Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning

It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS− conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS− condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS− compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS− in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia

Modality-dependent "what" and "where" preparatory processes in auditory and visual systems

The present study examined the modality specificity and spatio-temporal dynamics of "what" and "where" preparatory processes in anticipation of auditory and visual targets using ERPs and a cue-target paradigm. Participants were presented with an auditory (Experiment 1) or a visual (Experiment 2) cue that signaled them to attend to the identity or location of an upcoming auditory or visual target. In both experiments, participants responded faster to the location compared to the identity conditions. Multivariate spatio-temporal partial least square (ST-PLS) analysis of the scalp-recorded data revealed supramodal "where" preparatory processes between 300-600 msec and 600-1200 msec at central and posterior parietal electrode sites in anticipation of both auditory and visual targets. Furthermore, preparation for pitch processing was captured at modality-specific temporal regions between 300 and 700 msec, and preparation for shape processing was detected at occipital electrode sites between 700 and 1150 msec. The spatio-temporal patterns noted above were replicated when a visual cue signaled the upcoming response (Experiment 2). Pitch or shape preparation exhibited modality-dependent spatio-temporal patterns, whereas preparation for target localization was associated with larger amplitude deflections at multimodal, centro-parietal sites preceding both auditory and visual targets. Using a novel paradigm, the study supports the notion of a division of labor in the auditory and visual pathways following both auditory and visual cues that signal identity or location response preparation to upcoming auditory or visual targets

Models of persecutory delusions: a mechanistic insight into the early stages of psychosis

Identifying robust markers for predicting the onset of psychosis has been a key challenge for early detection research. Persecutory delusions are core symptoms of psychosis, and social cognition is particularly impaired in first-episode psychosis patients and individuals at risk for developing psychosis. Here, we propose new avenues for translation provided by hierarchical Bayesian models of behaviour and neuroimaging data applied in the context of social learning to target persecutory delusions. As it comprises a mechanistic model embedded in neurophysiology, the findings of this approach may shed light onto inference and neurobiological causes of transition to psychosis

The co-occurrence of multisensory facilitation and cross-modal conflict in the human brain

Perceptual objects often comprise a visual and auditory signature which arrives simultaneously through distinct sensory channels, and cross-modal features are linked by virtue of being attributed to a specific object. Continued exposure to cross-modal events sets up expectations about what a given object most likely "sounds" like, and vice versa, thereby facilitating object detection and recognition. The binding of familiar auditory and visual signatures is referred to as semantic, multisensory integration. While integration of semantically-related cross-modal features is behaviorally advantageous, situations of sensory dominance of one modality at the expense of another, impairs performance. In the present study, magnetoencephalography recordings of semantically-related cross-modal and unimodal stimuli captured the spatiotemporal patterns underlying multisensory processing at multiple stages. At early stages, 100ms after stimulus onset, posterior parietal brain regions responded preferentially to cross-modal stimuli irrespective of task instructions or the degree of semantic relatedness between the auditory and visual components. As participants were required to classify cross-modal stimuli into semantic categories, activity in superior temporal and posterior cingulate cortices increased between 200 and 400ms. As task instructions changed to incorporate cross-modal conflict, a process whereby auditory and visual components of cross-modal stimuli were compared to estimate their degree of congruence, multisensory processes were captured in parahippocampal, dorsomedial, and orbitofrontal cortices 100 and 400ms after stimulus onset. Our results suggest that multisensory facilitation is associated with posterior parietal activity as early as 100ms after stimulus onset. However, as participants are required to evaluate cross-modal stimuli based on their semantic category or their degree of congruence, multisensory processes extend in cingulate, temporal, and prefrontal cortices

Modality-independent processes in cued motor preparation revealed by cortical potentials

We used event-related potentials (ERPs) in a crossmodal stimulus-response compatibility paradigm to identify modality-independent aspects of rule processing and cued response facilitation. Participants responded to a lateralized target with the ipsilateral (compatible) or contralateral (incompatible) hand. Cue-target modality and cue-target order were manipulated. The cue preceded the target in half of the trials, and the target preceded the cue in the other half. For half of the participants, a visual cue signalled the response rule to an auditory target, while in other half, an auditory cue signalled the response rule to a visual target. Behavioural results showed a significant cue facilitation effect with response times faster for trials when the cue preceded the target, regardless of cue-target modality. The overall fastest response times were obtained in auditory cue-visual target trials. We performed groupwise independent component analysis of the cortical potentials and identified two modality-independent spatiotemporal patterns related to experimental effects. The first pattern, which resembled the early part of a contingent-negative waveform, was associated with response rule processing, regardless of cue-target presentation order and modality. The second pattern showed amplitude modulations that were dependent on stimulus modality. However, this pattern also correlated with faster response times only when the cue preceded the target and regardless of cue-target modality. Source analysis suggested that the response rule processing pattern originated from the posterior parietal, motor and cingulate regions. The pattern associated with the cue-first facilitation effect originated from cingulate and medial frontal regions. The effects carried by both patterns showed temporal overlap in the interval between the first and second stimulus presentation, but with differences in their relation to response rule processing and behavioural facilitation

