in the functional activity and connectivity within the dopaminergic reward circuitry have previously been proven in schizophrenia (Richter et al, 2015), bipolar disorder (Trost et al, 2014) and depression (Goya-Maldonado et al, 2015). Here we demonstrate that even in healthy subjects without psychopathology exposure to stress in childhood and young adulthood is associated with altered neural mechanisms underlying reward processing.…”

Section: Discussionmentioning

confidence: 99%

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Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus

Richter

Krämer

Diekhof

et al. 2019

NeuroImage: Clinical

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Accumulating evidence suggests altered function of the mesolimbic reward system resulting from exposure to early adversity. The present study investigated the combined long-term impact of adversity until young adulthood on neuronal reward processing and its interaction with individual resilience processes. In this functional magnetic resonance imaging study, 97 healthy young adults performed a reward-based decision-making task. Adversity as well as resilience were assessed retrospectively using the validated childhood trauma questionnaire, trauma history questionnaire and a resilience scale. Subjects with high adversity load showed reduced reward-related bottom-up activation in the ventral striatum (VS), ventral tegmental area (VTA) and hippocampus (HP) as compared to the low adversity group. However, high resilience traits in individuals with high adversity load were associated with an increased activation in the VTA and HP, indicating a possible resilience-related protective mechanism. Moreover, when comparing groups with high to low adversity, psychophysiological interaction analyses highlighted an increased negative functional coupling between VS and VTA as well as between VS and anteroventral prefrontal cortex (avPFC) during reward acceptance, and an impaired top-down control of the VS by the avPFC during reward rejection. In turn, combination of high adversity and high resilience traits was associated with an improved functional coupling between VTA, VS and HP. Thereby, the present findings identify neural mechanisms mediating interacting effects of adversity and resilience, which could be targeted by early intervention and prevention.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus

Richter

Krämer

Diekhof

et al. 2019

NeuroImage: Clinical

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“…Both AcbSh and OFC were core regions of the mesocorticolimbic dopamine system, and previous studies revealed their synchronized activation during fMRI acquisition in reward processing (Carlson et al, 2011). Contrary to the generally accepted theory that impaired top-down control of frontal-striatum connectivity leads to deficits in schizophrenia (Richter et al, 2015), our study indicates that a reverse bottom-up dysfunction from AcbSh to OFC resulted in the unregulated reward system of MAM rats. Moreover, since the mechanism of rTMS was dopaminergic-involved, and TMS could induce elevation of extracellular dopamine and glutamate in Acb (Zangen and Hyodo, 2002;Aleman, 2013), we suggest that the decreased EC was normalized after early-stage rTMS treatment.…”

Section: Right Acbsh-ofc Ec Was Demonstrated As a Substantial Biomarker In Schizophreniacontrasting

confidence: 72%

Early-Stage Repetitive Transcranial Magnetic Stimulation Altered Posterior–Anterior Cerebrum Effective Connectivity in Methylazoxymethanol Acetate Rats

et al. 2021

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The aim of the current resting-state functional magnetic resonance imaging (fMRI) study was to investigate the potential mechanism of schizophrenia through the posterior–anterior cerebrum imbalance in methylazoxymethanol acetate (MAM) rats and to evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an early-stage intervention. The rats were divided into four groups: the MAM-sham group, vehicle-sham group, MAM-rTMS group, and vehicle-rTMS group. The rTMS treatment was targeted in the visual cortex (VC) in adolescent rats. Granger Causality Analysis (GCA) was used to evaluate the effective connectivity between regions of interest. Results demonstrated a critical right VC–nucleus accumbens (Acb)–orbitofrontal cortex (OFC) pathway in MAM rats; significant differences of effective connectivity (EC) were found between MAM-sham and vehicle-sham groups (from Acb shell to OFC: t = −2.553, p = 0.021), MAM-rTMS and MAM-sham groups (from VC to Acb core: t = −2.206, p = 0.043; from Acb core to OFC: t = 4.861, p < 0.001; from Acb shell to OFC: t = 4.025, p = 0.001), and MAM-rTMS and vehicle-rTMS groups (from VC to Acb core: t = −2.482, p = 0.025; from VC to Acb shell: t = −2.872, p = 0.012; from Acb core to OFC: t = 4.066, p = 0.001; from Acb shell to OFC: t = 3.458, p = 0.004) in the right hemisphere. Results of the early-stage rTMS intervention revealed that right nucleus accumbens played the role as a central hub, and VC was a potentially novel rTMS target region during adolescent schizophrenia. Moreover, the EC of right nucleus accumbens shell and orbitofrontal cortex was demonstrated to be a potential biomarker. To our knowledge, this was the first resting-state fMRI study using GCA to assess the deficits of a visual-reward neural pathway and the effectiveness of rTMS treatment in MAM rats. More randomized controlled trials in both animal models and schizophrenia patients are needed to further elucidate the disease characteristics.

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“…Specifically, prelimbic cortex is implicated in behaviors relevant to negative symptomatology, such as goal-directed behavior (Chudasama et al 2001 ; Killcross and Coutureau 2003 ). Cortico-accumbal inputs play a role in cognitive function, such as working memory and attention, and a recent patient fMRI study showed synchrony deficits between mPFC and accumbens in schizophrenics (French and Totterdell 2003 ; Richter et al 2015 ). Limbic structures including NAc have been hypothesized to underlie some of the behavioral abnormalities in schizophrenia and show abnormalities in patient brain scans (Grace 2000 ; van Erp et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia

et al. 2017

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The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.

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Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia

Cited by 20 publications

References 44 publications

Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus

Resilience to adversity is associated with increased activity and connectivity in the VTA and hippocampus

Early-Stage Repetitive Transcranial Magnetic Stimulation Altered Posterior–Anterior Cerebrum Effective Connectivity in Methylazoxymethanol Acetate Rats

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia

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