Disturbance at the self-other boundary in schizophrenia: Linking phenomenology to clinical neuroscience.

In this selective review, we describe the current neuroscientific literature on disturbances of the self-other boundary in schizophrenia as they relate to structural and experiential aspects of the self. Within these two broad categories, the structural self includes body ownership and agency, and the experiential self includes self-reflection, source monitoring, and self-referential and autobiographical memory. Further, we consider how disturbances in these domains link to the phenomenology of schizophrenia. We identify faulty internal predictive coding as a potential mechanism of disturbance in body ownership and agency, which results in susceptibility to bias (over- or under-attributing outcomes to one's own actions or intentions). This is reflected in reduced activity in the temporoparietal junction (TPJ), a heteromodal association area implicated in several aspects of self-other processing, as well as reduced fronto-parietal functional connectivity. Deficits of the experiential self in schizophrenia may stem from a lack of salience of self-related information, whereby the mental representation of self is not as rich as in healthy controls and therefore does not result in the same level of privileged processing. As a result, memory for self-referential material and autobiographical memory processes is impaired, which hinders creation of a cohesive life narrative. Impairments of the experiential self implicate abnormal activation patterns along the cortical midline, including medial prefrontal cortex and posterior cingulate/precuneus, as well as TPJ. In fact, TPJ appears to be involved in all the reviewed aspects of the self-other disturbance. We conclude with suggestions for future work, including implications for interventions with critical timing considerations.

Neurophysiological indices of face processing in people with psychosis and their siblings: An event-related potential study.

People with schizophrenia experience difficulties with social interactions. One contributor to these social deficits is dysfunction in processing facial features and facial emotional expressions. However, it is not known whether face processing deficits are evident in those with other psychotic disorders or in those genetically at-risk for psychosis (i.e., first-degree relatives of those with psychosis). We assessed event-related potentials (ERPs) during a facial and emotion processing task in 100 people with a diagnosis of schizophrenia or another psychotic condition (PSY), 32 of their siblings (SIB) and 45 healthy comparison participants (CTL). In separate blocks, participants identified the sex (male or female) or emotion (happy, angry, neutral) of faces. In a comparison condition, participants indicated whether buildings had one or two floors. ERPs were examined in two stages. First, we compared ERPs across the emotion, sex and building identification conditions. Second, we compared ERPs among the three different facial emotions. PSY exhibited significantly lower amplitudes over parietal-occipital regions between 111 and 151 ms when viewing faces but not buildings than CTL, consistent with a face-selective N170 ERP component deficit. The SIB group was intermediate for faces, but not significantly different than PSY or CTL. During emotion identification, all three groups showed increased N170 amplitudes to angry and happy versus neutral expressions, with no group differences. In follow up analyses, we examined differences between PSY with or without affective psychosis, and differences between those with schizophrenia versus other psychotic disorders; there were no significant differences in these analyses. Face processing deficits assessed with ERPs were observed in a group of diverse psychotic disorders, though deficits were not seen to be modulated by facial emotion expression. Additionally, N170 deficits are not evident in siblings of those with PSY.

Linking social motivation, general motivation, and social cognition to interpersonal functioning in schizophrenia: insights from exploratory graph analysis.

Motivation in general, and social motivation in particular are important for interpersonal functioning in individuals with schizophrenia. Still, their roles after accounting for social cognition, are not well understood. The sample consisted of 147 patients with schizophrenia. General motivation was measured using the Behavioral inhibition/activation scale (BIS/BAS). Social motivation was measured by Passive social withdrawal and Active social avoidance items from PANSS. Interpersonal functioning was evaluated with Birchwood's Social Functioning Scale (SFS). We used Exploratory Graph Analysis for network estimation and community detection. Active social avoidance, passive social withdrawal, and social withdrawal/engagement (from SFS) were the most important nodes. In addition, three distinct communities were identified: Social cognition, Social motivation, and Interpersonal functioning. Notably, the BIS and BAS measures of general motivation were not part of any community. BAS showed stronger links to functioning than BIS. Passive social withdrawal was more strongly linked to interpersonal functioning than social cognitive abilities. Results suggest that social motivation, especially social approach, is more closely related to interpersonal functioning in schizophrenia than general motivation. In contrast, we found that general motivation was largely unrelated to social motivation. This pattern highlights the importance of type of motivation for understanding variability in interpersonal difficulties in schizophrenia.

