Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex.

To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a variant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli determines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al., 2016). This neural population switched their preference for stimuli over the course of the trial depending on whether the stimuli signaled the need to engage cognitive control to override a prepotent response. Cues evoked visual responses that appeared in parietal neurons first, whereas population activity encoding contextual information instructed by cues was stronger and more persistent in PFC. Increasing cognitive control demand biased the representation of contextual information toward the PFC and augmented the temporal correlation of task-defined information encoded by neurons in the two areas. Oscillatory dynamics in local field potentials differed between cortical areas and carried as much information about task conditions as spike rates. We found that, at the single-neuron level, patterns of activity evoked by the task were nearly identical between the two cortical areas. Nonetheless, distinct population dynamics in PFC and parietal cortex were evident. suggesting differential contributions to cognitive control.SIGNIFICANCE STATEMENT We recorded neural activity in PFC and parietal cortex of monkeys performing a task that measures cognitive control deficits in schizophrenia. This allowed us to characterize computations performed by neurons in the two areas to support forms of cognitive control disrupted in the disease. Subpopulations of neurons in the two areas exhibited parallel modulations in firing rate; and as a result, all patterns of task-evoked activity were distributed between PFC and parietal cortex. This included the presence in both cortical areas of neurons reflecting proactive and reactive cognitive control dissociated from stimuli or responses in the task. However, differences in the timing, strength, synchrony, and correlation of information encoded by neural activity were evident, indicating differential contributions to cognitive control.

Comparing the functional neuroanatomy of proactive and reactive control between patients with schizophrenia and healthy controls.

Cognitive control deficits are associated with impaired executive functioning in schizophrenia. The Dual Mechanisms of Control framework suggests that proactive control requires sustained dorsolateral prefrontal activity, whereas reactive control marshals a larger network. However, primate studies suggest these processes are maintained by dual-encoding regions. To distinguish between these theories, we compared the distinctiveness of proactive and reactive control functional neuroanatomy. In a reanalysis of data from a previous study, 47 adults with schizophrenia and 56 controls completed the Dot Pattern Expectancy task during an fMRI scan examining proactive and reactive control in frontoparietal and medial temporal regions. Areas suggesting specialized control or between-group differences were tested for association with symptoms and task performance. Elastic net models additionally explored these areas' predictive abilities regarding performance. Most regions were active in both reactive and proactive control. However, evidence of specialized proactive control was found in the left middle and superior frontal gyri. Control participants showed greater proactive control in the left middle and right inferior frontal gyri. Elastic net models moderately predicted task performance and implicated various frontal gyri regions in control participants, with additional involvement of anterior cingulate and posterior parietal regions for reactive control. Elastic nets for patient participants implicated the inferior and superior frontal gyri, and posterior parietal lobe. Specialized cognitive control was unassociated with either performance or schizophrenia symptomatology. Future work is needed to clarify the distinctiveness of proactive and reactive control, and its role in executive deficits in severe psychopathology.

Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks.

BACKGROUND: Schizophrenia is a disorder characterized by pervasive deficits in cognitive functioning. However, few well-powered studies have examined the degree to which cognitive performance is impaired even among individuals with schizophrenia not currently on antipsychotic medications using a wide range of cognitive and reinforcement learning measures derived from cognitive neuroscience. Such research is particularly needed in the domain of reinforcement learning, given the central role of dopamine in reinforcement learning, and the potential impact of antipsychotic medications on dopamine function. METHODS: The present study sought to fill this gap by examining healthy controls (N = 75), unmedicated (N = 48) and medicated (N = 148) individuals with schizophrenia. Participants were recruited across five sites as part of the CNTRaCS Consortium to complete tasks assessing processing speed, cognitive control, working memory, verbal learning, relational encoding and retrieval, visual integration and reinforcement learning. RESULTS: Individuals with schizophrenia who were not taking antipsychotic medications, as well as those taking antipsychotic medications, showed pervasive deficits across cognitive domains including reinforcement learning, processing speed, cognitive control, working memory, verbal learning and relational encoding and retrieval. Further, we found that chlorpromazine equivalency rates were significantly related to processing speed and working memory, while there were no significant relationships between anticholinergic load and performance on other tasks. CONCLUSIONS: These findings add to a body of literature suggesting that cognitive deficits are an enduring aspect of schizophrenia, present in those off antipsychotic medications as well as those taking antipsychotic medications.

Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia.

The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al., 2012) and used linear multielectrode arrays to record neural activity in the MD and PFC simultaneously. We found that the two structures made clearly different contributions to distributed processing for cognitive control: MD neurons were specialized for decision-making and response selection, whereas prefrontal neurons were specialized to preferentially encode the environmental state on which the decision was based. In addition, we observed that functional coupling between MD and PFC was strongest when the decision as to which of the two responses in the task to execute was being made. These findings delineate unique contributions of MD and PFC to distributed processing for cognitive control and characterized neural dynamics in this network associated with normative cognitive control performance.SIGNIFICANCE STATEMENT Cognitive control is fundamental to healthy human executive functioning (Miller and Cohen, 2001) and deficits in patients with schizophrenia relate to decreased functional activation of the MD thalamus and the prefrontal cortex (Minzenberg et al., 2009), which are reciprocally linked (Goldman-Rakic and Porrino, 1985; Xiao et al., 2009). We carry out simultaneous neural recordings in the MD and PFC while monkeys perform a cognitive control task translated from patients with schizophrenia to relate thalamocortical dynamics to cognitive control performance. Our data suggest that state representation and decision-making computations for cognitive control are preferentially performed by PFC and MD, respectively. This suggests experiments to parse decision-making and state representation deficits in patients while providing novel computational targets for future therapies.

Task-related neural mechanisms of persecutory ideation in schizophrenia and community monozygotic twin-pairs.

Perceptions of spiteful behavior are common, distinct from rational fear, and may undergird persecutory ideation. To test this hypothesis and investigate neural mechanisms of persecutory ideation, we employed a novel economic social decision-making task, the Minnesota Trust Game (MTG), during neuroimaging in patients with schizophrenia (n = 30) and community monozygotic (MZ) twins (n = 38; 19 pairs). We examined distinct forms of mistrust, task-related brain activation and connectivity, and investigated relationships with persecutory ideation. We tested whether co-twin discordance on these measurements was correlated to reflect a common source of underlying variance. Across samples persecutory ideation was associated with reduced trust only during the suspiciousness condition, which assessed spite sensitivity given partners had no monetary incentive to betray. Task-based activation contrasts for specific forms of mistrust were limited and unrelated to persecutory ideation. However, task-based connectivity contrasts revealed a dorsal cingulate anterior insula network sensitive to suspicious mistrust, a left frontal-parietal (lF-P) network sensitive to rational mistrust, and a ventral medial/orbital prefrontal (vmPFC/OFC) network that was sensitive to the difference between these forms of mistrust (all p < .005). Higher persecutory ideation was predicted only by reduced connectivity between the vmPFC/OFC and lF-P networks (p = .005), which was only observed when the intentions of the other player were relevant. Moreover, co-twin differences in persecutory ideation predicted co-twin differences in both spite sensitivity and in vmPFC/OFC-lF-P connectivity. This work found that interconnectivity may be particularly important to the complex neurobiology underlying persecutory ideation, and that unique environmental variance causally linked persecutory ideation, decision-making, and brain connectivity.

Salience and central executive networks track overgeneralization of conditioned-fear in post-traumatic stress disorder.

BACKGROUND: Generalization of conditioned-fear, a core feature of post-traumatic stress disorder (PTSD), has been the focus of several recent neuroimaging studies. A striking outcome of these studies is the frequency with which neural correlates of generalization fall within hubs of well-established functional networks including salience (SN), central executive (CEN), and default networks (DN). Neural substrates of generalization found to date may thus reflect traces of large-scale brain networks that form more expansive neural representations of generalization. The present study includes the first network-based analysis of generalization and PTSD-related abnormalities therein. METHODS: fMRI responses in established intrinsic connectivity networks (ICNs) representing SN, CEN, and DN were assessed during a generalized conditioned-fear task in male combat veterans (N = 58) with wide-ranging PTSD symptom severity. The task included five rings of graded size. Extreme sizes served as conditioned danger-cues (CS+: paired with shock) and safety-cues (CS-), and the three intermediate sizes served as generalization stimuli (GSs) forming a continuum-of-size between CS+ and CS-. Generalization-gradients were assessed as behavioral and ICN response slopes from CS+, through GSs, to CS-. Increasing PTSD symptomatology was predicted to relate to less-steep slopes indicative of stronger generalization. RESULTS: SN, CEN, and DN responses fell along generalization-gradients with levels of generalization within and between SN and CEN scaling with PTSD symptom severity. CONCLUSIONS: Neural substrates of generalized conditioned-fear include large-scale networks that adhere to the functional organization of the brain. Current findings implicate levels of generalization in SN and CEN as promising neural markers of PTSD.

