Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

Outcome after restorative proctocolectomy and ileal pouch-anal anastomosis in children and adults.

BACKGROUND: Studies comparing the outcome of ileal pouch-anal anastomosis (IPAA) in children and adults are scarce. This complicates decision-making in young patients. The aim of this study was to compare adverse events and pouch function between children and adults who underwent IPAA. METHODS: This cross-sectional cohort study included all consecutive children (aged less than 18 years) and adults with a diagnosis of inflammatory bowel disease or familial adenomatous polyposis who underwent IPAA in a tertiary referral centre between 2000 and 2015. Adverse events were assessed by chart review, and pouch function by interview using a pouch function score (PFS). RESULTS: In total, 445 patients underwent IPAA: 41 children (median age 15 years) and 404 adults (median age 39 years), with a median follow-up of 22 (i.q.r. 8-68) months. Being overweight (P = 0·001), previous abdominal surgery (P = 0·018), open procedures (P < 0·001) and defunctioning ileostomy (P = 0·014) were less common among children than adult patients. The occurrence of anastomotic leakage, surgical fistulas, chronic pouchitis and Crohn's of the pouch was not associated with paediatric age at surgery, nor was pouch failure. The development of anastomotic strictures was associated with having IPAA surgery during childhood (odds ratio 4·22, 95 per cent c.i. 1·13 to 15·77; P = 0·032). Pouch function at last follow-up was similar in the children and adult groups (median PFS 5·0 versus 6·0 respectively; P = 0·194). CONCLUSION: Long-term pouch failure rates and pouch function were similar in children and adults. There is no need for a more cautious attitude to use of IPAA in children based on concerns about poor outcome.

Five year follow-up of non-psychotic adults with frequent auditory verbal hallucinations: are they still healthy?

BACKGROUND: Previously, we described 103 adults (mean age 41 years) who experienced frequent, auditory verbal hallucinations (AVH), in the absence of a need for mental healthcare. Importantly, these adults were largely past the peak incidence age for psychosis (15-35 years). It is unclear if these older individuals with AVH are still at increased risk for psychosis or other psychopathology. To address this question, we conducted a 5-year follow-up of previously included individuals (103 with AVH, 60 controls). METHOD: Eighty-one adults with AVH (78.6%) and forty-nine controls (81.7%) could be contacted and were willing to participate. Participants were screened for psychosis and a need for mental healthcare at follow-up using the Comprehensive Assessment of Symptoms and History interview (CASH). Need for mental healthcare was defined as a clinical diagnosis as identified using the CASH and/or treatment by a mental healthcare specialist. Phenomenology of AVH was assessed with the PSYRATS Auditory Hallucinations Rating Scale. RESULTS: Five individuals with AVH (6.2%) had developed psychosis and 32 (39.5%) had developed a need for mental healthcare. Voice-related distress at baseline significantly predicted need for mental healthcare. AVH persisted in most individuals (86.4%), without significant changes in phenomenology. None of the controls had developed psychotic symptoms, and need for mental healthcare (n = 6, 12.2%) was significantly lower in this group. CONCLUSIONS: These findings suggest that frequent AVH in non-psychotic adults past the peak incidence age for psychosis constitute a rather static symptom and that individuals with AVH may be best viewed as situated on a need for care continuum.

Aberrant resting-state connectivity in non-psychotic individuals with auditory hallucinations.

BACKGROUND: Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. METHOD: Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. RESULTS: In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. CONCLUSIONS: Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain.

Auditory verbal hallucinations in patients with borderline personality disorder are similar to those in schizophrenia.

