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Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose–response and (iv) select primary outcomes for future trials.
In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment.
A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30–40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = −0.48 to −0.76), improved symptoms of paranoia (d = −0.19 to −0.38), and lower depressed and anxious mood (d = −0.03 to −0.29). The intervention effect was evident after the third session.
CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.
To define the frequency and characteristics of acute neurologic complications in children hospitalised with infective endocarditis and to identify risk factors for neurologic complications.
Retrospective cohort study of children aged 0–18 years hospitalised at a tertiary children’s hospital from 1 January, 2008 to 31 December, 2017 with infective endocarditis.
Sixty-eight children met Duke criteria for infective endocarditis (43 definite and 25 possible). Twenty-three (34%) had identified neurologic complications, including intracranial haemorrhage (25%, 17/68) and ischaemic stroke (25%, 17/68). Neurologic symptoms began a median of 4.5 days after infective endocarditis symptom onset (interquartile range 1, 25 days), though five children were asymptomatic and diagnosed on screening neuroimaging only. Overall, only 56% (38/68) underwent neuroimaging during acute hospitalisation, so additional asymptomatic neurologic complications may have been missed. Children with identified neurologic complications compared to those without were older (48 versus 22% ≥ 13 years old, p = 0.031), more often had definite rather than possible infective endocarditis (96 versus 47%, p < 0.001), mobile vegetations >10mm (30 versus 11%, p = 0.048), and vegetations with the potential for systemic embolisation (65 versus 29%, p = 0.004). Six children died (9%), all of whom had neurologic complications.
Neurologic complications of infective endocarditis were common (34%) and associated with mortality. The true frequency of neurologic complications was likely higher because asymptomatic cases may have been missed without screening neuroimaging. Moving forward, we advocate that all children with infective endocarditis have neurologic consultation, examination, and screening neuroimaging. Additional prospective studies are needed to determine whether early identification of neurologic abnormalities may direct management and ultimately reduce neurologic morbidity and overall mortality.
The purpose of this study was to examine whether self-efficacy predicted pediatric concussion symptom severity and explore whether affective mood states (e.g., depression) influenced this relationship.
Children (8–17 years) who were diagnosed with a concussion within 30 days of injury participated in the study (n = 105). Following a clinical assessment, participants and caregivers completed questionnaires that assessed overall concussion symptom severity and current depression symptoms. Participants also completed ratings capturing self-efficacy for managing concussion recovery.
Linear regression models revealed that greater levels of self-efficacy predicted lower parent- (R2 = 0.10, p = .001) and youth-rated (R2 = 0.23, p < .001) concussion symptom severity. Interestingly, depression symptoms moderated the relationship between self-efficacy and concussion symptom severity.
Findings provide initial support for a relationship between self-efficacy and concussion outcomes and highlight the influence of depressive symptoms. Interventions that optimize youth’s self-efficacy have the potential to increase treatment adherence, reduce concussion symptom severity, and improve recovery prognosis.
Assessment of risks of illnesses has been an important part of medicine for decades. We now have hundreds of ‘risk calculators’ for illnesses, including brain disorders, and these calculators are continually improving as more diverse measures are collected on larger samples.
We first replicated an existing psychosis risk calculator and then used our own sample to develop a similar calculator for use in recruiting ‘psychosis risk’ enriched community samples. We assessed 632 participants age 8–21 (52% female; 48% Black) from a community sample with longitudinal data on neurocognitive, clinical, medical, and environmental variables. We used this information to predict psychosis spectrum (PS) status in the future. We selected variables based on lasso, random forest, and statistical inference relief; and predicted future PS using ridge regression, random forest, and support vector machines.
Cross-validated prediction diagnostics were obtained by building and testing models in randomly selected sub-samples of the data, resulting in a distribution of the diagnostics; we report the mean. The strongest predictors of later PS status were the Children's Global Assessment Scale; delusions of predicting the future or having one's thoughts/actions controlled; and the percent married in one's neighborhood. Random forest followed by ridge regression was most accurate, with a cross-validated area under the curve (AUC) of 0.67. Adjustment of the model including only six variables reached an AUC of 0.70.
Results support the potential application of risk calculators for screening and identification of at-risk community youth in prospective investigations of developmental trajectories of the PS.
Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis.
Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up.
The association of stress with positive (β = −0.14, p = 0.010) and negative affect (β = 0.11, p = 0.020) was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect (β = 0.06, p = 0.019) and psychotic experiences (β = 0.05, p = 0.037) was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up (B = 6.29, p = 0.034). In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity (e.g. indirect effect: B = −2.13, p = 0.026), but no evidence that stress reactivity mediated the association between childhood trauma and transition (e.g. indirect effect: B = 0.14, p = 0.506).
Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals.
Women of childbearing age often experience mental health problems, receive psychotropic medication and are admitted to mental health units. Approximately 40% of pregnancies are unplanned and many women experience perinatal mental health problems. It is therefore vital that consideration is given to reproductive health in mental health policy. We aimed to evaluate the consideration of pregnancy and breastfeeding in the policies of an inpatient mental health service.
The policies of a regional inpatient psychiatric unit were independently reviewed by two researchers. Policies that had implications for pregnancy and breastfeeding for patients were identified. Whether or not these policies considered pregnancy and breastfeeding and the detail of this consideration was evaluated.
One hundred and thirteen policies were evaluated. Forty had implications for pregnancy but only 10 of these mentioned pregnancy and only 3 in detail. Only 3 of the 28 policies that had relevance to breastfeeding mothers mentioned it and none discussed it in detail. Key areas of omission included prescribing, seclusion and restraint and cultural and religious considerations.
Pregnancy and breastfeeding were almost entirely absent in the ward policies of our inpatient unit. Their consideration in the acute setting is vital. An individual or group of individuals should be responsible for ensuring that reproductive health is considered in all policies as well as in a larger specific policy suitable for referencing. The rights of the reproductive woman should be comprehensively considered in inpatient mental health care policy.
Our objectives were to explore attitudes regarding food retail policy and government regulation among managers of small food stores and examine whether manager views changed due to the 2014 Minneapolis Staple Foods Ordinance, a city policy requiring retailers to stock specific healthy products.
Manager interviewer-administered surveys were used to assess views on food retail policy four times from 2014 to 2017. We examined baseline views across manager and store and neighbourhood characteristics using cross-sectional regression analyses and examined changes over time using mixed regression models. In 2017, open-ended survey questions asked about manager insights on the Minneapolis Staple Foods Ordinance.
Minneapolis, MN, where the ordinance was enacted, and St. Paul, MN, a control community, USA.
Managers from 147 small food retail stores.
At baseline, 48 % of managers were likely to support a policy requiring stores to stock healthy foods/beverages, 67·5 % of managers were likely to support voluntary programmes to help retailers stock healthy foods and 23·7 % agreed government regulation of business is good/necessary. There was a significant increase in overall support for food retail policies and voluntary programmes from 2014 to 2017 (P < 0·01); however, neither increase differed by city, suggesting no differential impact from the ordinance. Minneapolis store managers reported some challenges with ordinance compliance and offered suggestions for how local government could provide support.
Findings suggest that managers of small food retail stores are becoming increasingly amenable to healthy food policies; yet, challenges need to be addressed to ensure healthy food is available to all customers.
It remains poorly understood how negative symptoms are experienced in the daily lives of individuals in the early stages of psychosis. We aimed to investigate whether altered affective experience, anhedonia, social anhedonia, and asociality were more pronounced in individuals with an at-risk mental state for psychosis (ARMS) and individuals with first-episode psychosis (FEP) than in controls.
We used the experience sampling methodology (ESM) to assess negative symptoms, as they occurred in the daily life of 51 individuals with FEP and 46 ARMS, compared with 53 controls.
Multilevel linear regression analyses showed no overall evidence for a blunting of affective experience. There was some evidence for anhedonia in FEP but not in ARMS, as shown by a smaller increase of positive affect (BΔat−risk v. FEP = 0.08, p = 0.006) as the pleasantness of activities increased. Against our expectations, no evidence was found for greater social anhedonia in any group. FEP were more often alone (57%) than ARMS (38%) and controls (35%) but appraisals of the social situation did not point to asociality.
Overall, altered affective experience, anhedonia, social anhedonia and asociality seem to play less of a role in the daily life of individuals in the early stages of psychosis than previously assumed. With the experience of affect and pleasure in daily life being largely intact, changing social situations and appraisals thereof should be further investigated to prevent development or deterioration of negative symptoms.
Implementation of genome-scale sequencing in clinical care has significant challenges: the technology is highly dimensional with many kinds of potential results, results interpretation and delivery require expertise and coordination across multiple medical specialties, clinical utility may be uncertain, and there may be broader familial or societal implications beyond the individual participant. Transdisciplinary consortia and collaborative team science are well poised to address these challenges. However, understanding the complex web of organizational, institutional, physical, environmental, technologic, and other political and societal factors that influence the effectiveness of consortia is understudied. We describe our experience working in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, a multi-institutional translational genomics consortium.