Understanding the Causal Pathway of Social Determinants of Psychosis: The Role of Social Functioning, Relevance of Animal Models, and Implications for Treatment.

There is mounting evidence that the social determinants of psychosis operate via a long and circuitous route. Here, we comment on the striking findings from a recent study by Ku et al., that area-level social environmental factors yield social disability and increased risk for schizophrenia through intervening variables and over a long time course. We discuss the relevance of animal models of social isolation to understand how environmental factors interrelate with individual-level mechanisms. We also discuss treatment implications, including the search for novel psychopharmacological treatments for reduced social motivation, and the need for a comprehensive prediction and prevention model.

Neuroimaging of social motivation during winning and losing: Associations with social anhedonia across the psychosis spectrum.

BACKGROUND: Individuals with psychosis spectrum disorders (PSD) have difficulty developing social relationships. This difficulty may reflect reduced response to social feedback involving functional alterations in brain regions that support the social motivation system: ventral striatum, orbital frontal cortex, insula, dorsal anterior cingulate cortex, and amygdala. Whether these alterations span PSD is unknown. METHODS: 71 individuals with PSD, 27 unaffected siblings, and 37 control participants completed a team-based fMRI task. After each trial, participants received performance feedback paired with the expressive face of a teammate or opponent. A 2 × 2 (win versus loss outcome x teammate versus opponent) repeated measures ANOVA by group was performed on activation in the five key regions of interest during receipt of feedback. RESULTS: Across groups, three social motivation regions, ventral striatum, orbital frontal cortex, and amygdala, showed sensitivity to feedback (significant main effect of outcome), with greater activation during win versus loss trials, regardless of whether the feedback was from a teammate or opponent. In PSD, ventral striatum and orbital frontal cortex activation to win feedback was negatively correlated with social anhedonia scores. CONCLUSIONS: Patterns of neural activation during social feedback were similar in PSD, their unaffected siblings, and healthy controls. Across the psychosis spectrum, activity in key social motivation regions during social feedback was associated with individual differences in social anhedonia.

Brevundimonas vesicularis isolation from a Labrador Retriever with Bacteremia, Endocarditis, Spinal Epidural Empyema, and Polyarthritis.

A 7 yr old spayed female Labrador retriever was evaluated for progressive nonambulatory tetraparesis, obtundation, joint pain, and pyrexia. The dog was diagnosed with spinal epidural empyema, bacteremia, endocarditis, and polyarthritis based on magnetic resonance imaging, echocardiography, joint fluid analysis, and blood culture. Blood culture isolated a rare and atypical pathogen, Brevundimonas vesicularis in conjunction with Escherchia coli. The patient was treated with a 10 mo antibiotic course, and clinical signs quickly resolved. This is the first report of B vesicularis in association with bacteremia, endocarditis, spinal empyema, and polyarthritis in a dog.

Reorganization of the functional connectome from rest to a visual perception task in schizophrenia and bipolar disorder.

Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited to network segregation and were more evident in SZ (clustering coefficient, modularity) than in BD (clustering coefficient) compared to HC. State differences were found across groups for segregation (local efficiency) and integration (characteristic path length). There was no group-by-state interaction for any graph index. In summary, aberrant network organization compared to HC was confirmed, and was more evident in SZ than in BD. Yet, reorganization was largely intact in both disorders. These findings help to constrain models of dysconnection in SZ and BD, suggesting that the extent of functional dysconnectivity in these disorders tends to persist across changes in mental state.

Aberrant reward processing to positive versus negative outcomes across psychotic disorders.

