Striatal Response to Reward Anticipation as a Biomarker for Schizophrenia and Negative Symptoms: Effects, Test-Retest Reliability, and Stability Across Sites.

BACKGROUND: Ventral striatal hypoactivation during reward anticipation has consistently been observed in patients with schizophrenia. In addition, that hypoactivation has been shown to correlate negatively with negative symptoms, and in particular with apathy. However, little is known about the stability of these results over time and their reliability across different centers. METHODS: In total, 67 patients with schizophrenia (15 females) and 55 healthy controls (13 females) were recruited in 2 centers in Switzerland and Germany. To assess the neural bases of reward anticipation, all participants performed a variant of the Monetary Incentive Delay task while undergoing event-related functional magnetic resonance imaging at baseline and after 3 months. Stability over time was measured using intra-class correlation (ICC(A,1)) and stability between centers was measured with mixed models. RESULTS: Results showed the expected ventral striatal hypoactivation in patients compared to controls during reward anticipation. We showed that these results were stable across centers. The primary analysis did not reveal an effect of time. Test-retest reliability was moderate for controls, and poor for patients. We did not find an association between ventral striatal hypoactivation and negative symptoms in patients. CONCLUSIONS: Our results align with the hypothesis that ventral striatal activation is related to modulation of motivational saliency during reward anticipation. They also confirm that patients with schizophrenia show impaired reward anticipation. However, the poor test-retest reliability and the absence of an association with symptoms suggests that further research is needed before ventral striatal activity can be used as a biomarker on the individual patient level.

Adaptive coding of reward in schizophrenia, its change over time and relation to apathy.

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range, and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears affected in different domains, and in the reward domain in particular. Here we tested adaptive coding of reward in a large group of patients with schizophrenia (N = 86) and controls (N = 66). We assessed 1) the association between adaptive coding deficits and symptoms; 2) the longitudinal stability of deficits (the same task was performed three months apart); 3) the stability of results between two experimental sites. We used fMRI and the Monetary Incentive Delay task to assess participant' adaptation to two different reward ranges: a narrow and a wide range. We used a region of interest analysis, evaluating adaptation within striatal and visual regions. Patients and controls underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, due to a decreased slope in the narrow reward range, with respect to that of control participants in striatal but not visual regions. This pattern was observed at both research sites. Upon re-test, patients increased their narrow range slopes, showing improved adaptive coding, whereas controls slightly reduced them. At re-test, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal a practice effect in patients, leading to improvement, with steeper slopes upon retest. However, in some patients, an overly steep slope may result in poor discriminability of larger rewards, due to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (re-test, overadaptation) situations may contribute to the multiple motivational symptoms in schizophrenia.

Striatal Functional Hypoconnectivity in Patients With Schizophrenia Suffering From Negative Symptoms, Longitudinal Findings.

BACKGROUND: Negative symptoms in schizophrenia (SZ), such as apathy and diminished expression, have limited treatments and significantly impact daily life. Our study focuses on the functional division of the striatum: limbic-motivation and reward, associative-cognition, and sensorimotor-sensory and motor processing, aiming to identify potential biomarkers for negative symptoms. STUDY DESIGN: This longitudinal, 2-center resting-state-fMRI (rsfMRI) study examines striatal seeds-to-whole-brain functional connectivity. We examined connectivity aberrations in patients with schizophrenia (PwSZ), focusing on stable group differences across 2-time points using intra-class-correlation and associated these with negative symptoms and measures of cognition. Additionally, in PwSZ, we used negative symptoms to predict striatal connectivity aberrations at the baseline and used the striatal aberration to predict symptoms 9 months later. STUDY RESULTS: A total of 143 participants (77 PwSZ, 66 controls) from 2 centers (Berlin/Geneva) participated. We found sensorimotor-striatum and associative-striatum hypoconnectivity. We identified 4 stable hypoconnectivity findings over 3 months, revealing striatal-fronto-parietal-cerebellar hypoconnectivity in PwSZ. From those findings, we found hypoconnectivity in the bilateral associative striatum with the bilateral paracingulate-gyrus and the anterior cingulate cortex in PwSZ. Additionally, hypoconnectivity between the associative striatum and the superior frontal gyrus was associated with lower cognition scores in PwSZ, and weaker sensorimotor striatum connectivity with the superior parietal lobule correlated negatively with diminished expression and could predict symptom severity 9 months later. CONCLUSIONS: Importantly, patterns of weaker sensorimotor striatum and superior parietal lobule connectivity fulfilled the biomarker criteria: clinical significance, reflecting underlying pathophysiology, and stability across time and centers.