A key aspect of the CSER consortium was the juxtaposition of site-specific measures with the need to identify consensus measures related to clinical utility and to create a core set of harmonized measures. During this harmonization process, we sought to minimize participant burden, accommodate project-specific choices, and use validated measures that allow data sharing.
Identifying platforms to ensure swift communication between teams and management of materials and data were essential to our harmonization efforts. Funding agencies can help consortia by clarifying key study design elements across projects during the proposal preparation phase and by providing a framework for data sharing data across participating projects.
In summary, time and resources must be devoted to developing and implementing collaborative practices as preparatory work at the beginning of project timelines to improve the effectiveness of research consortia.
Altered neurocognitive function in schizophrenia could reflect both genetic and illness-specific effects.
To use functional magnetic resonance imaging to discriminate between the influences of the genetic risk for schizophrenia and environmental factors on the neural substrate of verbal fluency, a candidate schizophrenia endophenotype using a case control twin design.
We studied 23 monozygotic twin pairs: 13 pairs discordant for schizophrenia and 10 pairs of healthy volunteer twins. Groups were matched for age, gender, handedness, level of education, parental socio-economic status, and ethnicity. Behavioural performance and regional brain activation during a phonological verbal fluency task were assessed.
Relative to healthy control twins, both patients and their non-psychotic co-twins produced fewer correct responses and showed less activation in the medial temporal region and inferior frontal gyrus. Twins with schizophrenia showed greater activation than both their non-psychotic co-twins and controls in right lateral temporal cortex, reflecting reduced deactivation during word generation while their non-psychotic co-twins showed greater activation in the left temporal cortex.
Both genetic vulnerability to schizophrenia and schizophrenia were associated with impaired verbal fluency performance, reduced engagement of the medial temporal region and dorsal inferior frontal gyrus. Schizophrenia was specifically associated with an additional reduction in deactivation in the right temporal cortex.
DTI studies in schizophrenia have consistently reported decreased fractional anisotropy (FA, an index of white matter microstructure) in patients. There is little evidence as to the genetic or environmental determinants of this difference however. Studies of twins with schizophrenia allow us to estimate these influences. We report a cross-sectional case control study of twins with and without schizophrenia.
We recruited mono- and di-zygotic twins concordant and discordant for DSM schizophrenia from across the United Kingdom, referred by their treating psychiatrists. We recruited healthy control twins from the Institute of Psychiatry Volunteer Twin Register and by national media advertisements. Clinical diagnoses were confirmed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott, 1978). Zygosity was confirmed by DNA analysis. Eleven pairs of monozygotic twins concordant for schizophrenia, 10 pairs of monozygotic and seven pairs of dizygotic twins discordant for schizophrenia, 24 pairs of healthy monozygotic twins and 20 pairs of healthy dizygotic twins were recruited.
Subjects were scanned with an optimized DTI sequence at 1.5T. Scans were warp-corrected, masked, and FA calculated at each voxel. FA maps were then co-registered to a study-specific FA template using SPM2 and group differences calculated on segmented white-matter FA maps using non-parametric XBAM_v3.4.
Results are presented of analyses comparing twins with schizophrenia with their well co-twin, linear trend analyses comparing healthy controls with well di and mono-zygotic co-twins, and a heritability analysis of the healthy controls.
Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders.
The present investigation examined the impact of DAAO genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers.
We tested the hypotheses that the high-risk variant of DAAO would be associated with altered prefrontal function and functional connectivity in schizophrenic and bipolar patients.
We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype and their interaction on brain activation and functional connectivity.
In schizophrenic patients relative to bipolar patients and controls, the high-risk variant of DAAO was associated with lower deactivation in the left precuneus and greater activation in the right calcarine and posterior cingulate gyrus during task performance. In addiction, these areas expressed altered functional connectivity with the rest of the brain in schizophrenic patients relative to bipolar patients and controls.
Our results suggest that genetic variation in DAAO has a significant impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in specific brain regions.
Cannabis is the world's most widely used illicit drug. It can impair verbal learning and induce psychosis, both acutely and possibly following long term use. But, where cannabis acts in the brain to impair verbal learning and induce psychotic symptoms is unclear. The aim of this study was to clarify how one of the main psychoactive ingredients of cannabis, delta-9-tetrahydrocannabinol (THC) acts on the brain to impair verbal learning and induce psychotic symptoms.
