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.

Functional Magnetic Resonance Imaging Signatures of Pavlovian and Instrumental Valuation Systems during a Modified Orthogonalized Go/No-go Task.

Motivational (i.e., Pavlovian) values interfere with instrumental responding and can lead to suboptimal decision-making. In humans, task-based neuroimaging studies have only recently started illuminating the functional neuroanatomy of Pavlovian biasing of instrumental control. To provide a mechanistic understanding of the neural dynamics underlying the Pavlovian and instrumental valuation systems, analysis of neuroimaging data has been informed by computational modeling of conditioned behavior. Nonetheless, because of collinearities in Pavlovian and instrumental predictions, previous research failed to tease out hemodynamic activity that is parametrically and dynamically modulated by coexistent Pavlovian and instrumental value expectations. Moreover, neural correlates of Pavlovian to instrumental transfer effects have so far only been identified in extinction (i.e., in the absence of learning). In this study, we devised a modified version of the orthogonalized go/no-go paradigm, which introduced Pavlovian-only catch trials to better disambiguate trial-by-trial Pavlovian and instrumental predictions in both sexes. We found that hemodynamic activity in the ventromedial pFC covaried uniquely with the model-derived Pavlovian value expectations. Notably, modulation of neural activity encoding for instrumental predictions in the supplementary motor cortex was linked to successful action selection in conflict conditions. Furthermore, hemodynamic activity in regions pertaining to the limbic system and medial pFC was correlated with synergistic Pavlovian and instrumental predictions and improved conditioned behavior during congruent trials. Altogether, our results provide new insights into the functional neuroanatomy of decision-making and corroborate the validity of our variant of the orthogonalized go/no-go task as a behavioral assay of the Pavlovian and instrumental valuation systems.

Transition to schizophrenia in acute and transient psychotic disorders.

BACKGROUND: The diagnostic category of acute and transient psychotic disorders (ATPD) was introduced in ICD-10. Subsequent studies have called into question its validity and reliability. AIMS: To determine the pattern of diagnostic revision to schizophrenia in first-ever diagnosed ATPD. METHOD: Using data drawn from the Scottish Morbidity Record, we estimated incidence and diagnostic change in first-ever diagnosed ATPD in Scottish hospitals between January 1997 and December 2010 (n = 2923). RESULTS: The average incidence of ATPD was 4.1 per 100 000 population per year. Diagnostic stability was estimated at 53.9% over an average of approximately 4 years of observation. The most common diagnostic shift was to schizophrenia (12.6%), over an average of 1.7 years. Estimates of the transition risks for schizophrenia were 80% at 2.8 years and 90% at 4.6 years. Longer first admission to hospital, younger age at onset and male gender were associated with increased risk and earlier development of schizophrenia. CONCLUSIONS: Routinely collected data suggest that approximately one in eight individuals with first-ever diagnosed ATPD will develop schizophrenia within 3-5 years. Those at high risk of transition may benefit from monitoring for possible diagnostic change.

Teaching therapeutic seizure criteria to psychiatrists.

OBJECTIVES: Following on from our previous work looking at the interrater reliability of assessing seizure adequacy for electroconvulsive therapy (ECT), we sought to examine whether a specific teaching module could improve the reliability of visual inspection of electroencephalography (EEG) recordings for specific features of seizure length, presence of polyspike, δ wave activity, and post-ictal suppression. METHODS: Twelve medical practitioners at varying levels of training and ECT experience rated 15 EEG traces after minimal training and a further set of 15 EEG traces after a more detailed training. Results were analyzed to examine the interrater reliability of the EEG features and the overall assignment of traces as meeting "old" (1995) or "new" (2005) Royal College of Psychiatrists criteria for therapeutic seizures compared with the agreed ratings of 2 experienced ECT practitioners ("standard ratings"). RESULTS: There was evidence for a specific training effect for the "old" criteria with an improvement in the interrater reliability (generalized κ, 0.590 vs 0.813) associated with a significantly better estimation of seizure length as assessed by comparison of the root mean square difference from the standard ratings (mean, 7.83 vs 4.49; P < 0.003). The interrater reliability for the new criteria did not improve (generalized κ, 0.599 vs 0.581) but was already at quite a good standard. Examination of individual features did demonstrate improvement in the rating of δ activity (generalized κ, 0.564 vs 0.655) and post-ictal suppression (generalized κ, 0.553 vs 0.611) after the training. When these 2 criteria were grouped together (δ suppression), interrater reliability was shown to be significantly improved after the training (generalized κ, 0.568 vs 0.659). Although not statistically significant, the participants reported that the training improved their confidence in using both criteria for therapeutic seizures (old: 49% vs 67%; new: 27% vs 48%). CONCLUSIONS: The reliability of assessments of seizure length, presence of δ activity, and post-ictal suppression can be measurably improved with a specific teaching module. Using the δ suppression criteria together with the accurate estimation of seizure length on EEG may have greater clinical utility when it comes to instructing trainees in ECT administration, assessment of therapeutic seizures, and developing protocols for dose adjustment.