BACKGROUND: Auditory verbal hallucinations (AVH) in patients with borderline personality disorder (BPD) are frequently claimed to be brief, less severe and qualitatively different from those in schizophrenia, hence the term 'pseudohallucinations'. AVH in BPD may be more similar to those experienced by healthy individuals, who experience AVH in a lower frequency and with a more positive content than AVH in schizophrenia. In this study the phenomenology of AVH in BPD patients was compared to that in schizophrenia and to AVH experienced by non-patients. METHOD: In a cross-sectional setting, the phenomenological characteristics of AVH in 38 BPD patients were compared to those in 51 patients with schizophrenia/schizoaffective disorder and to AVH of 66 non-patients, using the Psychotic Symptom Rating Scales (PSYRATS). RESULTS: BPD patients experienced AVH for a mean duration of 18 years, with a mean frequency of at least daily lasting several minutes or more. The ensuing distress was high. No differences in the phenomenological characteristics of AVH were revealed among patients diagnosed with BPD and those with schizophrenia/schizoaffective disorder, except for 'disruption of life', which was higher in the latter group. Compared to non-patients experiencing AVH, BPD patients had higher scores on almost all items. CONCLUSIONS: AVH in BPD patients are phenomenologically similar to those in schizophrenia, and different from those in healthy individuals. As AVH in patients with BPD fulfil the criteria of hallucinations proper, we prefer the term AVH over 'pseudohallucinations', so as to prevent trivialization and to promote adequate diagnosis and treatment.

Childhood trauma and auditory verbal hallucinations.

BACKGROUND: Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices. METHOD: A total of 127 non-psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated. RESULTS: Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics. CONCLUSIONS: These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder.

Raised faecal calprotectin is associated with subsequent symptomatic relapse, in children and adolescents with inflammatory bowel disease in clinical remission.

BACKGROUND: Reliable data on inflammatory biomarkers for predicting relapse of paediatric inflammatory bowel disease (IBD) are lacking. AIM: To investigate the predictive value of faecal calprotectin (FC) and CRP for symptomatic relapse in pediatric IBD in clinical remission. METHODS: In this cross-sectional cohort study, patients <18 years with Crohn's disease or ulcerative colitis in clinical remission ≥3 months were included. At baseline, clinical and biochemical disease activity were assessed using the abbreviated-Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, and FC and CRP respectively. Disease course over the subsequent 12 months was retrospectively assessed. RESULTS: In total, 114 patients (56% males; median age 14.9 years) were included. Baseline FC was higher in patients that developed symptomatic relapse [median (IQR), relapse 370 µg/g (86-1100) vs. remission 122 µg/g (40-344), P = 0.003]. Baseline FC was predictive of symptomatic relapse within 6 months [HR per 250 µg/g (95% CI): 1.46 (1.21-1.77), P < 0.001], with good predictive accuracy (AUC: 0.82). Optimal FC cut-off was 350 µg/g, with positive and negative predictive value of 41% and 96%. Baseline CRP was higher in patients that developed symptomatic relapse [median (IQR), relapse 1.0 µg/g (0.6-5.0) vs. remission 1.0 µg/g (0.4-2.0), P = 0.033]. Baseline CRP was predictive of symptomatic relapse within 6 months from baseline [HR per 1 mg/L (95% CI): 1.10 (1.02-1.19), P = 0.011], with fair predictive accuracy (AUC: 0.72). Optimal CRP cut-off was 1.0 mg/L, with positive and negative predictive value of 21% and 94%. CONCLUSIONS: Faecal calprotectin and CRP are predictive of symptomatic relapse and may be valuable in management of paediatric IBD in clinical remission.

The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines.

Thiopurines are commonly used drugs in the therapy of Crohn's disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn's disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn's disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn's disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.

The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity.