Comparing adaptive coding of reward in bipolar I disorder and schizophrenia.

Deficits in neural processing of reward have been described in both bipolar disorder (BD) and schizophrenia (SZ), but it remains unclear to what extent these deficits are caused by similar mechanisms. Efficient reward processing relies on adaptive coding which allows representing large input spans by limited neuronal encoding ranges. Deficits in adaptive coding of reward have previously been observed across the SZ spectrum and correlated with total symptom severity. In the present work, we sought to establish whether adaptive coding is similarly affected in patients with BD. Twenty-five patients with BD, 27 patients with SZ and 25 healthy controls performed a variant of the Monetary Incentive Delay task during functional magnetic resonance imaging in two reward range conditions. Adaptive coding was impaired in the posterior part of the right caudate in BD and SZ (trend level). In contrast, BD did not show impaired adaptive coding in the anterior caudate and right precentral gyrus/insula, where SZ showed deficits compared to healthy controls. BD patients show adaptive coding deficits that are similar to those observed in SZ in the right posterior caudate. Adaptive coding in BD appeared more preserved as compared to SZ participants especially in the more anterior part of the right caudate and to a lesser extent also in the right precentral gyrus. Thus, dysfunctional adaptive coding could constitute a fundamental deficit in severe mental illnesses that extends beyond the SZ spectrum.

Adaptive coding occurs in object categorization and may not be associated with schizotypal personality traits.

Processing more likely inputs with higher sensitivity (adaptive coding) enables the brain to represent the large range of inputs coming in from the world. Healthy individuals high in schizotypy show reduced adaptive coding in the reward domain but it is an open question whether these deficits extend to non-motivational domains, such as object categorization. Here, we develop a novel variant of a classic task to test range adaptation for face/house categorization in healthy participants on the psychosis spectrum. In each trial of this task, participants decide whether a presented image is a face or a house. Images vary on a face-house continuum and appear in both wide and narrow range blocks. The wide range block includes most of the face-house continuum (2.50-97.5% face), while the narrow range blocks limit inputs to a smaller section of the continuum (27.5-72.5% face). Adaptive coding corresponds to better performance for the overlapping smaller section of the continuum in the narrow range than in the wide range block. We find that participants show efficient use of the range in this task, with more accurate responses in the overlapping section for the narrow range blocks relative to the wide range blocks. However, we find little evidence that range adaptation in our object categorization task is reduced in healthy individuals scoring high on schizotypy. Thus, reduced range adaptation may not be a domain-general feature of schizotypy.

Self-monitoring in schizophrenia: Weighting exteroceptive visual signals against self-generated vestibular cues.

Disturbances in self-monitoring are core symptoms of schizophrenia. Some research suggests an over-reliance on exteroceptive cues and a reduced weighting of self-generated interoceptive signals to guide perception. The vestibular sense provides important self-generated information about the body in space. Alterations of vestibular function are reported in schizophrenia, but it is unknown whether internally generated vestibular information is discounted in favour of exteroceptive input. In this study, we test for evidence of an over-reliance on exteroceptive visual cues and a reduced weighting of vestibular signals in guiding perception. In a group of individuals with schizophrenia and healthy controls, we used a well-studied visual illusion - the Tilt Illusion - to probe the respective weight given to visual and vestibular cues in judging line orientation. The Tilt Illusion reveals that perceived orientation of a vertical grating is biased by the orientation in its surround. This illusion increases when the head is tilted, due to the reduced reliability of vestibular information that would otherwise provide an internally generated reference for vertical. We predicted that an over-reliance on exteroceptive cues in schizophrenia would lead to a reduced susceptibility to the effects of head position on Tilt Illusion strength. We find no difference between patients and controls. Both groups show comparable Tilt Illusion magnitudes that increase when the head is tilted. Thus, our findings suggest that chronic patients with schizophrenia adequately combine self-generated vestibular cues and exteroceptive visual input to judge line verticality. A stronger reliance on exteroceptive information over internally generated signals in guiding perception is not evident in our data. Deficits in self-monitoring might therefore be modality specific or state dependant.

Agency Deficits in a Human Genetic Model of Schizophrenia: Insights From 22q11DS Patients.