Dynamic reorganization of the frontal parietal network during cognitive control and episodic memory.

Higher cognitive functioning is supported by adaptive reconfiguration of large-scale functional brain networks. Cognitive control (CC), which plays a vital role in flexibly guiding cognition and behavior in accordance with our goals, supports a range of executive functions via distributed brain networks. These networks process information dynamically and can be represented as functional connectivity changes between network elements. Using graph theory, we explored context-dependent network reorganization in 56 healthy adults performing fMRI tasks from two cognitive domains that varied in CC and episodic-memory demands. We examined whole-brain modular structure during the DPX task, which engages proactive CC in the frontal-parietal cognitive-control network (FPN), and the RiSE task, which manipulates CC demands at encoding and retrieval during episodic-memory processing, and engages FPN, the medial-temporal lobe and other memory-related networks in a context dependent manner. Analyses revealed different levels of network integration and segregation. Modularity analyses revealed greater brain-wide integration across tasks in high CC conditions compared to low CC conditions. Greater network reorganization occurred in the RiSE memory task, which is thought to require coordination across multiple brain networks, than in the DPX cognitive-control task. Finally, FPN, ventral attention, and visual systems showed within network connectivity effects of cognitive control; however, these cognitive systems displayed varying levels of network reorganization. These findings provide insight into how brain networks reorganize to support differing task contexts, suggesting that the FPN flexibly segregates during focused proactive control and integrates to support control in other domains such as episodic memory.

Abnormal neural functions associated with motor inhibition deficits in schizophrenia and bipolar disorder.

Deficits in response inhibition have been observed in schizophrenia and bipolar disorder; however, the neural origins of the abnormalities and their relevance to genetic liability for psychosis are unknown. We used a stop-signal task to examine motor inhibition and associated neural processes in schizophrenia patients (n = 57), bipolar disorder patients (n = 21), first-degree biological relatives of patients with schizophrenia (n = 34), and healthy controls (n = 56). Schizophrenia patients demonstrated motor control deficits reflected in longer stop-signal reaction times and elongated reaction times. With the possibility of needing to inhibit a button press, both schizophrenia and bipolar disorder patients showed diminished reductions of the P300 brain response and only the healthy controls demonstrated adjustments in response execution time, as measured by response-locked lateralized readiness potentials. Schizotypal traits in the biological relatives were associated with less P300 modulation consistent with the motor-related anomalies being associated with subtle schizophrenia-spectrum symptomatology in family members. The two patient groups had elongated response selection processes as manifest in the delayed onset of the stimulus-locked lateralized readiness potential. The bipolar disorder group was unique in showing significantly diminished neural responses to the stop-signal to inhibit a response. Antipsychotic medication dosage was related to worse motor inhibition, thus motor inhibition deficits in schizophrenia may be partially explained by the effect of pharmacological agents. Failed modulation of brain processes in relation to response inhibition probability and the lengthening of motor response selection appear to be transdiagnostic abnormalities spanning schizophrenia and bipolar disorder.

Neural signatures underlying deliberation in human foraging decisions.

Humans have a remarkable capacity to mentally project themselves far ahead in time. This ability, which entails the mental simulation of events, is thought to be fundamental to deliberative decision making, as it allows us to search through and evaluate possible choices. Many decisions that humans make are foraging decisions, in which one must decide whether an available offer is worth taking, when compared to unknown future possibilities (i.e., the background). Using a translational decision-making paradigm designed to reveal decision preferences in rats, we found that humans engaged in deliberation when making foraging decisions. A key feature of this task is that preferences (and thus, value) are revealed as a function of serial choices. Like rats, humans also took longer to respond when faced with difficult decisions near their preference boundary, which was associated with prefrontal and hippocampal activation, exemplifying cross-species parallels in deliberation. Furthermore, we found that voxels within the visual cortices encoded neural representations of the available possibilities specifically following regret-inducing experiences, in which the subject had previously rejected a good offer only to encounter a low-valued offer on the subsequent trial.

