Risk for midlife psychosis in women: critical gaps and opportunities in exploring perimenopause and ovarian hormones as mechanisms of risk.

Women show a heightened risk for psychosis in midlife that is not observed in men. The menopausal transition (i.e. perimenopause) and accompanying changes in ovarian hormones are theorized to account for this midlife increase in risk. This narrative review aims to empirically examine these theories by reviewing studies of midlife and perimenopausal psychosis risk in women and potential ovarian hormone mechanisms of effects. Clinical and pre-clinical studies examining the effects of midlife age, menopausal stage, and ovarian hormones across adulthood on psychosis risk were identified. Synthesis of this body of work revealed that the peak ages of midlife psychosis risk in women overlap with the age range of key menopausal stages (especially the perimenopausal transition), although studies directly assessing menopausal stage are lacking. Studies examining ovarian hormone effects have almost exclusively focused on earlier developmental stages and events (e.g. pregnancy, the menstrual cycle) and show increases in psychotic symptoms in women and female rats during periods of lower estradiol levels. Estrogen treatment also tends to enhance the effects of neuroleptics in females across species at various reproductive phases. Initial data are promising in suggesting a role for menopausal stage and ovarian hormones in psychosis risk. However, critical gaps in our knowledge base remain, as there is a tendency to rely on indirect and proxy measures of menopausal status and hormones. Opportunities for future research are discussed with the goal of increasing research in this critical area of women's health.

Variables influencing conditioning-evoked hallucinations: overview and future applications.

Hallucinations occur in the absence of sensory stimulation and result in vivid perceptual experiences of nonexistent events that manifest across a range of sensory modalities. Approaches from the field of experimental and cognitive psychology have leveraged the idea that associative learning experiences can evoke conditioning-induced hallucinations in both animals and humans. In this review, we describe classical and contemporary findings and highlight the variables eliciting these experiences. We also provide an overview of the neurobiological mechanisms, along with the associative and computational factors that may explain hallucinations that are generated by representation-mediated conditioning phenomena. Through the integration of animal and human research, significant advances into the psychobiology of hallucinations are possible, which may ultimately translate to more effective clinical applications.

Oculomotor corollary discharge signaling is related to repetitive behavior in children with autism spectrum disorder.

Corollary discharge (CD) signals are "copies" of motor signals sent to sensory regions that allow animals to adjust sensory consequences of self-generated actions. Autism spectrum disorder (ASD) is characterized by sensory and motor deficits, which may be underpinned by altered CD signaling. We evaluated oculomotor CD using the blanking task, which measures the influence of saccades on visual perception, in 30 children with ASD and 35 typically developing (TD) children. Participants were instructed to make a saccade to a visual target. Upon saccade initiation, the presaccadic target disappeared and reappeared to the left or right of the original position. Participants indicated the direction of the jump. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of the presaccadic target and use it to inform perception. We used multilevel modeling to examine the influence of saccade landing site on trans-saccadic perceptual judgements. We found that, compared with TD participants, children with ASD were more sensitive to target displacement and less reliant on saccade landing site when spatial uncertainty of the post-saccadic target was high. This pattern was driven by ASD participants with less severe restricted and repetitive behaviors. These results suggest a relationship between altered CD signaling and core ASD symptoms.

Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia.

By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals-"copies" of motor signals sent to sensory areas-permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD-FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD-FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD-FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.SIGNIFICANCE STATEMENT People with schizophrenia sometimes experience abnormalities in a sense of agency, which may stem from abnormal sensory predictions about their own actions. Consistent with this notion, the current study found reduced structural connectivity in patients with schizophrenia in a specific brain pathway found to transmit such sensorimotor prediction signals in nonhuman primates. Reduced structural connectivity was correlated with behavioral evidence for impaired sensorimotor predictions and psychotic symptoms.

Disrupted Saccadic Corollary Discharge in Schizophrenia.