Schizophrenia is a chronic and disabling mental illness characterized by a disordered sense of self. Current theories suggest that deficiencies in the sense of control over one's actions (Sense of Agency, SoA) may underlie some of the symptoms of schizophrenia. However, it is not clear if agency deficits are a precursor or a result of psychosis. Here, we investigated full body agency using virtual reality in a cohort of 22q11 deletion syndrome participants with a genetic propensity for schizophrenia. In two experiments employing virtual reality, full body motion tracking, and online feedback, we investigated SoA in two separate domains. Our results show that participants with 22q11DS had a considerable deficit in monitoring their actions, compared to age-matched controls in both the temporal and spatial domain. This was coupled with a bias toward erroneous attribution of actions to the self. These results indicate that nonpsychotic 22q11DS participants have a domain general deficit in the conscious sensorimotor mechanisms underlying the bodily self. Our data reveal an abnormality in the SoA in a cohort with a genetic predisposition for schizophrenia, but without psychosis, providing evidence that deficits in delineation of the self may be a precursor rather than a result of the psychotic state.

Associations Between Negative Symptoms and Effort Discounting in Patients With Schizophrenia and Major Depressive Disorder.

Deficits in goal-directed decision making and motivation are hallmark characteristics of several neuropsychiatric disorders, including schizophrenia (SZ) and major depressive disorder (MDD). Studies using effort-based decision-making tasks have shown that both patients with SZ and MDD invest less physical effort in order to obtain rewards. However, how these motivational deficits relate to clinically assessed symptom dimensions such as apathy remains controversial. Using a grip-strength-based effort discounting task we assessed effort-based decision-making behavior in healthy controls (HC) (N = 18), patients with SZ (N = 42), and MDD (N = 44). We then investigated how effort discounting relates to different symptom dimensions. There were no differences in effort discounting between HC participants and patients with SZ or MDD. In addition, we did not observe a correlation between effort discounting and negative symptoms (NS) in patients with SZ or MDD. In conclusion, the current study does not support an association between effort discounting and NS in SZ or MDD. Further studies are needed to investigate effort discounting and its relation to psychopathological dimensions across different neuropsychiatric disorders.

How far to go in deconstructing negative symptoms? Behavioural and neural level evidence for the amotivation domain.

Negative symptoms in schizophrenia are conceptualised as loading onto two factors: amotivation and diminished expression, which relate to different behavioural and neural markers. This distinction has proven useful for understanding the cognitive, motivational and neural mechanisms involved in negative symptoms, and for the development of treatments. Recently, it has been advocated that an even finer distinction into five subdomains is needed to understand the mechanisms underlying negative symptoms, and to prevent masking specific treatment and intervention effects. However, it is currently unclear whether such a fine-grained approach offers additional insights grounded in theory. In the present work, we focused on the factor amotivation, which has been shown to selectively correlate with the propensity to discount rewards in the face of effort and with the activity in the ventral striatum during reward anticipation. In a reanalysis of these studies we explored whether subdomains of amotivation - avolition, asociality, anhedonia - showed preferential correlation with these previously identified behavioural and neural markers. We show that for both behavioural and neural markers, a fine-grained model with the three subdomains did not better explain the data than a model with the amotivation factor only. Moreover, none of the three subdomains correlated significantly more or less with the behavioural or neural markers. Thus, no additional information was gained on amotivation in schizophrenia by selectively looking at its three subdomains. Consequently, the two-factor solution currently remains a valid option for the study of negative symptoms and further research is needed for behavioural and neural validation of the five-factor model.

Clinical, behavioural and neural validation of the PANSS amotivation factor.

Negative symptoms in schizophrenia have been suggested to map onto two distinct factors - amotivation and diminished expression. Only recently, two-factor solutions for measuring negative symptoms have been proposed for the Positive and Negative Symptom Scale (PANSS), the most commonly used scale to assess the psychopathology of patients with schizophrenia. We aimed to validate the PANSS two-factor structure on a clinical, behavioural and neural level. For this multi-level validation, we reanalysed several datasets with patients for whom both the Brief Negative Symptom Assessment Scale (BNSS) and PANSS data were collected. We used a clinical dataset (n = 120) as well as behavioural data from an effort-based decision making task (n = 31) and functional neuroimaging data from a monetary incentive delay task (n = 41). Both tasks have previously been shown to be associated with BNSS amotivation. On the clinical level, the PANSS amotivation and diminished expression were highly correlated with their BNSS counterparts. On the behavioural level, we found that the PANSS amotivation factor but not the diminished expression factor specifically associated with willingness to invest effort to obtain a reward. On the neural level, PANSS amotivation was specifically related to reduced ventral striatal activation during reward anticipation. Our data confirm that the PANSS clearly allows distinguishing amotivation from diminished expression, as it relates selectively to specific aspects of behaviour and brain function. Our results will allow a re-analysis and sharing of existing datasets that used the PANSS to further substantiate the distinction between the two factors in neuroscientific studies and clinical trials.

