Neuroimaging oxytocin modulation of social reward learning in schizophrenia.

BACKGROUND: Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms. AIMS: To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. METHOD: We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human. RESULTS: During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms. CONCLUSIONS: During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia.

The importance of pro-social processing, and ameliorating dysfunction in schizophrenia. An FMRI study of oxytocin.

Schizophrenia is often a severe and debilitating mental illness, frequently associated with impairments in social cognition that hinder individuals' abilities to relate to others and integrate effectively in society. Oxytocin has emerged as a putative therapeutic agent for treating social deficits in schizophrenia, but the mode of action remains unclear. This placebo-controlled crossover study aimed to elucidate the neural underpinnings of oxytocin administration in patients with schizophrenia. 20 patients with schizophrenia were examined using functional magnetic resonance imaging under oxytocin (40 IU) or placebo nasal spray. Participants performed a stochastically rewarded decision-making task that incorporated elements of social valence provided by different facial expressions, i.e. happy, angry and neutral. Oxytocin attenuated the normal bias in selecting the happy face accompanied by reduced activation in a network of brain regions that support mentalising, processing of facial emotion, salience, aversion, uncertainty and ambiguity in social stimuli, including amygdala, temporo-parietal junction, posterior cingulate cortex, precuneus and insula. These pro-social effects may contribute to the facilitation of social engagement and social interactions in patients with schizophrenia and warrant further investigation in future clinical trials for social cognitive impairments in schizophrenia.

In the eye of the beholder? Oxytocin effects on eye movements in schizophrenia.

BACKGROUND: Individuals with schizophrenia have difficulty in extracting salient information from faces. Eye-tracking studies have reported that these individuals demonstrate reduced exploratory viewing behaviour (i.e. reduced number of fixations and shorter scan paths) compared to healthy controls. Oxytocin has previously been demonstrated to exert pro-social effects and modulate eye gaze during face exploration. In this study, we tested whether oxytocin has an effect on visual attention in patients with schizophrenia. METHODS: Nineteen male participants with schizophrenia received intranasal oxytocin 40UI or placebo in a double-blind, placebo-controlled, crossover fashion during two visits separated by seven days. They engaged in a free-viewing eye-tracking task, exploring images of Caucasian men displaying angry, happy, and neutral emotional expressions; and control images of animate and inanimate stimuli. Eye-tracking parameters included: total number of fixations, mean duration of fixations, dispersion, and saccade amplitudes. RESULTS: We found a main effect of treatment, whereby oxytocin increased the total number of fixations, dispersion, and saccade amplitudes, while decreasing the duration of fixations compared to placebo. This effect, however, was non-specific to facial stimuli. When restricting the analysis to facial images only, we found the same effect. In addition, oxytocin modulated fixation rates in the eye and nasion regions. DISCUSSION: This is the first study to explore the effects of oxytocin on eye gaze in schizophrenia. Oxytocin had enhanced exploratory viewing behaviour in response to both facial and inanimate control stimuli. We suggest that the acute administration of intranasal oxytocin may have the potential to enhance visual attention in schizophrenia.

High-Density Adaptive Ten Ten: Proposal for Electrode Nomenclature for High-Density EEG.

PURPOSE: High-density EEG (HD-EEG) systems and electrical source imaging techniques have revolutionized our ability to assess the potential sources of epileptiform activity and other EEG features. Nonetheless, clinical use of HD-EEG is hampered by the lack of a standardized electrode nomenclature system and the inherent difficulties encountered in visually reviewing recordings. Inefficient visual review of HD-EEG remains a major barrier to incorporating these techniques into routine clinical care. METHODS: Extension of the 10-10 is first defined by the addition of 2 reference curves: the -10% and -20% axial reference curves. Electrode positions over the face are named based on facial bony structures (N = nasion, Z = zygomatic prominence, M = mandible) and over the back of the head on posterior landmarks (I = inion, S = subinion, B = Base). Then, following the 10% incremental distance rule, we define additional electrode positions. Electrodes with nonstandard positions are clustered around the closest 10-10 electrode, deemed their cardinal point. RESULTS: The 256-electrode Geodesic Sensor Net mapped to 96 of the 120 extended 10-10 cardinal electrodes. CONCLUSIONS: Electrode position nomenclature that builds upon the international standard 10-10 system allows electroencephalographers to identify spatial areas of interest in HD-EEG relative to positions in routine use. A standard viewing montage for HD-EEG and its application with electrical source imaging boost efficiency when reviewing data and improve accuracy in recognizing epileptiform discharges. Additionally, our proposed system is not limited to a specific HD-EEG system, electrode count, or electrode layout.