BACKGROUND: A large proportion (25-46%) of adults with inflammatory bowel disease in remission has symptoms of irritable bowel syndrome (IBS), which are thought to reflect ongoing inflammation. Data on paediatric inflammatory bowel disease patients are lacking. AIM: To investigate (i) the prevalence of IBS-type symptoms in paediatric inflammatory bowel disease patients in remission and (ii) the relationship of IBS-type symptoms with biochemical markers of disease activity. METHODS: This cross-sectional study included all patients (<18 years) with Crohn's disease or ulcerative colitis attending the out-patient clinic of one of three Dutch hospitals between March 2014 and June 2015. Clinical disease activity was determined using the abbreviated-PCDAI or PUCAI. Biochemical disease activity was assessed using faecal calprotectin and serum CRP. IBS-symptoms were assessed using physician-administered Rome III-questionnaires. RESULTS: We included 184 patients (92 female; mean age: 14.5 years) (Crohn's disease: 123, ulcerative colitis: 61). The prevalence of IBS-type symptoms in children with inflammatory bowel disease in clinical remission was 6.4% (95% CI: 2.5-11.1%; Crohn's disease: 4.5%; ulcerative colitis: 10.8%). Prevalence of IBS-type symptoms in children with faecal calprotectin <250 µg/g was 16.1% (95% CI: 7.6-25.8%; Crohn's disease: 16.7%; ulcerative colitis: 10.8%). No difference in faecal calprotectin or CRP was found between patients in clinical remission with or without IBS-type symptoms (faecal calprotectin: IBS+ median 58 µg/g, IBS- 221 µg/g, P = 0.12; CRP: IBS+ median 1.4 mg/L, IBS- 1.1 mg/L, P = 0.63). CONCLUSIONS: The prevalence of IBS-type symptoms in children with inflammatory bowel disease is highly dependent on the definition of remission. Nonetheless, the prevalence is much lower than that previously reported in studies in adult inflammatory bowel disease patients. IBS-type symptoms appear to be unrelated to gastrointestinal inflammation.

Reproducibility of brain activation during auditory verbal hallucinations.

Previous studies investigated fMRI-guided repetitive Transcranial Magnetic Stimulation (rTMS) as an alternative treatment for auditory verbal hallucinations (AVH). This tailor-made treatment focuses at directing the rTMS coil to the location where hallucinatory activation is maximal, as identified with fMRI scans of individual patients. For the effective use of such treatment it is important to determine whether brain activation during AVH can be reliably detected using fMRI. Thirty-three psychotic patients indicated the presence of AVH during two subsequent scans. Reproducibility was measured by calculating 1) the distance between local maxima of significantly activated clusters and 2) percentage overlap of activation patterns over the two scans. These measurements were obtained both in single subjects and on group-level in five regions of interest (ROIs). ROIs consisted of the areas that were most frequently activated during AVH. Scans were considered reproducible if the distance between local maxima was smaller than 2 cm, as rTMS-treatment may target an area of approximately 2-4 cm. The median distance between local maxima was smaller than 2 cm for all ROIs on single-subject level, as well as on group-level. In addition, on single-subject level median percentage overlap varied between 14 and 38% for the different ROIs. On group-level, this was substantially higher with percentages overlap varying between 34 and 98%. Based on these results, AVH-scans may be considered sufficiently reproducible to be suitable for fMRI-guided rTMS treatment.

Microstructural alterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupted connectivity between frontal and temporo-parietal language areas, giving rise to the misattribution of inner speech, is speculated to underlie this phenomenon. Disrupted connectivity should be reflected in the microstructure of the arcuate fasciculi (AF); the main connection between frontal and temporo-parietal language areas. In this study we compared microstructural properties of the AF and three other fiber tracts (cortical spinal tract, cingulum and uncinate fasciculus), between 44 schizophrenia patients with chronic severe hallucinations and 42 control subjects using diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI). The DTI scans were used to compute fractional anisotropy (FA) and to reconstruct the fiber bundles of interest, while the MTI scans were used to compute magnetic transfer ratio (MTR) values. The patient group showed a general decrease in FA for all bundles. In the arcuate fasciculus this decreased FA was coupled to a significant increase in MTR values. A correlation was found between mean MTR values in both arcuate fasciculi and the severity of positive symptoms. The combination of decreased FA and increased MTR values observed in the arcuate fasciculi in patients suggests increased free water concentrations, probably caused by degraded integrity of the axons or the supportive glia cells. This suggests that disintegrated fiber integrity in the connection between frontal and temporo-parietal language areas in the schizophrenia patients is associated with their liability for auditory verbal hallucinations.