The goal priority network as a neural substrate of Conscientiousness.

Conscientiousness is a personality trait associated with many important life outcomes, but little is known about the mechanisms that underlie it. We investigated its neural correlates using functional connectivity analysis in fMRI, which identifies brain regions that act in synchrony. We tested the hypothesis that a broad network resembling a combination of the salience and ventral attention networks, which we provisionally label the goal priority network (GPN), is a neural correlate of Conscientiousness. Self- and peer-ratings of Conscientiousness were collected in a community sample of adults who underwent a resting-state fMRI scan (N = 218). An independent components analysis yielded five components that overlapped substantially with the GPN. We examined synchrony within and between these GPN subcomponents. Synchrony within one of the components-mainly comprising regions of anterior insula, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex-was significantly associated with Conscientiousness. Connectivity between this component and the four other GPN components was also significantly associated with Conscientiousness. Our results support the hypothesis that variation in a network that enables prioritization of multiple goals may be central to Conscientiousness.

Monkey Prefrontal Neurons Reflect Logical Operations for Cognitive Control in a Variant of the AX Continuous Performance Task (AX-CPT).

Cognitive control is the ability to modify the behavioral response to a stimulus based on internal representations of goals or rules. We sought to characterize neural mechanisms in prefrontal cortex associated with cognitive control in a context that would maximize the potential for future translational relevance to human neuropsychiatric disease. To that end, we trained monkeys to perform a dot-pattern variant of the AX continuous performance task that is used to measure cognitive control impairment in patients with schizophrenia (MacDonald, 2008;Jones et al., 2010). Here we describe how information processing for cognitive control in this task is related to neural activity patterns in prefrontal cortex of monkeys, to advance our understanding of how behavioral flexibility is implemented by prefrontal neurons in general, and to model neural signals in the healthy brain that may be disrupted to produce cognitive control deficits in schizophrenia. We found that the neural representation of stimuli in prefrontal cortex is strongly biased toward stimuli that inhibit prepotent or automatic responses. We also found that population signals encoding different stimuli were modulated to overlap in time specifically in the case that information from multiple stimuli had to be integrated to select a conditional response. Finally, population signals relating to the motor response were biased toward less frequent and therefore less automatic actions. These data relate neuronal activity patterns in prefrontal cortex to logical information processing operations required for cognitive control, and they characterize neural events that may be disrupted in schizophrenia. SIGNIFICANCE STATEMENT: Functional imaging studies have demonstrated that cognitive control deficits in schizophrenia are associated with reduced activation of the dorsolateral prefrontal cortex (MacDonald et al., 2005). However, these data do not reveal how the disease has disrupted the function of prefrontal neurons to produce the observed deficits in cognitive control. Relating cognitive control to neurophysiological signals at a cellular level in prefrontal cortex is a necessary first step toward understanding how disruption of these signals could lead to cognitive control failure in neuropsychiatric disease. To that end, we translated a task that measures cognitive control deficits in patients with schizophrenia to monkeys and describe here how neural signals in prefrontal cortex relate to performance.

Fronto-temporal connectivity predicts cognitive empathy deficits and experiential negative symptoms in schizophrenia.

Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting-state functional connectivity between data-driven networks, or components (referred to as, inter-component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter-component connectivity at rest using a group-matched schizophrenia and control sample. We then assessed whether inter-component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity-symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter-component connectivity, a medial-fronto-temporal metric and an orbito-fronto-temporal metric were related to cognitive empathy. Moreover, the medial-fronto-temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111-1124, 2017. © 2016 Wiley Periodicals, Inc.

Neuroplastic changes in patients with schizophrenia undergoing cognitive remediation: triple-blind trial.