Several studies of reward processing in schizophrenia have shown reduced sensitivity to positive, but not negative, outcomes although inconsistencies have been reported. In addition, few studies have investigated whether patients show a relative deficit to social versus nonsocial rewards, whether deficits occur across the spectrum of psychosis, or whether deficits relate to negative symptoms and functioning. This study examined probabilistic implicit learning via two visually distinctive slot machines for social and nonsocial rewards in 101 outpatients with diverse psychotic disorders and 48 community controls. The task consisted of two trial types: positive (optimal to choose a positive vs. neutral machine) and negative (optimal to choose a neutral vs. negative machine), with two reward conditions: social (faces) and nonsocial (money) reward conditions. A significant group X trial type interaction indicated that controls performed better on positive than negative trials, whereas patients showed the opposite pattern of better performance on negative than positive trials. In addition, both groups performed better for social than nonsocial stimuli, despite lower overall task performance in patients. Within patients, worse performance on negative trials showed significant, small-to-moderate correlations with motivation and pleasure-related negative symptoms and social functioning. The current findings suggest reward processing disturbances, particularly decreased sensitivity to positive outcomes, extend beyond schizophrenia to a broader spectrum of psychotic disorders and relate to important clinical outcomes.

Intact differentiation of responses to socially-relevant emotional stimuli across psychotic disorders: An event-related potential (ERP) study.

Event-related potential (ERP) studies of motivated attention in schizophrenia typically show intact sensitivity to affective vs. non-affective images depicting diverse types of content. However, it is not known whether this ERP pattern: 1) extends to images that solely depict social content, (2) applies across a broad sample with diverse psychotic disorders, and (3) relates to self-reported trait social anhedonia. We examined late positive potential (LPP) amplitudes to images involving people that were normatively pleasant (affiliative), unpleasant (threatening), or neutral in 97 stable outpatients with various psychotic disorders and 38 healthy controls. Both groups showed enhanced LPP to pleasant and unpleasant vs. neutral images to a similar degree, despite lower overall LPP in patients. Within the patients, there were no significant LPP differences among subgroups (schizophrenia vs. other psychotic disorders; affective vs. non-affective psychosis) for the valence effect (pleasant/unpleasant vs. neutral). Higher social anhedonia showed a small, significant relation to lower LPP to pleasant images across all groups. These findings suggest intact motivated attention to social images extends across psychotic disorder subgroups. Dimensional transdiagnostic analyses revealed a modest association between self-reported trait social anhedonia and an LPP index of neural sensitivity to pleasant affiliative images.

At the intersection of anger, chronic pain, and the brain: A mini-review.

Chronic pain remains one of the most persistent healthcare challenges in the world. To advance pain treatment, experts have recently introduced research-driven subtypes of chronic pain based on proposed underlying mechanisms. Nociplastic pain (e.g., nonspecific chronic low back or fibromyalgia) is one such subtype which may involve a greater etiologic role for brain plasticity, painful emotions induced by life stress and trauma, and unhealthy emotion regulation. In particular, correlational and behavioral data link anger and the ways anger is regulated with the presence and severity of nociplastic pain. Functional neuroimaging studies also suggest nociplastic pain and healthy anger regulation demonstrate inverse patterns of activity in the medial prefrontal cortex and amygdala; thus, improving anger regulation could normalize activity in these regions. In this Mini-Review, we summarize these findings and propose a unified, biobehavioral model called the Anger, Brain, and Nociplastic Pain (AB-NP) Model, which can be tested in future research and may advance pain care by informing new treatments that address anger, anger regulation, and brain plasticity for nociplastic pain.

Structural and Functional Connectivity of Visual Cortex in Schizophrenia and Bipolar Disorder: A Graph-Theoretic Analysis.