Disruptions in corollary discharge (CD), motor signals that send information to sensory areas and allow for prediction of sensory states, are argued to underlie the perceived loss of agency in schizophrenia. Behavioral and neurophysiological evidence for CD in primates comes largely from the saccadic double-step task, which requires participants to make two visually triggered saccadic eye movements in brief succession. Healthy individuals use CD to anticipate the change in eye position resulting from the first saccade when preparing the second saccade. In the current study with human participants, schizophrenia patients and healthy controls of both sexes performed a modified double-step task. Most trials required a saccade to a single visual target (T1). On a subset of trials, a second target (T2) was flashed shortly following T1. Subjects were instructed to look directly at T2. Healthy individuals also use CD to make rapid, corrective responses following erroneous saccades to T1. To assess CD in schizophrenia, we examined the following on error trials: (1) frequency and latency of corrective saccades, and (2) mislocalization of the corrective (second) saccade in the direction predicted by a failure to use CD to account for the first eye movement. Consistent with disrupted CD, patients made fewer and slower error corrections. Importantly, the corrective saccade vector angle was biased in a manner consistent with disrupted CD. These results provide novel and clear evidence for dysfunctional CD in the oculomotor system in patients with schizophrenia. Based on neurophysiology work, these disturbances might have their basis in medial thalamus dysfunction. SIGNIFICANCE STATEMENT: According to the World Health Organization, acute schizophrenia carries more disability weight than any other disease, but its etiology remains unknown. One promising theory of schizophrenia highlights alterations in a sense of self, in which self-generated thoughts or actions are attributed externally. Disruptions in corollary discharge (CD), motor signals sent to sensory areas that allow for the prediction of impending sensations, are proposed to underlie these symptoms. Direct physiological evidence, however, is limited. In nonhuman primates, inactivation of mediodorsal thalamic neurons disrupts CD associated with eye movements. Using the same task, we show similar impairments in schizophrenia patients, consistent with disrupted CD. These findings allow us to link clinical phenomenology to primate neurophysiology and interpret findings within a biological framework.

Speed of saccade execution and inhibition associated with fractional anisotropy in distinct fronto-frontal and fronto-striatal white matter pathways.

Fast cancellation or switching of action plans is a critical cognitive function. Rapid signal transmission is key for quickly executing and inhibiting responses, and the structural integrity of connections between brain regions plays a crucial role in signal transmission speed. In this study, we used the search-step task, which has been used in nonhuman primates to measure dynamic alteration of saccade plans, in combination with functional and diffusion-weighted MRI. Functional MRI results were used to identify brain regions involved in the reactive control of gaze. Probabilistic tractography was used to identify white matter pathways connecting these structures, and the integrity of these connections, as indicated by fractional anisotropy (FA), was correlated with search-step task performance. Average FA from tracts between the right frontal eye field (FEF) and both right supplementary eye field (SEF) and the dorsal striatum were associated with faster saccade execution. Average FA of connections between the dorsal striatum and both right SEF and right inferior frontal cortex (IFC) as well as between SEF and IFC predicted the speed of inhibition. These relationships were largely behaviorally specific, despite the correlation between saccade execution and inhibition. Average FA of connections between the IFC and both SEF and the dorsal striatum specifically predicted the speed of inhibition, and connections between the FEF and SEF specifically predicted the speed of execution. In addition, these relationships were anatomically specific; correlations were observed after controlling for global FA. These data suggest that networks supporting saccade initiation and inhibition are at least partly dissociable. Hum Brain Mapp 37:2811-2822, 2016. © 2016 Wiley Periodicals, Inc.

Frontal-subcortical circuits involved in reactive control and monitoring of gaze.

Rapid and reactive control of movement is essential in a dynamic environment and is disrupted in several neuropsychiatric disorders. Nonhuman primate neurophysiology studies have made significant contributions to our understanding of how saccadic eye movements can be rapidly inhibited, changed, and monitored. These results highlight a frontostriatal network involved in gaze control and provide a strong basis for understanding how cognitive control of action is implemented in the human brain. The goal of the present study was to bridge human and nonhuman primate studies by investigating reactive control of eye movements during fMRI using a task that has been used in neurophysiology studies: the search-step task. This task requires a speeded response to a visual target (no-step trial). On a minority (40%) of trials, the target jumps to a new location and participants are instructed to inhibit the initially planned saccade and redirect gaze toward the new location (redirect trial). Compared with no-step trials, greater activation in a frontal oculomotor network, including frontal and supplementary eye fields (SEFs), and the striatum was observed during correctly executed redirect trials. Individual differences in stopping efficiency were related to striatal activation. Further, greater activation in SEF was in a region anterior to that activated during visually guided saccades and scaled positively with error magnitude, suggesting a prominent role in response monitoring. Combined, these data lend new evidence for a role of the striatum in reactive saccade control and further clarify the role of SEF in action inhibition and performance monitoring.