Dopamine manipulations drive changes in information sampling in healthy volunteers.

BACKGROUND: Information sampling is the cognitive process of accumulating information before committing to a decision. Patients across numerous disorders show decreased information sampling relative to controls. AIMS: Here, we used the Beads and the Best Choice Tasks to study the role of dopamine signaling in information sampling. METHODS: Participants were given placebo, amisulpride, or ropinirole in each session, in a double-blind cross-over design. RESULTS: We found that ropinirole (agonist) increased the number of beads drawn in the Beads Task specifically when participants faced a loss, and decreased the rank of the chosen option in the Best Choice Task. CONCLUSIONS: These effects are likely driven by a combination of effects at presynaptic D2 receptors, which affect dopamine release, and post-synaptic D2 receptors. Increased D2 relative to D1 receptor activation in the striatum leads to increased sampling in the loss condition in the Beads Task. It also leads to choice of a poorer ranked option in the Best Choice Task. Decreased D2 relative to D1 receptor activation leads to decreased sampling in the Beads Task in the loss condition.

Reduced susceptibility to the sound-induced flash fusion illusion in schizophrenia.

Schizophrenia is characterised by the presence of abnormal complex sensory perceptual experiences. Such experiences could arise as a consequence of dysfunctional multisensory integration. We used the sound-induced flash illusion paradigm, which probes audiovisual integration using elementary visual and auditory cues, in a sample of individuals with schizophrenia (n=40) and matched controls (n=22). Signal detection theory analyses were performed to characterise patients' and controls' sensitivity in distinguishing 1 and 2 flashes under varying auditory conditions. Both groups experienced significant fission illusions (whereby one visual flash, accompanied by two auditory beeps, is misperceived as two flashes) and fusion illusions (whereby two flashes, accompanied by one beep, are perceived as one flash). Patients showed significantly lower fusion illusion rates compared to HC, while the fission illusion occurred similarly frequently in both groups. However, using an SDT approach, we compared illusion conditions with unimodal visual conditions, and found that illusory visual perception was overall more strongly influenced by auditory input in HC compared to patients for both illusions. This suggests that multisensory integration may be impaired on a low perceptual level in SZ.

In-patient rehabilitation: clinical outcomes and cost implications.

Aims and method A retrospective evaluation was undertaken of the clinical and economic effectiveness of three in-patient rehabilitation units across one London National Health Service trust. Information on admission days and costs 2 years before and 2 years after the rehabilitation placement, length of rehabilitation placement and the discharge pathway was collected on 22 service users. Results There were statistically significant reductions in hospital admission days in the 2 years following rehabilitation compared with the 2 years before, further reflected in significantly lower bed costs. Longer length of rehabilitation placement was correlated with fewer admission days after the placement. A substantial proportion of the sample went into more independent living, some with no further admissions at follow-up. Clinical implications The findings suggest that in-patient rehabilitation is both clinically and cost effective: if benefits are sustained they will offset the cost of the rehabilitation placement.

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies.

BACKGROUND: Oxytocin (OXT) plays a prominent role in social cognition and may have clinical applications for disorders such as autism, schizophrenia and social anxiety. The neural basis of its mechanism of action remains unclear. METHODS: We conducted a systematic literature review of placebo-controlled imaging studies using OXT as a pharmacological manipulator of brain activity. RESULTS: We identified a total of 21 studies for inclusion in our review, and after applying additional selection criteria, 11 of them were included in our fMRI voxel-based meta-analysis. The results demonstrate consistent alterations in activation of brain regions, including the temporal lobes and insula, during the processing of social stimuli, with some variation dependent on sex and task. The meta-analysis revealed significant left insular hyperactivation after OXT administration, suggesting a potential modulation of neural circuits underlying emotional processing. LIMITATIONS: This quantitative review included only a limited number of studies, thus the conclusions of our analysis should be interpreted cautiously. This limited sample size precluded a more detailed exploration of potential confounding factors, such as sex or other demographic factors, that may have affected our meta-analysis. CONCLUSION: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity. The magnitude of this neural activation is largest in the temporal lobes, and a meta-analysis across all tasks and both sexes showed that the left insula demonstrated the most robust activation to OXT administration.

The 4th Schizophrenia International Research Society Conference, 5-9 April 2014, Florence, Italy: a summary of topics and trends.

The 4th Schizophrenia International Research Society Conference was held in Florence, Italy, April 5-9, 2014 and this year had as its emphasis, "Fostering Collaboration in Schizophrenia Research". Student travel awardees served as rapporteurs for each oral session, summarized the important contributions of each session and then each report was integrated into a final summary of data discussed at the entire conference by topic. It is hoped that by combining data from different presentations, patterns of interest will emerge and thus lead to new progress for the future. In addition, the following report provides an overview of the conference for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

Eluding the illusion? Schizophrenia, dopamine and the McGurk effect.

Perceptions are inherently probabilistic; and can be potentially manipulated to induce illusory experience by the presentation of ambiguous or improbable evidence under selective (spatio-temporal) constraints. Accordingly, perception of the McGurk effect, by which individuals misperceive specific incongruent visual and auditory vocal cues, rests upon effective probabilistic inference. Here, we report findings from a behavioral investigation of illusory perception and related metacognitive evaluation during audiovisual integration, conducted in individuals with schizophrenia (n = 30) and control subjects (n = 24) matched in terms of age, sex, handedness and parental occupation. Controls additionally performed the task after an oral dose of amisulpride (400 mg). Individuals with schizophrenia were observed to exhibit illusory perception less frequently than controls, despite non-significant differences in perceptual performance during control conditions. Furthermore, older individuals with schizophrenia exhibited reduced rates of illusory perception. Subsequent analysis revealed a robust inverse relationship between illness chronicity and the illusory perception rate in this group. Controls demonstrated non-significant modulation of perception by amisulpride; amisulpride was, however, found to elicit increases in subjective confidence in perceptual performance. Overall, these findings are consistent with the idea that impairments in probabilistic inference are exhibited in schizophrenia and exacerbated by illness chronicity. The latter suggests that associated processes are a potentially worthwhile target for therapeutic intervention.

Dysconnectivity in the frontoparietal attention network in schizophrenia.

Cognitive impairment is common in patients with schizophrenia, and even those with relatively preserved function perform worse than healthy volunteers (HVs) on attentional tasks. This is consistent with the hypothesis that connectivity - in the frontoparietal network (FPN) activated during attention - is disrupted in schizophrenia. We examined attentional effects on connectivity in the FPN, in schizophrenia, using magnetoencephalography (MEG). Twenty-three HVs and 19 first-episode schizophrenia patients were scanned during a simple visual change test, known to activate the FPN, in which attention was monitored and directed with an orthogonal flicker-detection task. Dynamic causal modeling (DCM) of evoked responses was used to assess effective connectivity - and its modulation by changes in the attended stimulus dimension - in the following network: higher visual area; temporoparietal junction (TPJ); intraparietal sulcus (IPS); dorsal anterior cingulate cortex; and ventrolateral prefrontal cortex. The final MEG analysis included 18 HVs and 14 schizophrenia patients. While all participants were able to maintain attention, HVs responded slightly, but non-significantly, more accurately than schizophrenia patients. HVs, but not schizophrenia patients, exhibited greater cortical responses to attended visual changes. Bayesian model comparison revealed that a DCM with attention dependent changes in both top-down and bottom-up connections best explained responses by patients with schizophrenia, while in HVs the best model required only bottom-up changes. Quantitative comparison of connectivity estimates revealed a significant group difference in changes in the right IPS-TPJ connection: schizophrenia patients showed relative reductions in connectivity during attended stimulus changes. Crucially, this reduction predicted lower intelligence. These data are consistent with the hypothesis that functional dysconnections in the FPN contribute to cognitive impairment in schizophrenia.