Examining motion speed processing in schizophrenia using the flash lag illusion.

Research on visual perception in schizophrenia suggests a deficit in motion processing. Specifically, difficulties with discriminating motion speed are commonly reported. However, speed discrimination tasks typically require participants to make judgments about the difference between two stimuli in a two-interval forced choice (2IFC) task. Such tasks not only tap into speed processing mechanisms, but also rely on higher executive functioning including working memory and attention which has been shown to be compromised in schizophrenia. We used the Flash Lag illusion to examine speed processing in patients with schizophrenia. Based on previous research showing a strong dependence between motion speed and the illusion magnitude, we expected a deficit in speed processing to alter this relationship. A motion processing deficit in patients would also predict overall reductions in perceived lag. We found the magnitude and speed dependence of the Flash Lag illusion to be similar in patients and controls. Together, the findings suggest no general abnormality in motion speed processing in schizophrenia.

Differential effects of vestibular processing on orienting exogenous and endogenous covert visual attention.

Recent research highlights the overwhelming role of vestibular information for higher order cognition. Central to body perception, vestibular cues provide information about self-location in space, self-motion versus object motion, and modulate the perception of space. Surprisingly, however, little research has dealt with how vestibular information combines with other senses to orient one's attention in space. Here we used passive whole body rotations as exogenous (Experiment 1) or endogenous (Experiment 2) attentional cues and studied their effects on orienting visual attention in a classical Posner paradigm. We show that-when employed as an exogenous stimulus-rotation impacts attention orienting only immediately after vestibular stimulation onset. However, when acting as an endogenous stimulus, vestibular stimulation provides a robust benefit to target detection throughout the rotation profile. Our data also demonstrate that vestibular stimulation boosts attentional processing more generally, independent of rotation direction, associated with a general improvement in performance. These data provide evidence for distinct effects of vestibular processing on endogenous and exogenous attention as well as alertness that differ with respect to the temporal dynamics of the motion profile. These data reveal that attentional spatial processing and spatial body perception as manipulated through vestibular stimulation share important brain mechanisms.

No evidence for abnormal priors in early vision in schizophrenia.

The predictive coding account of psychosis postulates the abnormal formation of prior beliefs in schizophrenia, resulting in psychotic symptoms. One domain in which priors play a crucial role is visual perception. For instance, our perception of brightness, line length, and motion direction are not merely based on a veridical extraction of sensory input but are also determined by expectation (or prior) of the stimulus. Formation of such priors is thought to be governed by the statistical regularities within natural scenes. Recently, the use of such priors has been attributed to a specific set of well-documented visual illusions, supporting the idea that perception is biased toward what is statistically more probable within the environment. The Predictive Coding account of psychosis proposes that patients form abnormal representations of statistical regularities in natural scenes, leading to altered perceptual experiences. Here we use classical vision experiments involving a specific set of visual illusions to directly test this hypothesis. We find that perceptual judgments for both patients and control participants are biased in accordance with reported probability distributions of natural scenes. Thus, despite there being a suggested link between visual abnormalities and psychotic symptoms in schizophrenia, our results provide no support for the notion that altered formation of priors is a general feature of the disorder. These data call for a refinement in the predictions of quantitative models of psychosis.

Contradiction processing in schizophrenia.

INTRODUCTION: Patients with schizophrenia present clinically with difficulties in manipulating contradictory information in the form of loose associations, surface contradictions and delusional beliefs. It is to date unclear whether patients can detect and process information that contradicts their beliefs and prior knowledge and whether this capacity is related to their symptoms and the nature of contradictory stimuli (e.g., personally significant information, emotional information). METHODS: We probed contradiction processing in patients with schizophrenia and healthy controls using sentence verification tasks that involve self-referential judgements (Experiment 1) and general knowledge (Experiment 2), while manipulating the emotional content of the stimuli. RESULTS: We found no differences between patients and controls either on reaction time (Experiment 1 & 2) or accuracy measures (Experiment 1). CONCLUSIONS: Our results show no general impairment in contradiction processing in schizophrenia. Rather, failures to detect and correct contradictions in symptoms such as formal though disorder or delusions could arise through a complex interplay between executive dysfunctions, stress and the emotional content of the information.