BackgroundPatients with schizophrenia have shown cognitive improvements following cognitive remediation, but the neuroplastic changes that support these processes are not fully understood.AimsTo use a triple-blind, placebo-controlled trial to examine neural activation before and after cognitive remediation or a computer skills training (CST) placebo (trial registration: NCT00995553)).MethodTwenty-seven participants underwent functional magnetic resonance imaging before and after being randomised to either cognitive remediation intervention or CST. Participants completed two variants of the N-back task during scanning and were assessed on measures of cognition, functional capacity, community functioning and symptoms.ResultsWe observed a group × time interaction in the left prefrontal cortex, wherein the cognitive remediation group showed increased activation. These changes correlated with improved task accuracy within the cognitive remediation group, whereas there was no relationship between changes in activation in untrained cognitive measures. Significant changes were not observed in other hypothesised areas for the cognitive remediation group.ConclusionsWe replicated the finding that cognitive remediation increases left lateral prefrontal activation during a working memory task in patients with schizophrenia, suggesting this may be an important neural target for these types of interventions.

The Web-Surf Task: A translational model of human decision-making.

Animal models of decision-making are some of the most highly regarded psychological process models; however, there remains a disconnection between how these models are used for pre-clinical applications and the resulting treatment outcomes. This may be due to untested assumptions that different species recruit the same neural or psychological mechanisms. We propose a novel human foraging paradigm (Web-Surf Task) that we translated from a rat foraging paradigm (Restaurant Row) to evaluate cross-species decision-making similarities. We examined behavioral parallels in human and non-human animals using the respective tasks. We also compared two variants of the human task, one using videos and the other using photos as rewards, by correlating revealed and stated preferences. We demonstrate similarities in choice behaviors and decision reaction times in human and rat subjects. Findings also indicate that videos yielded more reliable and valid results. The joint use of the Web-Surf Task and Restaurant Row is therefore a promising approach for functional translational research, aiming to bridge pre-clinical and clinical lines of research using analogous tasks.

The neural circuitry supporting goal maintenance during cognitive control: a comparison of expectancy AX-CPT and dot probe expectancy paradigms.

Goal maintenance is an aspect of cognitive control that has been identified as critical for understanding psychopathology according to criteria of the NIMH-sponsored CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and Research Domain Criteria (RDoC) initiatives. CNTRICS proposed the expectancy AX-CPT, and its visual-spatial parallel the dot probe expectancy (DPX), as valid measures of the cognitive and neural processes thought to be relevant for goal maintenance. The goal of this study was to specifically examine the functional neural correlates and connectivity patterns of both goal maintenance tasks in the same subset of subjects to further validate their neural construct validity and clarify our understanding of the nature and function of the neural circuitry engaged by the tasks. Twenty-six healthy control subjects performed both the letter (AX) and dot pattern (DPX) variants of the CPT during fMRI. Behavioral performance was similar between tasks. The 2 tasks engaged the same brain networks including dorsolateral prefrontal cortex (DLPFC) and dorsal parietal regions, supporting their validity as complementary measures of the goal maintenance construct. Interestingly there was greater engagement of the frontal opercular insula region during the expectancy AX-CPT (letter) and greater functional connectivity between the PFC and medial temporal lobe in the DPX (dot pattern). These differences are consistent with differential recruitment of phonological and visual-spatial processes by the two tasks and suggest that additional long-term memory systems may be engaged by the dot probe version.

Characteristics of canonical intrinsic connectivity networks across tasks and monozygotic twin pairs.

Intrinsic connectivity networks (ICNs) are becoming more prominent in the analyses of in vivo brain activity as the field of neurometrics has revealed their importance for augmenting traditional cognitive neuroscience approaches. Consequently, tools that assess the coherence, or connectivity, and morphology of ICNs are being developed to support inferences and assumptions about the dynamics of the brain. Recently, we reported trait-like profiles of ICNs showing reliability over time and reproducibility across different contexts. This study further examined the trait-like and familial nature of ICNs by utilizing two divergent task paradigms in twins. The study aimed to identify stable network phenotypes that exhibited sensitivity to individual differences and external perturbations in task demands. Analogous ICNs were detected in each task and these ICNs showed consistency in morphology and intranetwork coherence across tasks, whereas the ICN timecourse dynamics showed sensitivity to task demands. Specifically, the timecourse of an arm/hand sensorimotor network showed the strongest correlation with the timeline of a hand imitation task, and the timecourse of a language-processing network showed the strongest temporal association with a verb generation task. The area V1/simple visual stimuli network exhibited the most consistency in morphology, coherence, and timecourse dynamics within and across tasks. Similarly, this network exhibited familiality in all three domains as well. Hence, this experiment is a proof of principle that the morphology and coherence of ICNs can be consistent both within and across tasks, that ICN timecourses can be differentially and meaningfully modulated by a task, and that these domains can exhibit familiality.