15 healthy males with minimal exposure to cannabis, were studied on 2 occasions approximately 1 month apart, following oral administration of 10mg of THC or placebo 1 hour prior to scanning, in a double-blind design. MR images were acquired on a 1.5T GE camera while subjects performed a Verbal paired associates task with separate encoding followed by retrieval conditions, with the conditions repeated in the same sequence 4 times. We examined the main effects of drug, task and drug- task interactions.
Administration of THC abolished the normal linear decrement in parahippocampal activation across successive encoding blocks and was associated with a trend for impaired word recall. Administration of THC also altered the normal time-dependent change in ventral striatal activation during retrieval of word pairs which was directly correlated with concurrently induced psychotic symptoms.
These results suggest that impairment in learning and verbal memory associated with cannabis use may be mediated through its action in the medial temporal cortex while psychotic symptoms may be induced through its action in the ventral striatum.
Object working memory performance is abnormal in the early stages of schizophrenia. Such tasks recruit frontal and temporal cortices, possible sites of progressive change over the early illness course. We wanted to clarify if functional changes can be detected in the early stages of schizophrenia, to identify their anatomical location and their relationship to the stage of illness using a functional object working memory task in which the length of memory delay was manipulated.
40 subjects contributed: 10 first episode psychosis (FEp) patients, 16 with an at risk mental state (ARMS) and 14 healthy controls. We collected functional MRI data while the subjects performed a version of the delayed matching to sample (DMTS) task from the Cambridge Automated Neuropsychological Test Battery (CANTAB).
Behaviourally there was a trend to a group by delay interaction, the two patient groups making more errors at longer memory delays. At successful recognition a main effect of group was detected in the medial temporal lobe bilaterally, while a main effect of delay was detected in the left medial temporal lobe. At each length of memory delay the patient groups showed consistently greater activation of medial temporal regions when performing the task accurately.
Both ARMS & FEp groups showed greater activation than controls in the medial temporal cortex across all lengths of memory delay. These differences were not related to poorer task performance, but suggest an inefficiency mechanism that may correlate with the vulnerability to psychosis rather than pychosis per se.
There is considerable interest in the therapeutic potential of Cannabidiol (CBD), the second most abundant component of Cannabis. While delta-9-THC, the main psychoactive ingredient of cannabis, impairs memory and induces anxiety and psychotic symptoms acutely and increases the risk of psychotic disorders in regular cannabis users, CBD does not impair memory, may have anxiolytic and possibly antipsychotic effects. Hence, we compared directly the acute neural effects of these two active ingredients of cannabis, by combining pharmacological challenge with fMRI. Using a double-blind, repeated measures design and oral challenge with 10mg of delta-9-THC, 600mg of CBD or placebo in 15 healthy volunteers, we examined whether delta-9-THC and CBD have opposing effects on the neural substrates of verbal memory and fear processing and whether they also have opposing effects on the neural substrates of anxiety and psychotic symptoms induced by delta-9-THC. Delta-9-THC induced anxiety and psychotic symptoms acutely while there was a trend for a reduction in anxiety but no change in psychotic symptoms with CBD. During the memory task, delta-9-THC attenuated and CBD increased activation in the striatum bilaterally. Effect of delta-9-THC on striatal activation was inversely correlated with the psychotic symptoms induced by it concomitantly. During the processing of fearful faces, delta-9-THC increased and CBD attenuated activation in the amygdala and these effects correlated with their anxiogenic and anxiolytic effects respectively. These opposing effects of CBD on the key neural substrates for psychotic symptoms and anxiety induced by delta-9-THC may suggest its possible therapeutic role in countering these conditions.
The complex sulco-gyral pattern results from fetal and early childhood processes that shape the cortex anatomy from a smooth lissencephalic structure to a highly convoluted surface. Abnormal brain maturation has been suggested as risk factor for schizophrenia. Thus, measures of the cortical folding pattern could provide cues for the neurodevelopmental aspects of pathopsychology.
Brain morphometry softwares providing 3D sulci descriptors (e.g. surface) from MRI (Mangin, 2004 ; Cachia, 2007). This automatized method avoids biases inherent to image normalisation and partial volume effect. Therefore, statistics on sulcal measurements should generalize across patients. T1 MRI datasets were studied in at-risk subjects, adolescent onset schizophrenia, and patients with treatment-resistant depression and auditory hallucinations.