Failure to use corollary discharge to remap visual target locations is associated with psychotic symptom severity in schizophrenia.

Corollary discharge (CD) refers to "copies" of motor signals sent to sensory areas, allowing prediction of future sensory states. They enable the putative mechanisms supporting the distinction between self-generated and externally generated sensations. Accordingly, many authors have suggested that disturbed CD engenders psychotic symptoms of schizophrenia, which are characterized by agency distortions. CD also supports perceived visual stability across saccadic eye movements and is used to predict the postsaccadic retinal coordinates of visual stimuli, a process called remapping. We tested whether schizophrenia patients (SZP) show remapping disturbances as evidenced by systematic transsaccadic mislocalizations of visual targets. SZP and healthy controls (HC) performed a task in which a saccadic target disappeared upon saccade initiation and, after a brief delay, reappeared at a horizontally displaced position. HC judged the direction of this displacement accurately, despite spatial errors in saccade landing site, indicating that their comparison of the actual to predicted postsaccadic target location relied on accurate CD. SZP performed worse and relied more on saccade landing site as a proxy for the presaccadic target, consistent with disturbed CD. This remapping failure was strongest in patients with more severe psychotic symptoms, consistent with the theoretical link between disturbed CD and phenomenological experiences in schizophrenia.

Response inhibition and response monitoring in a saccadic double-step task in schizophrenia.

BACKGROUND: Cognitive control impairments are linked to functional outcome in schizophrenia. The goal of the current study was to investigate precise abnormalities in two aspects of cognitive control: reactively changing a prepared response, and monitoring performance and adjusting behavior accordingly. We adapted an oculomotor task from neurophysiological studies of the cellular basis of cognitive control in nonhuman primates. METHODS: 16 medicated outpatients with schizophrenia (SZ) and 18 demographically-matched healthy controls performed the modified double-step task. In this task, participants were required to make a saccade to a visual target. Infrequently, the target jumped to a new location and participants were instructed to rapidly inhibit and change their response. A race model provided an estimate of the time needed to cancel a planned movement. Response monitoring was assessed by measuring reaction time (RT) adjustments based on trial history. RESULTS: SZ patients had normal visually-guided saccadic RTs but required more time to switch the response to the new target location. Additionally, the estimated latency of inhibition was longer in patients and related to employment. Finally, although both groups slowed down on trials that required inhibiting and changing a response, patients showed exaggerated performance-based adjustments in RTs, which was correlated with positive symptom severity. CONCLUSIONS: SZ patients have impairments in rapidly inhibiting eye movements and show idiosyncratic response monitoring. These results are consistent with functional abnormalities in a network involving cortical oculomotor regions, the superior colliculus, and basal ganglia, as described in neurophysiological studies of non-human primates using an identical paradigm, and provide a translational bridge for understanding cognitive symptoms of SZ.

Visuospatial imagery and working memory in schizophrenia.

INTRODUCTION: The ability to form mental images that reconstruct former perceptual experiences is closely related to working memory (WM) ability. However, whereas WM deficits are established as a core feature of schizophrenia, an independent body of work suggests that mental imagery ability is enhanced in the disorder. Across two experiments we investigated mental imagery in schizophrenia and its relationship with WM. METHODS: In Experiment 1, individuals with schizophrenia (SZ: n=15) and matched controls (CO: n=14) completed a mental imagery generation and inspection task and a spatial delayed-response WM task. In Experiment 2, SZ (n=16) and CO (n=16) completed a novel version of the mental imagery task modified to increase WM maintenance demand. RESULTS: In Experiment 1, SZ demonstrated enhanced mental imagery performance, as evidenced by faster response times relative to CO, with preserved accuracy. However, enhanced mental imagery in SZ was accompanied by impaired WM as assessed by the delayed-response task. In Experiment 2, when WM maintenance load was increased, SZ no longer showed superior imagery performance. CONCLUSIONS: We found evidence for enhanced imagery manipulation in SZ despite their WM maintenance deficit. However, this imagery enhancement was abolished when WM maintenance demands were increased. This profile of enhanced imagery manipulation but impaired maintenance could be used to implement novel remediation strategies in the disorder.