Visual processing abnormalities in schizophrenia (SZ) are poorly understood, yet predict functional outcomes in the disorder. Bipolar disorder (BD) may involve similar visual processing deficits. Converging evidence suggests that visual processing may be relatively normal at early stages of visual processing such as early visual cortex (EVC), but that processing abnormalities may become more pronounced by mid-level visual areas such as lateral occipital cortex (LO). However, little is known about the connectivity of the visual system in SZ and BD. If the flow of information to, from, or within the visual system is disrupted by reduced connectivity, this could help to explain perceptual deficits. In the present study, we performed a targeted analysis of the structural and functional connectivity of the visual system using graph-theoretic metrics in a sample of 48 SZ, 46 BD, and 47 control participants. Specifically, we calculated parallel measures of local efficiency for EVC and LO from both diffusion weighted imaging data (structural) and resting-state (functional) imaging data. We found no structural connectivity differences between the groups. However, there was a significant group difference in functional connectivity and a significant group-by-region interaction driven by reduced LO connectivity in SZ relative to HC, whereas BD was approximately intermediate to the other 2 groups. We replicated this pattern of results using a different brain atlas. These findings support and extend theoretical models of perceptual dysfunction in SZ, providing a framework for further investigation of visual deficits linked to functional outcomes in SZ and related disorders.

Prefrontal working memory activity predicts episodic memory performance: A neuroimaging study.

Working memory (WM) and long term memory (LTM) are different neuropsychological processes, although distinction between these domains is an area of debate. LTM is thought to rely on hippocampal circuitry. Cognitive neuroscience models imply that WM processing may at least partially support LTM within regions of the prefrontal cortex (PFC). We sought to determine the association between PFC based WM processing and LTM in the visuospatial domain. In contrast to prior work, we aimed to query if WM was involved in learning and free recall trials as measured by standard neuropsychological tests of LTM. Forty-three older adults (24 with a diagnosis of amnestic Mild Cognitive Impairment and 19 elderly controls) were included in the analysis. Patients completed a fMRI task of visuospatial maintenance WM in which they were required to match a previously studied complex shape with one of two probes. Extent of activity in the right PFC during the WM task was tabulated for each patient. Hippocampal volume was quantified from T1 scans. On a separate day patients completed neuropsychological testing, including the Brief Visuospatial Memory Test- Revised (BVMT-R), which includes learning trials (total recall), delayed free recall, and recognition. Right PFC activity was associated with performance on BVMT-R total recall and delayed recall. Results from multiple regression showed that PFC activity explained an additional 9 % of the variance in memory performance above right hippocampal volume. These findings suggest that PFC processing that supports WM (including stimuli maintenance, retrieval, and selection) are also involved in LTM learning and recall.

Linking resting-state networks and social cognition in schizophrenia and bipolar disorder.

Individuals with schizophrenia and bipolar disorder show alterations in functional neural connectivity during rest. However, resting-state network (RSN) disruptions have not been systematically compared between the two disorders. Further, the impact of RSN disruptions on social cognition, a key determinant of functional outcome, has not been studied. Forty-eight individuals with schizophrenia, 46 with bipolar disorder, and 48 healthy controls completed resting-state functional magnetic resonance imaging. An atlas-based approach was used to examine functional connectivity within nine RSNs across the cortex. RSN connectivity was assessed via nonparametric permutation testing, and associations with performance on emotion perception, mentalizing, and emotion management tasks were examined. Group differences were observed in the medial and lateral visual networks and the sensorimotor network. Individuals with schizophrenia demonstrated reduced connectivity relative to healthy controls in all three networks. Individuals with bipolar disorder demonstrated reduced connectivity relative to controls in the medial visual network and connectivity within this network was significantly positively correlated with emotion management. In healthy controls, connectivity within the medial and lateral visual networks positively correlated with mentalizing. No significant correlations were found for either visual network in schizophrenia. Results highlight the role of altered early visual processing in social cognitive deficits in both schizophrenia and bipolar disorder. However, individuals with bipolar disorder appear to compensate for disrupted visual network connectivity on social cognitive tasks, whereas those with schizophrenia do not. The current study adds clarity on the neurophysiology underlying social cognitive deficits that result in impaired functioning in serious mental illness.

fMRI biomarkers of social cognitive skills training in psychosis: Extrinsic and intrinsic functional connectivity.

