Exploring the relationship between circulating inflammatory markers and the brain

No abstract available

Residual negative symptoms differentiate cognitive performance in clinically stable patients with schizophrenia and bipolar disorder

Cognitive deficits in various domains have been shown in patients with bipolar disorder and schizophrenia. The purpose of the present study was to examine if residual psychopathology explained the difference in cognitive function between clinically stable patients with schizophrenia and bipolar disorder. We compared the performance on tests of attention, visual and verbal memory and executive function of 25 patients with schizophrenia in remission and 25 euthymic bipolar disorder patients with that of 25 healthy controls. Mediation analysis was used to see if residual psychopathology could explain the difference in cognitive function between the patient groups. Both patient groups performed significantly worse than healthy controls on most cognitive tests. Patients with bipolar disorder displayed cognitive deficits that were milder but qualitatively similar to those of patients with schizophrenia. Residual negative symptoms mediated the difference in performance on cognitive tests between the two groups. Neither residual general psychotic symptoms nor greater antipsychotic doses explained this relationship. The shared variance explained by the residual negative and cognitive deficits that the difference between patient groups may be explained by greater frontal cortical neurophysiological deficits in patients with schizophrenia, compared to bipolar disorder. Further longitudinal work may provide insight into pathophysiological mechanisms that underlie these deficits

Mild inflammation causes a reduction in resting-state amplitude of low-frequency fluctuation in healthy adult males

Systemic inflammation has been associated with negative mood states and human sickness behaviour. Previous studies have shown an association between systemic inflammation and changes in task-related blood-oxygen-level-dependent activity and functional connectivity within large-scale networks. However, no study has examined the effect of inflammation on the magnitude of blood-oxygen-level-dependent low-frequency fluctuations at rest. We used a double-blind placebo-controlled crossover design to randomise 20 male subjects (aged 20–50 years) to receive either a Salmonella typhi vaccine or a placebo saline injection at two separate sessions. All participants underwent a resting-state functional magnetic resonance scan and a measure of inflammation (interleukin 6) and mood (Profile of Mood States) 3 h after injection. We compared the whole brain amplitude of low-frequency fluctuations between the vaccine and placebo conditions using a repeated measures design. Vaccine condition was associated with greater interleukin 6 levels (p < 0.001). Vaccine condition was also associated with lower amplitude of low-frequency fluctuations in the right and left frontal pole, superior frontal gyrus, paracingulate gyrus (Cluster 1) and the right mid and inferior frontal gyrus (Cluster 2) (p < 0.001, false discovery rate corrected). Lower amplitude of low-frequency fluctuations pertaining to first cluster correlated with greater total Profile of Mood States score (worse mood) (r = −0.38; p = 0.04). These results imply possible excitation/inhibition imbalance mechanisms during inflammation that may be a relevant target in psychiatric disease, especially mood disorders

Resting state connectivity and cognitive performance in adults with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 ± 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak −48, −18, −14; ZE = 5.65, pFWEcorr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = −0.77, p < 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population

Circulating Tumour Necrosis Factor is highly correlated with brainstem serotonin transporter availability in humans

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [123I] -beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8 weeks was associated with a significant reduction in 5-HTT availability (Z= 2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression

Mild exogenous inflammation blunts neural signatures of bounded evidence accumulation and reward prediction error processing in healthy male participants

Background: Altered neural haemodynamic activity during decision making and learning has been linked to the effects of inflammation on mood and motivated behaviours. So far, it has been reported that blunted mesolimbic dopamine reward signals are associated with inflammation-induced anhedonia and apathy. Nonetheless, it is still unclear whether inflammation impacts neural activity underpinning decision dynamics. The process of decision making involves integration of noisy evidence from the environment until a critical threshold of evidence is reached. There is growing empirical evidence that such process, which is usually referred to as bounded accumulation of decision evidence, is affected in the context of mental illness. Methods: In a randomised, placebo-controlled, crossover study, 19 healthy male participants were allocated to placebo and typhoid vaccination. Three to four hours post-injection, participants performed a probabilistic reversal-learning task during functional magnetic resonance imaging. To capture the hidden neurocognitive operations underpinning decision-making, we devised a hybrid sequential sampling and reinforcement learning computational model. We conducted whole brain analyses informed by the modelling results to investigate the effects of inflammation on the efficiency of decision dynamics and reward learning. Results: We found that during the decision phase of the task, typhoid vaccination attenuated neural signatures of bounded evidence accumulation in the dorsomedial prefrontal cortex, only for decisions requiring short integration time. Consistent with prior work, we showed that, in the outcome phase, mild acute inflammation blunted the reward prediction error in the bilateral ventral striatum and amygdala. Conclusions: Our study extends current insights into the effects of inflammation on the neural mechanisms of decision making and shows that exogenous inflammation alters neural activity indexing efficiency of evidence integration, as a function of choice discriminability. Moreover, we replicate previous findings that inflammation blunts striatal reward prediction error signals

Brain-stem serotonin transporter availability in maternal uniparental disomy and deletion Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a rare condition because of the deletion of paternal chromosomal material (del PWS), or a maternal uniparental disomy (mUPD PWS), at 15q11-13. Affective psychosis is more prevalent in mUPD PWS. We investigated the relationship between the two PWS genetic variants and brain-stem serotonin transporter (5-HTT) availability in adult humans. Mean brain-stem 5-HTT availability determined by [123I]-beta-CIT single photon emission tomography was lower in eight adults with mUPD PWS compared with nine adults with del PWS (mean difference −0.93, t = −2.85, P = 0.014). Our findings confirm an association between PWS genotype and brain-stem 5-HTT availability, implicating a maternally expressed/paternally imprinted gene, that is likely to account for the difference in psychiatric phenotypes between the PWS variants

