Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia

Beliefs—attitudes toward some state of the environment—guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia

The Dopamine D2-like Receptor: At the Nexus Between Self-Control and Addiction

Addictions are multi-dimensional disorders, consisting of several behavioral, affective and cognitive dysfunctions that contribute to the compulsive and persistent drug-seeking and taking that is common to them. Cognitive control, which includes the ability to flexibly and adaptively inhibit undesirable actions (including drug-seeking), is a particularly relevant dimension of addiction, with deficits in cognitive control occurring in response to experience with drugs of abuse, as well as predicting the susceptibility for future drug-taking behaviors. The bi-directional relationship between cognitive control and substance dependence raises the possibility that these processes are governed by a common neural circuitry and emerging evidence indicates that the dopamine D2-like receptor system may be the point of convergence of these phenomena. To determine the influence of the dopamine D2-like receptor system on cognitive control processes within the context of addictions, neuroimaging, behavioral and biochemical techniques were used to interrogate how naturally occurring and drug-induced variation in D2-like receptor system may alter cognitive-control processes. Individual differences in D2-like receptor availability, assessed with positron emission tomography, was positively related to adaptive responding following the reversal of stimulus-reward contingencies and to the sensitivity of individuals to positive feedback. Exposure to an escalating dose regimen of methamphetamine reduced D2-like receptor availability, and the degree of D2-like receptor dysfunction was correlated with the change in positive-feedback sensitivity. Cross-dimensional measurement of the D2-like receptor systems using in vivo and in vitro techniques provided evidence that deviations in D2-like receptor availability reflected actions on functionally and behaviorally relevant pools of D2-like receptors. Finally, evidence supporting the utility of spontaneous eye blink rate as a non-invasive measure of D2-like receptors was obtained from studies of rodents. These studies provide converging support, at multiple levels of analyses, that the D2-like receptor is a common molecular determinant of addiction and cognitive control, providing a mechanistic explanation for the bi-directional relationship between these processes

Author response: Paranoia as a deficit in non-social belief updating

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Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex

Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits

Paranoia and Belief Updating During a Crisis

The 2019 coronavirus (COVID-19) pandemic has made the world seem unpredictable. During such crises we can experience concerns that others might be against us, culminating perhaps in paranoid conspiracy theories. Here, we investigate paranoia and belief updating in an online sample (N=1,010) in the United States of America (U.S.A). We demonstrate the pandemic increased individuals’ self-rated paranoia and rendered their task-based belief updating more erratic. Local lockdown and reopening policies, as well as culture more broadly, markedly influenced participants’ belief-updating: an early and sustained lockdown rendered people’s belief updating less capricious. Masks are clearly an effective public health measure against COVID-19. However, state-mandated mask wearing increased paranoia and induced more erratic behaviour. Remarkably, this was most evident in those states where adherence to mask wearing rules was poor but where rule following is typically more common. This paranoia may explain the lack of compliance with this simple and effective countermeasure. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable, but at the same time predicted more rewards. In a follow-up study we found people who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines – again, mask attitude and conspiratorial beliefs were associated with erratic task behaviour and changed priors. Future public health responses to the pandemic might leverage these observations, mollifying paranoia and increasing adherence by tempering people’s expectations of other’s behaviour, and the environment more broadly, and reinforcing compliance