Common and specific cognitive deficits in schizophrenia: relationships to function.

The goals of the present study were to assess the interrelationships among tasks from the MATRICS and CNTRACS batteries, to determine the degree to which tasks from each battery capture unique variance in cognitive dysfunction in schizophrenia, and to determine the ability of tasks from each battery to predict functional outcome. Subjects were 104 schizophrenia patients and 132 healthy control subjects recruited as part of the CNTRACS initiative. All subjects completed four CNTRACS tasks and two tasks from the MATRICS battery: Brief Assessment of Cognition in Schizophrenia Symbol Coding and the Hopkins Verbal Learning Test. Functional outcome was also assessed in the schizophrenia subjects. In both the patient and control groups, we found significant intercorrelations between all higher order cognitive tasks (episodic memory, goal maintenance, processing speed, verbal learning) but minimal relationships with the visual task. For almost all tasks, scores were significantly related to measures of functional outcome, with higher associations between CNTRACS tasks and performance-based measures of function and between one of the MATRICS tasks and self-reported functioning, relative to the other functioning measures. After regressing out variance shared by other tasks, we continued to observe group differences in performance among task residuals, particularly for measures of episodic memory from both batteries, although these residuals did not correlate as robustly with functional outcome as raw test scores. These findings suggest that there exists both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia.

Value Representations of Spite Sensitivity in Psychosis on the Minnesota Trust Game.

BACKGROUND: Spite sensitivity provides a valuable construct to understand persecutory ideation and its underlying neural mechanisms. We examined the relationship between persecution and spite sensitivity in psychosis to identify their neural substrates. METHODS: In a 3T magnetic resonance imaging scanner, 49 participants with psychosis played the Minnesota Trust Game, in which they decided whether to take a small amount of money or trust a partner to choose between fair and unfair distributions of money. In some conditions, the partner benefited from the unfair option, while in others, the partner lost money. Participants who were untrusting in the second condition (suspiciousness) showed heightened sensitivity to spite. Behavioral measures included mistrust during the 2 conditions of the game, which were compared with Brief Psychiatric Rating Scale persecution and computational modeling. Functional connectivity and blood oxygen level-dependent analyses were also conducted on a priori regions during spite-sensitive decisions. RESULTS: Behavioral results replicated previous findings; participants who experienced more persecutory ideation trusted less, specifically in the suspiciousness condition. Functional connectivity findings showed that decreased connectivity between the orbitofrontal cortex-insula and the left frontoparietal network was associated with increased persecutory ideation and estimated spite-guilt (a marker of spite sensitivity). Additionally, we found differences between conditions in caudate nucleus, medial prefrontal cortex, and lateral orbitofrontal cortex activation. CONCLUSIONS: These findings provide a new perspective on the origin of positive symptoms by identifying primary brain circuits that are related to both spite sensitivity and persecutory ideation.

A Transdiagnostic Study of Effort-Cost Decision-Making in Psychotic and Mood Disorders.

BACKGROUND: Research suggests that effort-cost decision-making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology. HYPOTHESIS: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls. STUDY DESIGN: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview. STUDY RESULTS: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls. CONCLUSIONS: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms.

Dysfunctional Alpha Modulation as a Mechanism of Working Memory Impairment in Serious Mental Illness.

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: first, poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression. METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and memory capacity from the behavioral responses, and we quantified alpha using traditional wavelet analysis as well as a novel approach for isolating oscillatory alpha power from aperiodic elements of the EEG signal. RESULTS: We found that 1) greater prestimulus alpha power estimated using traditional wavelet analysis predicted behavioral errors; 2) poststimulus alpha suppression was reduced in the patient groups; and 3) reduced suppression was associated with a lower likelihood of memory storage. However, we also observed that the prestimulus alpha was larger among healthy control participants than patients, and single-trial analyses showed that it was the aperiodic elements of the prestimulus EEG-not oscillatory alpha-that predicted behavioral errors. DISCUSSION: These results suggest that working memory impairments in serious mental illness primarily reflect an impairment in the poststimulus encoding processes rather than reduced attentional engagement prior to stimulus onset.