Social cognitive skills training interventions for psychotic disorders have shown improvement in social cognitive performance tasks, but little was known about brain-based biomarkers linked to treatment effects. In this pilot study, we examined whether social cognitive skills training could modulate extrinsic and intrinsic functional connectivity in psychosis using functional magnetic resonance imaging (fMRI). Twenty-six chronic outpatients with psychotic disorders were recruited from either a Social Cognitive Skills Training (SCST) or an activity- and time-matched control intervention. At baseline and the end of intervention (12 weeks), participants completed two social cognitive tasks: a Facial Affect Matching task and a Mental State Attribution Task, as well as resting-state fMRI (rs-fMRI). Extrinsic functional connectivity was assessed using psychophysiological interaction (PPI) with amygdala and temporo-parietal junction as a seed region for the Facial Affect Matching Task and the Mental State Attribution task, respectively. Intrinsic functional connectivity was assessed with independent component analysis on rs-fMRI, with a focus on the default mode network (DMN). During the Facial Affect Matching task, we observed stronger PPI connectivity in the SCST group after intervention (compared to baseline), but no treatment-related change in the Control group. Neither group showed treatment-related changes in PPI connectivity during the Mental State Attribution task. During rs-fMRI, we found treatment-related changes in the DMN in the SCST group, but not in Control group. This study found that social cognitive skills training modulated both extrinsic and intrinsic functional connectivity in individuals with psychotic disorders after a 12-week intervention. These findings suggest treatment-related changes in functional connectivity as a potential brain-based biomarker of social cognitive skills training.

Reduced Neural Sensitivity to Social vs Nonsocial Reward in Schizophrenia.

BACKGROUND: Human beings find social stimuli rewarding, which is thought to facilitate efficient social functioning. Although reward processing has been extensively studied in schizophrenia, a few studies have examined neural processes specifically involved in social reward processing. This study examined neural sensitivity to social and nonsocial rewards in schizophrenia. METHODS: Twenty-seven patients with schizophrenia and 25 community controls completed a One-Armed Bandit Task, an implicit reinforcement learning task, in the scanner. There were 2 conditions with an identical trial structure, one with social rewards and the other with nonsocial rewards. The data were analyzed using a region of interest (ROI) approach, focusing on the ventral striatum, ventromedial prefrontal cortex, and anterior cingulate cortex. RESULTS: Across all 3 ROIs, patients showed reduced activation for social rewards compared to controls. However, the 2 groups showed comparable levels of activation for nonsocial rewards. Within the patient group, levels of neural activation in these ROIs during the social reward condition were associated with better performance. CONCLUSIONS: This study found reduced neural sensitivity in patients with schizophrenia in key reward-processing regions for social but not for nonsocial rewards. These findings suggest a relatively specific social reward-processing deficit in schizophrenia during an implicit reinforcement learning task.

Aberrant patterns of neural activity when perceiving emotion from biological motion in schizophrenia.

Social perceptual deficits in schizophrenia are well established. Recent work suggests that the ability to extract social information from bodily cues is reduced in patients. However, little is known about the neurobiological mechanisms underlying this deficit. In the current study, 20 schizophrenia patients and 16 controls completed two tasks using point-light animations during fMRI: a basic biological motion task and an emotion in biological motion task. The basic biological motion task was used to localize activity in posterior superior temporal sulcus (pSTS), a critical region for biological motion perception. During the emotion in biological motion task, participants viewed brief videos depicting happiness, fear, anger, or neutral emotions and were asked to decide which emotion was portrayed. Activity in pSTS and amygdala was interrogated during this task. Results indicated that patients showed overall reduced activation compared to controls in pSTS and at a trend level in amygdala across emotions, despite similar task performance. Further, a functional connectivity analysis revealed that controls, but not patients, showed significant positive connectivity between pSTS and left frontal regions as well as bilateral angular gyrus during the emotion in biological motion task. These findings indicate that schizophrenia patients show aberrant neural activity and functional connectivity when extracting complex social information from simple motion stimuli, which may contribute to social perception deficits in this disorder.

Approaches to Canine Heartworm Disease Treatment Among Alumni of a Single College of Veterinary Medicine.