Interrater reliability of 2 definitions of seizure adequacy in electroconvulsive therapy.

OBJECTIVES: Clear evidence of a generalized seizure is regarded as an essential component of a therapeutic electroconvulsive therapy (ECT) session. Recent criteria, in particular, the Royal College of Psychiatry ECT Handbook (2005), suggest that the pattern of electroencephalographic (EEG) seizure is more important than the duration of the seizure when assessing seizure adequacy. We examined the reliability of using EEG criteria compared to simple measures of seizure duration by reviewing 100 sample EEG printouts obtained during ECT sessions in a Scottish hospital ECT unit. METHODS: The EEGs were independently assessed by 3 clinicians (a "control" ECT consultant, an experienced ECT therapist, and a less experienced trainee) blind to each other's ratings. RESULTS: While there was good interrater reliability for measures of seizure duration, kappa scores for EEG criteria were much better for the more than the less experienced rater (κ = 0.68 vs 0.50). Even greater differences were seen for individual components: polyspike activity (κ = 0.80 vs 0.55), spike and wave complexes (κ = 0.80 vs 0.38), and postictal suppression (κ = 0.63 vs 0.35). CONCLUSIONS: The implications of these finding are briefly discussed in the context of developing rational criteria for assessing ECT efficacy that rely upon the consistent and replicable delivery of standardized ECT techniques and consequent training needs of ECT practitioners.

Neural correlates of weighted reward prediction error during reinforcement learning classify response to cognitive behavioral therapy in depression.

While cognitive behavioral therapy (CBT) is an effective treatment for major depressive disorder, only up to 45% of depressed patients will respond to it. At present, there is no clinically viable neuroimaging predictor of CBT response. Notably, the lack of a mechanistic understanding of treatment response has hindered identification of predictive biomarkers. To obtain mechanistically meaningful fMRI predictors of CBT response, we capitalize on pretreatment neural activity encoding a weighted reward prediction error (RPE), which is implicated in the acquisition and processing of feedback information during probabilistic learning. Using a conventional mass-univariate fMRI analysis, we demonstrate that, at the group level, responders exhibit greater pretreatment neural activity encoding a weighted RPE in the right striatum and right amygdala. Crucially, using multivariate methods, we show that this activity offers significant out-of-sample classification of treatment response. Our findings support the feasibility and validity of neurocomputational approaches to treatment prediction in psychiatry.

Spatiotemporal neural characterization of prediction error valence and surprise during reward learning in humans.

Reward learning depends on accurate reward associations with potential choices. These associations can be attained with reinforcement learning mechanisms using a reward prediction error (RPE) signal (the difference between actual and expected rewards) for updating future reward expectations. Despite an extensive body of literature on the influence of RPE on learning, little has been done to investigate the potentially separate contributions of RPE valence (positive or negative) and surprise (absolute degree of deviation from expectations). Here, we coupled single-trial electroencephalography with simultaneously acquired fMRI, during a probabilistic reversal-learning task, to offer evidence of temporally overlapping but largely distinct spatial representations of RPE valence and surprise. Electrophysiological variability in RPE valence correlated with activity in regions of the human reward network promoting approach or avoidance learning. Electrophysiological variability in RPE surprise correlated primarily with activity in regions of the human attentional network controlling the speed of learning. Crucially, despite the largely separate spatial extend of these representations our EEG-informed fMRI approach uniquely revealed a linear superposition of the two RPE components in a smaller network encompassing visuo-mnemonic and reward areas. Activity in this network was further predictive of stimulus value updating indicating a comparable contribution of both signals to reward learning.

Clozapine-induced interstitial nephritis - a rare but important complication: a case report.

INTRODUCTION: Given the limited range of effective drug treatments for patients with schizophrenia, increasing numbers of patients, often termed 'treatment-resistant' are prescribed clozapine. While the induction of neutropenia or agranulocytosis by clozapine is well appreciated, other rare potentially fatal adverse reactions may also occur including acute interstitial nephritis as reported in this case. CASE PRESENTATION: A 57-year-old Caucasian woman with treatment-resistant chronic schizophrenia developed acute renal failure following initiation of treatment with clozapine. The adverse reaction occurred after only four doses of the drug had been administered (titrated from 12.5 to 25 mg per day). After clozapine had been withdrawn, the patient's renal function returned to normal with no other changes to medication. The patient had been exposed to clozapine about 4 years previously when she had developed a similar reaction. CONCLUSION: Renal reactions to clozapine are extremely rare but, if not recognized promptly, may prove fatal. Psychiatrists need to be aware of this possible complication when clozapine is initiated.