ORCID Profile
0000-0001-8296-1742
Current Organisation
University of Cambridge
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Publisher: Cambridge University Press (CUP)
Date: 13-09-2014
DOI: 10.1017/S0033291713002328
Abstract: Emotional and behavioral problems are commonly associated with substance use in adolescence but it is unclear whether substance use precedes or follows mental health problems. The aim was to investigate longitudinal associations between externalizing and internalizing psychopathology and substance use in a prospective population study design. The s le was the Northern Finland Birth Cohort 1986 Study (NFBC 1986 n = 6349 3103 males). Externalizing and internalizing mental health problems were assessed at age 8 years (Rutter scales), substance use and externalizing and internalizing problems [Youth Self-Report (YSR)] at age 15–16 years, and hospital diagnoses for internalizing disorders (age 25) and criminal offences (age 20) from nationwide registers in adulthood. Externalizing problems at age 8 were associated with later substance use. After adjustment for sociodemographic factors, parental alcohol use and psychiatric disorders, and earlier externalizing and internalizing problems, substance use predicted criminality, especially among males, with the highest odds ratio (OR) for cannabis use [adjusted OR 6.2, 95% confidence interval (CI) 3.1–12.7]. Early internalizing problems were not a risk for later substance use. Female adolescent cannabis (OR 3.2, 95% CI 1.4–7.3) and alcohol (OR 2.1, 95% CI 1.1–4.2) use predicted internalizing disorders in adulthood. Externalizing problems precede adolescent substance use in both genders, whereas, among boys, substance use also precedes criminal offences. Internalizing problems may follow substance use in females. These associations were robust even when taking into account previous mental health problems.
Publisher: Cold Spring Harbor Laboratory
Date: 19-09-2018
DOI: 10.1101/421826
Abstract: Schizophrenia spectrum disorders and depression have been associated with reductions in brain activation during reward anticipation. It is not known whether brain signals associated with reward anticipation relate to psychopathology dimensions of depression or schizophrenia in childhood prior to adolescence. We examined whether fMRI brain correlates of reward anticipation related to psychotic-like experiences and symptoms of depression, in 2129 children from the ABCD study aged 9-10 years.Psychotic-like experiences and depression were assessed using the Prodromal Questionnaire Brief Child version and the K-SADS. We fused regional MRI summary statistics for reward anticipation activation in the ABCD study data release 1.0 (contrast of expected large reward versus neutral expectation). Relations between brain activation and psychopathology were assessed using linear regressions in R for 82 brain regions, corrected for multiple comparisons for the number of regions using false discovery rate. From several regressions, there was an isolated unilateral association between right parsorbitalis activation and psychotic-like experiences, but no other significant associations between brain activation and psychopathology. In 9-10 year old children, reward anticipation is not strongly related to psychotic-like experiences or depression. As previous evidence links depression and schizophrenia to reduced reward anticipation in adults and older adolescents, it appears likely that such associations develop over the adolescent period: this can be tested in follow-up studies of the ABCD cohort.
Publisher: Elsevier
Date: 2016
Publisher: Proceedings of the National Academy of Sciences
Date: 17-10-2006
Abstract: Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative s les of nonpsychotic adults ( n = 93) and people with schizophrenia ( n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year executive function testing and MRI were completed at age 33–35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.
Publisher: BMJ
Date: 05-04-2012
DOI: 10.1136/BMJ.E2233
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.SCHRES.2005.02.007
Abstract: It has become increasingly clear that the simple neurodevelopmental model fails to explain many aspects of schizophrenia including the timing of the onset, and the nature of the abnormal perceptions. Furthermore, we do not know why some members of the general population have anomalous experiences but remain well, while others enter the prodrome of psychosis, and a minority progress to frank schizophrenia. We suggest that genes or developmental damage result in in iduals vulnerable to dopamine deregulation. In contemporary society, this is often compounded by abuse of drugs such as hetamines and cannabis, which then propel the in idual into a state of dopamine-induced misinterpretation of the environment. Certain types of social adversity such as migration and social isolation, as well as affective change can also contribute to this. Thereafter, biased cognitive appraisal processes result in delusional interpretation of the abnormal perceptual experiences. Thus, a plausible model of the onset of psychosis needs to draw not only on neuroscience, but also on the insights of social psychiatry and cognitive psychology.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2015
Publisher: Springer Science and Business Media LLC
Date: 05-2004
DOI: 10.1007/S11920-004-0061-5
Abstract: Subtle developmental (motor, emotional, cognitive, and behavioral) abnormalities are often present in apparently healthy in iduals who later develop psychosis, suggesting that some aspects of causation are established before overt psychosis. These impairments may restrict information processing and social achievements years before manifesting psychosis. The main known risk factors in the development of schizophrenic psychosis are genetic factors, pregnancy and delivery complications, slow neuromotor development, and deviant cognitive and academic performance. However, their effect size and predictive power are small. Developmental precursors are not necessarily specific to schizophrenia, but also common to other psychotic disorders. No powerful risk factor, premorbid sign, or risk indicator has been identified that is useful for prediction of psychoses in the general population.