Pre-saccadic shifts of attention in individuals diagnosed with schizophrenia.

INTRODUCTION: Pathophysiological theories of schizophrenia (SZ) symptoms posit an abnormality in using predictions to guide behavior. One such prediction is based on imminent movements, via corollary discharge signals (CD) that relay information about planned movement kinematics to sensory brain regions. Empirical evidence suggests a reduced influence of sensorimotor predictions in individuals with SZ within multiple sensory systems, including in the visual system. One function of CD in the visual system is to selectively enhance visual sensitivity at the location of planned eye movements (pre-saccadic attention), thus enabling a prediction of the to-be-foveated stimulus. We expected pre-saccadic attention shifts to be less pronounced in individuals with SZ than in healthy controls (HC), resulting in unexpected sensory consequences of eye movements, which may relate to symptoms than can be explained in the context of altered allocation of attention. METHODS: We examined this question by testing 30 SZ and 30 HC on a pre-saccadic attention task. On each trial participants made a saccade to a cued location in an array of four stimuli. A discrimination target that was either congruent or incongruent with the cued location was briefly presented after the cue, during saccade preparation. Pre-saccadic attention was quantified by comparing accuracy on congruent trials to incongruent trials within the interval preceding the saccade. RESULTS: Although SZs were less accurate overall, the magnitude of the pre-saccadic attention effect generally did not differ across groups nor show a convincing relationship with symptom severity. We did, however, observe that SZ had reduced pre-saccadic attention effects when the discrimination target (probe) was presented at early stages of saccade planning, when pre-saccadic attention effects first emerged in HC. CONCLUSION: These findings suggest generally intact pre-saccadic shifts of attention in SZ, albeit slightly delayed. Results contribute to our understanding of altered sensory predictions in people with schizophrenia.

Stronger tilt aftereffects in individuals diagnosed with schizophrenia spectrum disorders but not bipolar disorder.

An altered use of context and experience to interpret incoming information has been posited to explain schizophrenia symptoms. The visual system can serve as a model system for examining how context and experience guide perception and the neural mechanisms underlying putative alterations. The influence of prior experience on current perception is evident in visual aftereffects, the perception of the "opposite" of a previously viewed stimulus. Aftereffects are associated with neural adaptation and concomitant change in strength of lateral inhibitory connections in visually responsive neurons. In a previous study, we observed stronger aftereffects related to orientation (tilt aftereffects) but not luminance (negative afterimages) in individuals diagnosed with schizophrenia, which we interpreted as potentially suggesting altered cortical (but not subcortical) adaptability and local changes in excitatory-inhibitory interactions. Here, we tested whether stronger tilt aftereffects were specific to individuals with schizophrenia or extended to individuals with bipolar disorder. We measured tilt aftereffects and negative afterimages in 32 individuals with bipolar disorder, and compared aftereffect strength to a previously reported group of 36 individuals with schizophrenia and 22 healthy controls. We observed stronger tilt aftereffects, but not negative afterimages, in individuals with schizophrenia as compared to both controls and individuals with bipolar disorder, who did not differ from each other. These results mitigate concerns that stronger tilt aftereffects in schizophrenia are a consequence of medication or of the psychosocial consequences of a severe mental illness.

Abnormal Oculomotor Corollary Discharge Signaling as a Trans-diagnostic Mechanism of Psychosis.

BACKGROUND AND HYPOTHESIS: Corollary discharge (CD) signals are "copies" of motor signals sent to sensory areas to predict the corresponding input. They are a posited mechanism enabling one to distinguish actions generated by oneself vs external forces. Consequently, altered CD is a hypothesized mechanism for agency disturbances in psychosis. Previous studies have shown a decreased influence of CD signals on visual perception in individuals with schizophrenia-particularly in those with more severe positive symptoms. We therefore hypothesized that altered CD may be a trans-diagnostic mechanism of psychosis. STUDY DESIGN: We examined oculomotor CD (using the blanking task) in 49 participants with schizophrenia or schizoaffective disorder (SZ), 36 bipolar participants with psychosis (BPP), and 40 healthy controls (HC). Participants made a saccade to a visual target. Upon saccade initiation, the target disappeared and reappeared at a horizontally displaced position. Participants indicated the direction of displacement. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of pre-saccadic target to inform perception. Thus, multi-level modeling was used to examine the influence of target displacement and saccade landing site on displacement judgements. STUDY RESULTS: SZ and BPP were equally less sensitive to target displacement than HC. Moreover, regardless of diagnosis, SZ and BPP with more severe positive symptoms were more likely to rely on saccade landing site. CONCLUSIONS: These results suggest that altered CD may be a trans-diagnostic mechanism of psychosis.