Optimal visuo-vestibular integration for self-motion perception in patients with unilateral vestibular loss.

Unilateral vestibular loss (UVL) is accompanied by deficits in processing of visual and vestibular self-motion cues. The present study examined whether multisensory integration of these two types of information is, nevertheless, intact in such patients. Patients were seated on a rotating platform with a screen simulating 3D rotation in front of them and asked to judge the relative magnitude of two successive rotations in the yaw plane in three conditions: vestibular stimulation, visual stimulation and bimodal stimulation (congruent stimuli from both modalities together). Similar to findings in healthy controls, UVL patients exhibited optimal multisensory integration during both ipsi- and contralesional rotations. The benefit of multisensory integration was more pronounced on the ipsilesional side. These results show that visuo-vestibular integration for passive self-motion is automatic and suggests that it functions without additional cognitive mechanisms, unlike more complex multisensory tasks such as postural control and spatial navigation, previously shown to be impaired in UVL patients.

Rethinking Body Ownership in Schizophrenia: Experimental and Meta-analytical Approaches Show no Evidence for Deficits.

Schizophrenia is a severe psychiatric disorder, in which patients experience an abnormal sense of self. While deficits in sensorimotor self-representation (agency) are well documented in schizophrenia, less is known about other aspects of bodily self-representation (body ownership). Here, we tested a large cohort (N = 59) of chronic schizophrenia patients and matched controls (N = 30) on a well-established body illusion paradigm, the Full Body Illusion (FBI). In this paradigm, changes in body ownership are induced through prolonged multisensory stimulation, in which participants are stroked on their back while seeing the stroking on the back of a virtual body. When the felt and seen stroking are synchronous, participants typically feel higher identification with the seen body as well as a drift in self-location towards it. However, when the stroking is asynchronous, no such changes occur. Our results show no evidence for abnormal body ownership in schizophrenia patients. A meta-analysis of previous work corroborates this result. Thus, while schizophrenia patients may be impaired in the sense of agency, their multisensory bodily self-representation, as tested here, seems to be unaffected by the illness.

Interoceptive signals impact visual processing: Cardiac modulation of visual body perception.

Multisensory perception research has largely focused on exteroceptive signals, but recent evidence has revealed the integration of interoceptive signals with exteroceptive information. Such research revealed that heartbeat signals affect sensory (e.g., visual) processing: however, it is unknown how they impact the perception of body images. Here we linked our participants' heartbeat to visual stimuli and investigated the spatio-temporal brain dynamics of cardio-visual stimulation on the processing of human body images. We recorded visual evoked potentials with 64-channel electroencephalography while showing a body or a scrambled-body (control) that appeared at the frequency of the on-line recorded participants' heartbeat or not (not-synchronous, control). Extending earlier studies, we found a body-independent effect, with cardiac signals enhancing visual processing during two time periods (77-130 ms and 145-246 ms). Within the second (later) time-window we detected a second effect characterised by enhanced activity in parietal, temporo-occipital, inferior frontal, and right basal ganglia-insula regions, but only when non-scrambled body images were flashed synchronously with the heartbeat (208-224 ms). In conclusion, our results highlight the role of interoceptive information for the visual processing of human body pictures within a network integrating cardio-visual signals of relevance for perceptual and cognitive aspects of visual body processing.

Multisensory effects on somatosensation: a trimodal visuo-vestibular-tactile interaction.

Vestibular information about self-motion is combined with other sensory signals. Previous research described both visuo-vestibular and vestibular-tactile bilateral interactions, but the simultaneous interaction between all three sensory modalities has not been explored. Here we exploit a previously reported visuo-vestibular integration to investigate multisensory effects on tactile sensitivity in humans. Tactile sensitivity was measured during passive whole body rotations alone or in conjunction with optic flow, creating either purely vestibular or visuo-vestibular sensations of self-motion. Our results demonstrate that tactile sensitivity is modulated by perceived self-motion, as provided by a combined visuo-vestibular percept, and not by the visual and vestibular cues independently. We propose a hierarchical multisensory interaction that underpins somatosensory modulation: visual and vestibular cues are first combined to produce a multisensory self-motion percept. Somatosensory processing is then enhanced according to the degree of perceived self-motion.

Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration.

Out-of-body experiences (OBEs) are illusory perceptions of one's body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient's behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient's symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs.