Elias Mouchlianitis

The detection of fear-relevant stimuli: are guns noticed as quickly as snakes?

Potentially dangerous stimuli are important contenders for the capture of visual-spatial attention, and it has been suggested that an evolved fear module is preferentially activated by stimuli that are fear relevant in a phylogenetic sense (e.g., snakes, spiders, angry faces). In this study, a visual search task was used to test this hypothesis by directly contrasting phylogenetically (snakes) and ontogenetically (guns) fear-relevant stimuli. Results showed that the modern threat was detected as efficiently as the more ancient threat. Thus, both guns and snakes attracted attention more effectively than neutral stimuli (flowers, mushrooms, and toasters). These results support a threat superiority effect but not one that is preferentially accessed by threat-related stimuli of phylogenetic origin. The results are consistent with the view that faster detection of threat in visual search tasks may be more accurately characterized as relevance superiority effects rather than as threat superiority effects.

Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive

INTRODUCTION Resistance to antipsychotic treatment is a significant clinical problem in patients with schizophrenia with approximately 1 in 3 showing limited or no response to repeated treatments with antipsychotic medication. The neurobiological basis for treatment resistance is unknown but recent evidence implicates glutamatergic function in the anterior cingulate cortex. We examined glutamate levels of chronically ill treatment-resistant patients directly compared to treatment-responsive patients. METHODS We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from 21 treatment-resistant and 20 treatment-responsive patients. All participants had a DSM-IV diagnosis of schizophrenia. Treatment-resistant patients were classified using the modified Kane criteria. The groups were matched for age, sex, smoking status, and illness duration. RESULTS Glutamate to creatine ratio levels were higher in treatment-resistant patients (Mean [SD] = 1.57 [0.24]) than in treatment-responsive patients (Mean[SD] = 1.38 [0.23]), (T[35] = 2.34, P = .025, 2-tailed), with a large effect size of d = 0.76. A model assuming 2 populations showed a 25% improvement in the fit of the Akaike weights (0.55) over a model assuming 1 population (0.44), producing group values almost identical to actual group means. DISCUSSION Increased anterior cingulate glutamate level is associated with treatment-resistant schizophrenia. This appears to be a stable neurobiological trait of treatment-resistant patients. We discuss possible explanations for glutamatergic dysfunction playing a significant role in resistance to conventional antipsychotic treatments, which are all dopamine-2 receptor blockers. Our findings suggest that glutamatergic treatments may be particularly effective in resistant patients and that 1H-MRS glutamate indices can potentially have clinical use.

Brain-imaging studies of treatment-resistant schizophrenia: a systematic review

Around 30% of patients with schizophrenia show an inadequate response to antipsychotics-ie, treatment resistance. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify these patients earlier. Additionally, studies examining the effect of clozapine on the brain can help to identify aspects of clozapine that make it uniquely effective in patients with treatment resistance. We did a systematic search of PubMed between Jan 1, 1980, and April 13, 2015, to identify all neuroimaging studies that examined treatment-resistant patients or longitudinally assessed the effects of clozapine treatment. We identified 330 articles, of which 61 met the inclusion criteria. Replicated differences between treatment-resistant and treatment-responsive patients include reductions in grey matter and perfusion of frontotemporal regions, and increases in white matter and basal ganglia perfusion, with effect sizes ranging from 0·4 to greater than 1. Clozapine treatment led to reductions in caudate nucleus volume in three separate studies. The available evidence supports the hypothesis that some of the neurobiological changes seen in treatment-resistant schizophrenia lie along a continuum with treatment-responsive schizophrenia, whereas other differences are categorical in nature and have potential to be used as biomarkers. However, further replication is needed, and for neuroimaging findings to be clinically translatable, future studies need to focus on a-priori hypotheses and be adequately powered.

Attentional Control and Suppressing Negative Thought Intrusions in Pathological Worry.

Adaptive behavior relies on the ability to effectively and efficiently ignore irrelevant information, an important component of attentional control. The current research found that fundamental difficulties in ignoring irrelevant material are related to dispositional differences in trait propensity to worry, suggesting a core deficit in attentional control in high worriers. The degree of deficit in attentional control correlated with the degree of difficulty in suppressing negative thought intrusions in a worry assessment task. A cognitive training procedure utilizing a flanker task was used in an attempt to improve attentional control. Although the cognitive training was largely ineffective, improvements in attentional control were associated with improvements in the ability to suppress worry-related thought intrusions. Across two studies, the findings indicate that the inability to control worry-related negative thought intrusions is associated with a general deficiency in attentional control.

Presynaptic Serotoninergic Regulation of Emotional Processing: A Multimodal Brain Imaging Study

BACKGROUND The amygdala is a central node in the brain network that processes aversive emotions and is extensively innervated by dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) neurons. Alterations in DRN 5-HT1A receptor availability cause phenotypes characterized by fearful behavior in preclinical models. However, it is unknown whether 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in humans or whether it modulates connectivity in brain networks involved in emotion processing. To answer this question, we investigated the relationship between DRN 5-HT1A receptor availability and amygdala reactivity to aversive emotion and functional connectivity within the amygdala-cortical network. METHODS We studied 15 healthy human participants who underwent positron emission tomography scanning with [(11)C]CUMI-101, a 5-HT1A partial agonist radioligand, and functional magnetic resonance imaging of brain responses during an incidental emotion processing task including happy, fearful, and neutral faces. Regional estimates of 5-HT1A receptor binding potential (nondisplaceable) were obtained by calculating total volumes of distribution for presynaptic DRN and amygdala. Connectivity between the amygdala and corticolimbic areas was assessed using psychophysiologic interaction analysis with the amygdala as the seed region. RESULTS Analysis of the fear versus neutral contrast revealed a significant negative correlation between amygdala response and DRN binding potential (nondisplaceable) (r = -.87, p < .001). Availability of DRN 5-HT1A receptors positively correlated with amygdala connectivity with middle frontal gyrus, anterior cingulate cortex, bilateral precuneus, and left supramarginal gyrus for fearful (relative to neutral) faces. CONCLUSIONS Our data show that DRN 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in the amygdala and the modulation of amygdala-cortical connectivity.

White matter changes in treatment refractory schizophrenia: Does cognitive control and myelination matter?

Widespread white matter abnormalities have been reported in schizophrenia, a disorder frequently characterised as a dysconnection syndrome. White matter connectivity in schizophrenia has been predominantly investigated using diffusion weighted imaging, with reductions in fractional anisotropy throughout the brain often interpreted as an indicator of abnormal myelination. However, diffusion weighted imaging lacks specificity and as such a number of microstructural factors besides myelin may be contributing to these results. We utilised multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in medicated patients with chronic schizophrenia, stratified by treatment response status, and healthy controls, in order to assess myelin water fraction (MWF) in these groups. In addition, we assessed cognitive control using the Stroop task to investigate how response inhibition relates to myelination in patients and controls. Both treatment resistant (n = 22) and treatment responsive (n = 21) patients showed reduced MWF compared to healthy controls (n = 24) in bilateral fronto-occipital fasciculi, particularly evident in the vicinity of the striatum und extending to the cerebellum, with no difference between patient groups. Patients showed greater reaction time interference on the Stroop task compared to healthy controls, with no difference between patient groups. Stroop interference was significantly negatively correlated with MWF in the corpus callosum across groups, and MWF differences in this region mediated the behavioural group effects on the Stroop task. These findings support the suitability of mcDESPOT as a myelin-specific measure of abnormal connectivity in schizophrenia, and suggest that treatment resistant schizophrenia is not characterised by more severe abnormalities in myelination or cognitive control compared to treatment responsive schizophrenia.

S148. DIFFERENTIAL NEURAL REWARD MECHANISMS IN TREATMENT RESPONSIVE AND TREATMENT RESISTANT SCHIZOPHRENIA

Abstract Background The significant proportion of schizophrenia patients refractory to treatment targeting the dopamine system suggests that more than one mechanism may cause psychotic symptoms. Reinforcement learning tasks have frequently been employed in schizophrenia to assess dopaminergic functioning and reward processing, but studies have not directly compared groups of treatment-refractory and non-refractory patients. Methods In the current functional magnetic resonance imaging study 21 patients with treatment resistant schizophrenia (TRS), 21 patients with non-treatment resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilising emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE) signaling and the differential impact of emotional bias on these reward signals were compared between groups. Results Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favouring selection of the happy faces. The pattern of RPE signaling was similar in HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation. The TRS patients differed from the NTR patients in the relationship between emotional bias and subcortical RPE signal during negative feedback. Discussion TRS can be dissociated from NTR on the basis of a different neural mechanism underlying their symptoms. The data support the hypothesis that a favourable response to antipsychotic treatment may be contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality in distinct cognitive mechanisms interacting with this response.

O6.8. GLUTAMATERGIC DYSFUCTION AND TREATMENT RESPONSE IN MINIMALLY TREATED AND CHRONIC SCHIZOPHRENIA PATIENTS

Abstract Background Glutamatergic dysfunction as a result of NMDA receptor hypofunction has been implicated in antipsychotic treatment-resistant schizophrenia, however its nature in very early stages and chronic stages of the disease is still unknown. Data on glutamate and treatment response are currently limited in two separate studies, one in first-episode patients (Egerton et al., 2012) and one in chronic patients (Mouchlianitis et al., 2016). Here we acquired proton magnetic resonance spectroscopy measures from a large sample of minimally treated first episode and chronic schizophrenia patients, and a group of matched healthy controls. Both first-episode and chronic schizophrenia groups were further stratified by treatment response. This allowed us to investigate glutamatergic dysfunction in both early and later stages of the diseases in relation to treatment-response. Methods We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from bilateral anterior cingulate cortex (ACC) from 170 participants. 137 participants with a diagnosis of schizophrenia (according to ICD-10 criteria) and 33 healthy controls matched for age, sex, and socioeconomic background consented to participate in this study. The patient sample included 95 minimally treated first-episode patients, with illness duration less than 36 months, of which 65 has shown good response and 26 have shown persistent psychotic symptoms; and a group of 42 chronically-ill patients with illness duration over 3 years. The chronic group was classified into 21 antipsychotic treatment-resistant patients and 21 antipsychotic treatment-responsive patients. 1H-MRS data were analyzed using a standard basis function within LC-Model. Our primary measure was glutamate to creatine ratio (Glu/Cre) and its correlation to N-Acetylaspartic acid to creatine ratio (NAA/Cre). Results The main new finding is that first-episode patients with persistent psychotic symptoms show significantly higher Glu/Cr and NAA/Cr correlation R(23)=0.76, P<0.001.compared to first-episode patients in remission R(65)=0.43, P<0.00, Fisher’s r-to-z, Z=1.97, P<0.05, effect size d=0.48. Compared to healthy controls (who did not show any Glu/Cr to and NAA/Cr correlation R(33)=0.24, P=0.33) the FEP-resistant group showed a significant difference, Z=2.6, P<0.005, representing a large effect size of d=0.87 but not the FEP-responsive group, Z=0.97, P=0.17. Remarkably, when we examined first-episode patients with antipsychotic exposure of less than 6 months, we found an extremely high correlation in the non-responsive group R(5)=0.95, P=0.01, compared to the responsive-group,R(20)=0.44, P<0.05, which reflected a large effect size of d=0.99. Chronically-ill resistant patients showed a significant correlation R(21)=0.48, P<0.05 and responsive trend-level correlation R(21)=0.41, P=0.07, but neither group differed from healthy controls. Discussion Our study provides the first 1H-MRS evidence for acute metabolic perturbations in glutamatergic neurotransmission in minimally treated schizophrenia patients with persistent psychotic symptoms. These are absent in later stages of the disease for both treatment-resistant and treatment-responsive patients. It is likely that neurodegenerative processes resulting from excitotoxity due glutamatergic dysfuntion are most impactful within the first few months from illness onset. Our data point to the urgent need to identify reliable biomarkers for the prediction of antipsychotic treatment-response and the development of novel interventions to address glutamatergic perturbations at the beginning of their illness.

Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing

Importance Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation (F1, 93 = 5.559; P = .02; F1, 93 = 5.009; P = .03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction (F1, 93 = 7.448; P = .01). Conclusion and Relevance The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

Salience attribution and its relationship to cannabis-induced psychotic symptoms.

Background Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. Method We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography. Results There was no significant difference in aberrant salience between the groups [F1,32 = 1.12, p = 0.30 (implicit); F1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = −0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = −2.05, p = 0.04). Conclusions Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.