Associations between N-Acetylaspartate and white matter integrity in individuals with schizophrenia and unaffected relatives.

Compromised white matter has been reported in schizophrenia; however, few studies have investigated neurochemical abnormalities underlying microstructural differences. N-acetylaspartate (NAA) is used to synthesize myelin and is often reduced in persons with schizophrenia (PSZ) and their unaffected first-degree relatives (REL). Low levels of NAA could affect white matter by preventing the synthesis or repair of myelin. We used magnetic resonance spectroscopy and diffusion tensor imaging to investigate the relationship between NAA and white matter integrity in PSZ. REL were included to examine whether putative relationships are associated with symptom expression or illness liability. 52 controls, 23 REL and 25 PSZ underwent 7T proton magnetic resonance spectroscopy and/or 3T diffusion tensor imaging. NAA in the visual cortex and basal ganglia were measured and compared across groups. Diffusivity measures were compared across groups using tract-based spatial statistics and related to NAA concentrations. Visual cortex NAA was significantly reduced in PSZ compared to controls. White matter integrity did not differ between groups. Reduced cortical and subcortical NAA were associated with diffusivity measures of poor white matter microstructure. These data suggest that levels of neural NAA may be related to white matter integrity similarly across individuals with schizophrenia, those at genetic risk, and controls.

Structural connectivity of an interoception network in schizophrenia.

Interoception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but few studies have explored potential neural underpinnings. The current study aims to investigate the anatomical connectivity of a previously identified interoception network in individuals with schizophrenia, and the relationship between network structural connectivity and both emotional functioning and clinical symptoms. Thirty-five participants with schizophrenia (SZ) and 36 healthy control participants (HC) underwent diffusion tensor imaging (DTI) and performed tasks measuring emotional functioning. Probabilistic tractography was used to identify white matter tracts connecting key hubs in an interoception network. Microstructural integrity of these tracts was compared across groups and correlated with measures of emotional functioning and symptom severity. Compared with HC, SZ exhibited altered structural connectivity in the interoception network. In HC, the structural connectivity of the network was significantly correlated with emotion recognition, supporting a link between the interoception network and emotional functioning. However, this correlation was much weaker in SZ. These findings suggest that altered interoception may have implications for illness mechanisms of schizophrenia, especially in relation to emotional deficits.

Blunted pupil light reflex is associated with negative symptoms and working memory in individuals with schizophrenia.

Two largely separate lines of research have documented altered pupillary dynamics in individuals diagnosed with schizophrenia. An older set of studies has demonstrated reductions in the pupillary light reflex (PLR) in individuals with schizophrenia; however, clinical and cognitive correlates of this blunted PLR have been relatively unexplored. More recently, a large body of work has demonstrated reductions in pupillary dilation in response to cognitive demands in individuals with schizophrenia, and the degree of this blunted pupil dilation has been related to more severe cognitive deficits and motivational negative symptoms. These clinically relevant alterations in the cognitive modulation of pupil size have been interpreted as reflecting insufficient information processing resources or inappropriate effort allocation. To begin to bridge these two lines of work, we investigated the PLR in 34 individuals with schizophrenia and 30 healthy controls and related the amplitude of the PLR to motivational negative symptoms and cognitive performance. Consistent with prior work, we found that the PLR was reduced in individuals with schizophrenia, and furthermore, that these measurements were highly reliable across individuals. Blunted constriction was associated with more severe motivational negative symptoms and poorer working memory among individuals with schizophrenia. These observed correlates provide a bridge between older literature documenting an altered PLR and more recent work reporting associations between negative symptoms, cognition, and blunted pupillary dilation in response to cognitive demands in individuals with schizophrenia. We provide possible mechanistic interpretations of our data and consider a parsimonious explanation for reduced cognitive- and light-related modulation of pupil size.

Investigating Motor Preparation in Autism Spectrum Disorder With and Without Attention Deficit/Hyperactivity Disorder.