This descriptive study was designed to ascertain the current heartworm treatment strategies employed by veterinary graduates of a single college of veterinary medicine, to assess the frequency with which each of these treatment strategies is prescribed, and to report the motivation behind the use of these treatment strategies. A survey containing a combination of multiple-choice and open-ended questions was distributed via e-mail with an online link during 2013 to graduates of the University of Georgia College of Veterinary Medicine. Demographic data and opinions regarding treatment for cases of canine heartworm disease (HWD) were obtained, and motivation for recommending different treatment strategies was assessed. Nearly all 170 respondents (99%) indicated that they recommend melarsomine dihydrochloride for first-line treatment of canine HWD. Exercise restriction (80%) and monthly heartworm preventive (75%) were components of the treatment approach to HWD with no clinical signs. The majority of respondents (74%) indicated that when first-line treatment recommendations were declined, they endorsed long-term administration of ivermectin (i.e., "slow-kill" method) despite current American Heartworm Society guidelines that recommend against the use of long-term macrocyclic lactone administration for the monotherapy treatment of canine HWD. Respondents also indicated that owners' financial concerns frequently result in modification of HWD treatment. Routine inclusion of exercise restriction is commonly, but not universally, utilized and may represent an opportunity for improvement in the management of this disease. In addition, when first-line recommendations for heartworm disease treatment are declined, a two-dose melarsomine protocol instead of the slow-kill method should be considered.

Alterations to task positive and task negative networks during executive functioning in Mild Cognitive Impairment.

Poor executive functioning increases risk of decline in Mild Cognitive Impairment (MCI). Executive functioning can be conceptualized within the framework of working memory. While some components are responsible for maintaining representations in working memory, the central executive is involved in the manipulation of information and creation of new representations. We aimed to examine the neural correlates of these components of working memory using a maintenance working memory and visuospatial reasoning task. Twenty-five patients with amnestic MCI and 19 elderly controls (EC) completed functional MRI during reasoning and maintenance working memory tasks. In MCI, maintenance working memory was associated with hypoactivation of right frontoparietal regions and hyperactivation of left prefrontal cortex, coupled with attenuation of default mode network (DMN) relative to EC. During reasoning, MCI showed hypoactivation of parietal regions, coupled with attenuation of anterior DMN and increased deactivation of posterior DMN relative to EC. Comparing the reasoning task to the maintenance working memory task yields the central executive. In MCI, the central executive showed hypoactivation of right parietal lobe and increased deactivation of posterior DMN compared to EC. Consistent with prior work on executive functioning, MCI show different neural circuitry during visuospatial reasoning, including changes to both task positive frontoparietal regions, as well as to deactivation patterns within the DMN. Both hyperactivation of task positive networks and increased deactivation of DMN may be compensatory.

The neural correlates of self-referential memory encoding and retrieval in schizophrenia.

BACKGROUND: Enhanced memory for self-oriented information is known as the self-referential memory (SRM) effect. fMRI studies of the SRM effect have focused almost exclusively on encoding, revealing selective engagement of the medial prefrontal cortex (mPFC) during "self" relative to other processing conditions. Other critical areas for self-processing include ventrolateral prefrontal cortex (vlPFC), temporo-parietal junction (TPJ) and posterior cingulate/precuneus (PCC/PC). Previous behavioral studies show that individuals with schizophrenia fail to benefit from this memory boost. However, the neural correlates of this deficit, at either encoding or retrieval, are unknown. METHODS: Twenty individuals with schizophrenia and 16 healthy controls completed an event-related fMRI SRM paradigm. During encoding, trait adjectives were judged in terms of structural features ("case" condition), social desirability ("other" condition), or as self-referential ("self" condition). Participants then completed an unexpected recognition test (retrieval phase). We examined BOLD activation during both encoding and retrieval within mPFC, vlPFC, TPJ, and PCC/PC regions-of-interest (ROIs). RESULTS: During encoding, fMRI data indicated both groups had greater activation during the "self" relative to the "other" condition across ROIs. Controls showed this primarily in mPFC whereas patients showed this in PCC/PC. During retrieval, fMRI data indicated controls showed differentiation across ROIs between "self" and "other" conditions, but patients did not. CONCLUSIONS: Results suggest regional differences in the neural processing of self-referential information in individuals with schizophrenia, perhaps because representation of the self is not as well established in patients relative to controls. The current study presents novel findings that add to the literature implicating impaired self-oriented processing in schizophrenia.