Mild inflammation in healthy males induces fatigue mediated by changes in effective connectivity within the insula

Background: Systemic inflammation is associated with sickness behaviors such as low mood and fatigue. Activity patterns within the insula are suggested to coordinate these behaviors but have not been modeled. We hypothesized that mild systemic inflammation would result in changes in effective connectivity between the viscerosensory and the visceromotor regions of the insula. Methods: We used a double-blind, crossover design to randomize 20 male subjects to receive either a Salmonella typhi vaccine or a placebo saline injection at two separate sessions. All participants underwent a resting-state functional magnetic resonance scan 3 hours after injection. We determined behavioral and inflammatory changes, using the Profile of Mood States questionnaire and interleukin-6 levels. We extracted effective connectivity matrices between bilateral mid/posterior (viscerosensory) and anterior (visceromotor) insular cortices using spectral dynamic causal modeling. We applied parametric empirical Bayes and mediation analysis to determine a vaccination effect on effective connectivity and whether this mediated behavioral changes. Results: The vaccine condition was associated with greater interleukin-6 levels and greater fatigue 3 hours after the injection. Activity within the right mid/posterior insula increased the activity within the bilateral anterior insular regions. This connectivity was augmented by vaccination over a 99% posterior confidence threshold. The right mid/posterior insula-to-left anterior insula connectivity was significantly associated with fatigue and mediated the association between inflammation and increased fatigue scores. Conclusions: These results demonstrate that increased effective connectivity between specific nodes of the insula can model and mediate the association between inflammation and fatigue in males

Association of Magnetoencephalographically Measured High-Frequency Oscillations in Visual Cortex With Circuit Dysfunctions in Local and Large-scale Networks During Emerging Psychosis

Importance: Psychotic disorders are characterized by impairments in neural oscillations, but the nature of the deficit, the trajectory across illness stages, and functional relevance remain unclear. Objectives: To examine whether changes in spectral power, phase locking, and functional connectivity in visual cortex are present during emerging psychosis and whether these abnormalities are associated with clinical outcomes. Design, Setting, and Participants: In this cross-sectional study, participants meeting clinical high-risk criteria for psychosis, participants with first-episode psychosis, participants with affective disorders and substance abuse, and a group of control participants were recruited. Participants underwent measurements with magnetoencephalography and magnetic resonance imaging. Data analysis was carried out between 2018 and 2019. Main Outcomes and Measures: Magnetoencephalographical activity was examined in the 1- to 90-Hz frequency range in combination with source reconstruction during a visual grating task. Event-related fields, power modulation, intertrial phase consistency, and connectivity measures in visual and frontal cortices were associated with neuropsychological scores, psychosocial functioning, and clinical symptoms as well as persistence of subthreshold psychotic symptoms at 12 months. Results: The study participants included those meeting clinical high-risk criteria for psychosis (n = 119; mean [SD] age, 22 [4.4] years; 32 men), 26 patients with first-episode psychosis (mean [SD] age, 24 [4.2] years; 16 men), 38 participants with affective disorders and substance abuse (mean [SD] age, 23 [4.7] years; 11 men), and 49 control participants (mean age [SD], 23 [3.6] years; 16 men). Clinical high-risk participants and patients with first-episode psychosis were characterized by reduced phase consistency of β/γ-band oscillations in visual cortex (d = 0.63/d = 0.93). Moreover, the first-episode psychosis group was also characterized by reduced occipital γ-band power (d = 1.14) and altered visual cortex connectivity (d = 0.74-0.84). Impaired fronto-occipital connectivity was present in both clinical high-risk participants (d = 0.54) and patients with first-episode psychosis (d = 0.84). Importantly, reductions in intertrial phase coherence predicted persistence of subthreshold psychosis in clinical high-risk participants (receiver operating characteristic area under curve = 0.728; 95% CI, 0.612-0.841; P = .001). Conclusions and Relevance: High-frequency oscillations are impaired in the visual cortex during emerging psychosis and may be linked to behavioral and clinical impairments. Impaired phase consistency of γ-band oscillations was also associated with the persistence of subthreshold psychosis, suggesting that magnetoencephalographical measured neural oscillations could constitute a biomarker for clinical staging of emerging psychosis

Thalamo-cortical circuits during sensory attenuation in emerging psychosis: a combined magnetoencephalography and dynamic causal modelling study

Evidence suggests that schizophrenia (ScZ) involves impairments in sensory attenuation. It is currently unclear, however, whether such deficits are present during early-stage psychosis as well as the underlying network and the potential as a biomarker. To address these questions, Magnetoencephalography (MEG) was used in combination with computational modeling to examine M100 responses that involved a "passive" condition during which tones were binaurally presented, while in an "active" condition participants were asked to generate a tone via a button press. MEG data were obtained from 109 clinical high-risk for psychosis (CHR-P) participants, 23 people with a first-episode psychosis (FEP), and 48 healthy controls (HC). M100 responses at sensor and source level in the left and right thalamus (THA), Heschl's gyrus (HES), superior temporal gyrus (STG) and right inferior parietal cortex (IPL) were examined and dynamic causal modeling (DCM) was performed. Furthermore, the relationship between sensory attenuation and persistence of attenuated psychotic symptoms (APS) and transition to psychosis was investigated in CHR-P participants. Sensory attenuation was impaired in left HES, left STG and left THA in FEP patients, while in the CHR-P group deficits were observed only in right HES. DCM results revealed that CHR-P participants showed reduced top-down modulation from the right IPL to the right HES. Importantly, deficits in sensory attenuation did not predict clinical outcomes in the CHR-P group. Our results show that early-stage psychosis involves impaired sensory attenuation in auditory and thalamic regions but may not predict clinical outcomes in CHR-P participants