This study investigated motor preparation and action-consequence prediction using the lateralized readiness potential (LRP). Motor impairments are common in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which commonly co-occur. Alterations in predictive processes may impact motor planning. Whether motor planning deficits are characteristic of ASD broadly or magnified in the context of co-morbid ADHD is unclear. ASD children with (ASD + ADHD; n = 12) and without (ASD - ADHD; n = 9) comorbid ADHD and typical controls (n = 29) performed voluntary motor actions that either did or did not result in auditory consequences. ASD - ADHD children demonstrated LRP enhancement when their action produced an effect while ASD + ADHD children had attenuated responses regardless of action-effect pairings. Findings suggest influence of ADHD comorbidity on motor preparation and prediction in ASD.

Psychosis in transgender and gender non-conforming individuals: A review of the literature and a call for more research.

Epidemiological studies have described higher rates of psychotic disorder diagnoses in transgender, as compared to cisgender, individuals. With the exception of this work and a small number of published case studies, however, there has been little consideration of gender diversity in psychosis research or clinical care. In this paper, we will review and critically evaluate the limited literature on gender diversity and clinical psychosis and articulate the critical need for more work in this field, more specifically on the following areas and how they bear on clinical care: 1) diagnostic biases; 2) how chronic non-affirmation and bias, gender dysphoria, and other gender minority stressors may operate as trauma and can contribute to clinically significant psychotic symptoms; 3) the potential impact of gender-affirming care, such as hormone therapies, on mental health and barriers for receiving such care in transgender and nonbinary individuals; and 4) culturally-sensitive and gender-affirming approaches for addressing psychosis. Finally, we consider ways in which researchers may engage in ethical, gender-affirming, and accurate approaches to better address gender identity in psychosis research. We hope that such research will aid in the creation of clinical guidelines for understanding, diagnosing, and treating psychosis in gender diverse individuals.

Ocular measures during associative learning predict recall accuracy.

The ability to form associations between stimuli and commit those associations to memory is a cornerstone of human cognition. Dopamine and noradrenaline are critical neuromodulators implicated in a range of cognitive functions, including learning and memory. Eye blink rate (EBR) and pupil diameter have been shown to index dopaminergic and noradrenergic activity. Here, we examined how these ocular measures relate to accuracy in a paired-associate learning task where participants (N = 73) learned consistent object-location associations over eight trials consisting of pre-trial fixation, encoding, delay, and retrieval epochs. In order to examine how within-subject changes and between-subject changes in ocular metrics related to accuracy, we mean centered individual metric values on each trial based on within-person and across-subject means for each epoch. Within-participant variation in EBR was positively related to accuracy in both encoding and delay epochs: faster EBR within the individual predicted better retrieval. Differences in EBR across participants was negatively related to accuracy in the encoding epoch and in early trials of the pre-trial fixation: faster EBR, relative to other subjects, predicted poorer retrieval. Visual scanning behavior in pre-trial fixation and delay epochs was also positively related to accuracy in early trials: more scanning predicted better retrieval. We found no relationship between pupil diameter and accuracy. These results provide novel evidence supporting the utility of ocular metrics in illuminating cognitive and neurobiological mechanisms of paired-associate learning.

Reconciling competing mechanisms posited to underlie auditory verbal hallucinations.

Perception is not the passive registration of incoming sensory data. Rather, it involves some analysis by synthesis, based on past experiences and context. One adaptive consequence of this arrangement is imagination-the ability to richly simulate sensory experiences, interrogate and manipulate those simulations, in service of action and decision making. In this paper, we will discuss one possible cost of this adaptation, namely hallucinations-perceptions without sensory stimulation, which characterize serious mental illnesses like schizophrenia, but which also occur in neurological illnesses, and-crucially for the present piece-are common also in the non-treatment-seeking population. We will draw upon a framework for imagination that distinguishes voluntary from non-voluntary experiences and explore the extent to which the varieties and features of hallucinations map onto this distinction, with a focus on auditory-verbal hallucinations (AVHs)-colloquially, hearing voices. We will propose that sense of agency for the act of imagining is key to meaningfully dissecting different forms and features of AVHs, and we will outline the neural, cognitive and phenomenological sequelae of this sense. We will conclude that a compelling unifying framework for action, perception and belief-predictive processing-can incorporate observations regarding sense of agency, imagination and hallucination. This article is part of the theme issue 'Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation'.