Decreased in sulci surface were detected in whole brain sulcal indices and in regional sulcal indices. Decreases in global sulcal indices were detected in most patient groups, except in at risk subjects. Decreases in local sulcal indices were detected in langage-related areas in resistant hallucinators (Cachia 2007), and confined to left temporal regions in adolescent schizophrenia (Pentilla, submitted). In patients with treatment-resistant depression, sulci descriptors differed in right hemisphere sulci adjacent to limbic regions (Pentilla, submitted).
The potential of the gyrification pattern for the inference of neuroimage-based developmental biomarkers will be further examined using multivariate classification approaches (Duchesnay 2006).
. Mangin et al., Neuroimage 2004 - Cachia et al., Neuroimage 2007 – Duchesnay et al., Neuroimage 2006
Previous DTI studies in schizophrenia have all found decreased white matter integrity in the patients, though the location of these differences has varied. This may be due to the use of region-of-interest methods and underpowered studies. We used voxel-based DTI to examine a much larger sample of patients with schizophrenia and controls.
Seventy-six patients with DSM-IV schizophrenia and 76 controls matched for age, gender, handedness, IQ, and education were scanned with an optimized DTI sequence at 1.5T. FA maps were co-registered using SPM2 and group differences calculated using non-parametric XBAM_v3.4. Mean FA was extracted from each significant cluster and correlated with illness duration in the patients. Cluster FA was compared between the 15 patients with a few days exposure to antipsychotics and 30 matched patients who had been treated for over a year.
At thresholds of <1 false positive (voxel p<0.01, cluster p<0.0005), there were widespread reductions in FA in the patient group. These areas included bilateral cingulum, superior & inferior longitudinal fasciculus, left uncinate and the genu of the corpus callosum. There were no areas of increased FA in patients relative to controls. In our secondary analyses, there were no significant correlations between the mean FA extracted from any of these clusters and duration of illness, and no significant differences between the briefly medicated and chronically medicated groups.
Schizophrenia is associated with FA reductions distributed widely in white matter, but these differences do not correlate with duration of illness, and do not segregate with medication.
People with ‘prodromal’ symptoms have a very high risk of developing psychosis. We used functional MRI to examine the neurocognitive basis of this vulnerability.
Cross-sectional comparison of subjects with an ARMS (n=17), first episode schizophreniform psychosis (n=10) and healthy volunteers (n=15). Subjects were studied using functional MRI while they performed an overt verbal fluency task, a random movement generation paradigm and an N-Back working memory task.
During an N-Back task the ARMS group engaged inferior frontal and posterior parietal cortex less than controls but more than the first episode group. During a motor generation task, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than the first episode group. During verbal fluency using ‘Easy’ letters, the ARMS group demonstrated intermediate activation in the left inferior frontal cortex, with first episode groups showing least, and controls most, activation. When processing ‘Hard’ letters, differential activation was evident in two left inferior frontal regions. In its dorsolateral portion, the ARMS group showed less activation than controls but more than the first episode group, while in the opercular part of the left inferior frontal gyrus / anterior insula activation was greatest in the first episode group, weakest in controls and intermediate in the ARMS group.
The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have just developed psychosis but less severe.
To examine the effect of a polymorphism in the Dopamine Transporter (DAT) gene on brain activation during executive function and, for the first time:
1. determine the extent to which this is altered in schizophrenia and
2. use a verbal fluency paradigm.
This is relevant since:
1. DAT plays a key role in the regulation of dopamine, which modulates cortical activation during cognitive tasks and
2. a disruption of dopamine function is a fundamental pathophysiological feature of schizophrenia.
Functional magnetic resonance imaging was used to measure whole-brain responses during overt verbal fluency in 85 subjects: 44 healthy volunteers and 41 DSM-IV schizophrenia patients. Main effects of genotype and diagnostic group on activation and their interaction were estimated using an ANOVA in SPM5.
The 10-repeat allele of the 3'UTR VNTR was associated with greater activation than the 9-repeat allele in the left (Z=4.8; FWEp=0.005) and right (Z=4.2; FWEp=0.057) anterior insula and with decreased activation in the rostral anterior cingulate (Z=4.3 FWEp=0.04) during word generation (versus baseline). These effects were irrespective of diagnostic group but generally more marked in patients. There were also strong trends for groupxgenotype interactions in the left middle frontal gyrus and the left nucleus accumbens. Analysis was controlled for task performance, IQ, antipsychotic medication, psychopathology and demographics.
Cortical function during executive tasks is normally modulated by variation in the DAT gene, effect which is dependent on the brain region. DAT's effect may be altered in schizophrenia patients, which may reflect altered central dopamine function.