Translational Perspectives for Computational Neuroimaging

Functional neuroimaging has made fundamental contributions to our understanding of brain function. It remains challenging, however, to translate these advances into diagnostic tools for psychiatry. Promising new avenues for translation are provided by computational modeling of neuroimaging data. This article reviews contemporary frameworks for computational neuroimaging, with a focus on forward models linking unobservable brain states to measurements. These approaches-biophysical network models, generative models, and model-based fMRI analyses of neuromodulation-strive to move beyond statistical characterizations and toward mechanistic explanations of neuroimaging data. Focusing on schizophrenia as a paradigmatic spectrum disease, we review applications of these models to psychiatric questions, identify methodological challenges, and highlight trends of convergence among computational neuroimaging approaches. We conclude by outlining a translational neuromodeling strategy, highlighting the importance of openly available datasets from prospective patient studies for evaluating the clinical utility of computational models

Dopamine-induced changes in neural network patterns supporting aversive conditioning

The aim of the present paper is to assess the effects of altered dopamine (DA) transmission on the functional connectivity among brain regions mediating aversive conditioning in humans. To this aim, we analyzed a previous published data set from a double-blind design combined with functional magnetic resonance imaging (fMRI) recordings in which healthy volunteers were randomly assigned to one of three drug groups: amphetamine (an indirect DA agonist), haloperidol (DA D2 receptor antagonist), and placebo. Participants were exposed to an aversive classical conditioning paradigm using cutaneous electrical stimulation as the unconditioned stimulus (US), and visual cues as the conditioned stimuli (CS) where one colour (CS+) was followed by the US in 33% of the trials and another colour (CS-) had no consequences. All participants reported awareness of stimulus contingencies. Group analysis of fMRI data revealed that the left ventral striatum (VS) and amygdala activated in response to the CS+ in all the three groups. Because of their activation patterns and documented involvement in aversive conditioning, both regions were used as seeds in the functional connectivity analysis. To constrain the functional networks obtained to relate to the conditioned response, we also correlated seed activity with the Galvanic Skin Response (GSR). In the placebo group, the right ventral tegmental area/substantia nigra (VTA/SN), bilateral caudate, right parahippocampal gyrus, left inferior parietal lobule (IPL), bilateral postcentral gyrus, bilateral middle frontal (BA 46), orbitofrontal, and ventromedial prefrontal cortices (PFC, BA 10/11) correlated with the VS and amygdala seeds in response to the CS+ compared to the CS-. Enhancing dopamine transmission via amphetamine was associated with reduced task differences and significant functional connectivity for both CS+ and CS- conditions between the left VS seed and regions modulated by DA, such as the left VTA/SN, right caudate, left amygdala, left middle frontal gyrus (BA 46), and bilateral ventromedial PFC (BA 10). Blocking dopamine transmission via haloperidol was associated with significant functional connectivity across an alternate network of regions including the left amygdala seed and the right insula, the left ACC (BA 24/32), bilateral IPL (BA 40), precuneus (BA 7), post-central gyrus, middle frontal gyrus (BA 46), and supplementary motor area (SMA, BA 6) to the CS+ versus the CS-. These data provide insight into the distinct effects of DA agents on the functional connectivity between striatal, limbic, and prefrontal areas

Neural arbitration between social and individual learning systems

Decision making requires integrating knowledge gathered from personal experiences with advice from others. The neural underpinnings of the process of arbitrating between information sources has not been fully elucidated. In this study, we formalized arbitration as the relative precision of predictions, afforded by each learning system, using hierarchical Bayesian modeling. In a probabilistic learning task, participants predicted the outcome of a lottery using recommendations from a more informed advisor and/or self-sampled outcomes. Decision confidence, as measured by the number of points participants wagered on their predictions, varied with our definition of arbitration as a ratio of precisions. Functional neuroimaging demonstrated that arbitration signals were independent of decision confidence and involved modality-specific brain regions. Arbitrating in favor of self-gathered information activated the dorsolateral prefrontal cortex and the midbrain, whereas arbitrating in favor of social information engaged the ventromedial prefrontal cortex and the amygdala. These findings indicate that relative precision captures arbitration between social and individual learning systems at both behavioral and neural levels

Inflexible social inference in individuals with subclinical persecutory delusional tendencie

It has been suspected that abnormalities in social inference (e.g., learning others’ intentions) play a key role in the formation of persecutory delusions (PD). In this study, we examined the association between subclinical PD and social inference, testing the prediction that proneness to PD is related to altered social inference and beliefs about others’ intentions. We included 151 participants scoring on opposite ends of Freeman’s Paranoia Checklist (PCL). The participants performed a probabilistic advice-taking task with a dynamically changing social context (volatility) under one of two experimental frames. These frames differentially emphasized possible reasons behind unhelpful advice: (i) the adviser’s possible intentions (dispositional frame) or (ii) the rules of the game (situational frame). Our design was thus 2x2 factorial (high vs. low delusional tendencies, dispositional vs. situational frame). We found significant group-by- frame interactions, indicating that in the situational frame high PCL scorers took advice less into account than low scorers. Additionally, high PCL scorers believed more frequently that incorrect advice was delivered intentionally and that such misleading behaviour was directed towards them personally. Overall, our results suggest that social inference in individuals with subclinical PD tendencies is shaped by negative prior beliefs about the intentions of others and is thus less sensitive to the attributional framing of adviser-related information. These findings may help future attempts of identifying individuals at risk for developing psychosis and understanding persecutory delusions in psychosis