Publisher: Informa UK Limited
Date: 16-10-2014
DOI: 10.1080/13546805.2013.840569
Abstract: This is one of the very few studies to investigate the specific executive function rocessing speed component of response initiation in subjects at familial risk (FR) for psychosis, and the first such study in subjects at clinical risk (CR) for psychosis. Participants (N = 177) were members of the general population-based Northern Finland 1986 Birth Cohort in the following four groups: FR for psychosis (n = 62), CR for psychosis (n = 21), psychosis (n = 25) and control subjects (n = 69). The response initiation of these groups was compared in three different tests: Semantic fluency, Stockings of Cambridge and Spatial working memory. The two risk groups did not differ significantly from control group, but differed from, and outperformed the psychosis group in semantic fluency response initiation. Response initiation deficits were not evident in a non-help seeking psychosis high-risk s le.
Publisher: Public Library of Science (PLoS)
Date: 18-07-2014
Publisher: Springer-Verlag
Date: 2006
Abstract: The RESCUEicp (Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of intracranial pressure) study has been established to determine whether decompressive craniectomy has a role in the management of patients with traumatic brain injury and raised intracranial pressure that does not respond to initial treatment measures. We describe the concept of decompressive craniectomy in traumatic brain injury and the rationale and protocol of the RESCUEicp study.
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2021
DOI: 10.1101/2021.02.06.21251073
Abstract: Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large s le of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures and 14 white matter tracts. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippoc us. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical and white matter micro-structure may be linked to the genetic mechanisms of schizophrenia.
Publisher: Royal College of Psychiatrists
Date: 27-07-2020
DOI: 10.1192/BJP.2020.28
Publisher: BMJ
Date: 22-02-2003
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/13546800344000345
Abstract: Laws, Kondel, and McKenna (1999) previously reported a case study analysis of a schizophrenic patient (TC) with severe formal thought disorder (FTD). Examining consistency across item and modality of input, Laws et al. documented an impairment of access to semantic knowledge in TC. Following substantial improvement in his FTD, we readministered the same extensive battery of neuropsychological tests tapping semantic memory functioning. Whilst TC's naming remained relatively good, it also became more consistent across both time and modality. Tasks tapping language comprehension and understanding of semantic association revealed some significant improvements. Nevertheless, TC showed a residual propensity to verify false information. Improvement in FTD in schizophrenia was accompanied by a better and more stable semantic memory performance in TC. The findings are consistent with, and expand upon the original suggestion that thought disorder reflects disorganised access to semantic memory.
Publisher: Elsevier
Date: 2009
Publisher: Cambridge University Press (CUP)
Date: 09-2014
DOI: 10.1016/J.EURPSY.2013.10.006
Abstract: To analyse associations between brain morphology and longitudinal and cross-sectional measures of outcomes in schizophrenia in a general population s le. The s le was the Northern Finland 1966 Birth Cohort. In 1999–2001, structural brain MRI and measures of clinical and functional outcomes were analysed for 54 in iduals with schizophrenia around the age of 34. Sex, total grey matter, duration of illness and the use of antipsychotic medication were used as covariates. After controlling for multiple covariates, increased density of the left limbic area was associated with less hospitalisations and increased total white matter volume with being in remission. Higher density of left frontal grey matter was associated with not being on a disability pension and higher density of the left frontal lobe and left limbic area were related to better functioning. Higher density of the left limbic area was associated with better longitudinal course of illness. This study, based on unselected general population data, long follow-up and an extensive database, confirms findings of previous studies, that morphological abnormalities in several brain structures are associated with outcome. The difference in brain morphology in patients with good and poor outcomes may reflect separable aetiologies and developmental trajectories in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 07-1995
DOI: 10.1007/BF02191805
Abstract: Non-alcoholic fatty liver disease (NAFLD) initially presents as steatosis, which can progress to non-alcoholic steatohepatitis (NASH), and often presents clinically alongside metabolic syndromes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are regularly utilized to treat type 2 diabetes mellitus. The GLP-1 RA-liraglutide-ameliorates liver enzymes, histological features, and liver fat content of patients with NASH. However, few studies have examined whether the effect of GLP-1 RAs depends on changes in the patient's body mass index (BMI). Therefore, this retrospective study aimed to investigate whether the efficacy of liraglutide depended on the baseline BMI or a reduction in BMI. Fifty-five Japanese patients with type 2 diabetes mellitus and NAFLD who received liraglutide treatment for 24 weeks were assessed. The association between BMI and liver function or fibrosis was evaluated based on the aspartate aminotransferase, alanine aminotransferase, and fibrosis-4 indices. We found that 24 weeks of liraglutide treatment improved liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD, regardless of BMI changes or obesity status. Our findings provide important insight into the impact of BMI on liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD who are treated with liraglutide.
Publisher: Cold Spring Harbor Laboratory
Date: 21-03-2022
DOI: 10.1101/2022.03.19.22272444
Abstract: Higher educational attainment is observationally associated with lower risk of Alzheimer’s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer’s disease may be mediated via increased brain reserve. We used two-s le Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes, and Alzheimer’s disease. Summary statistics were obtained from genome-wide association studies of educational attainment ( n =1,131,881), late-onset Alzheimer’s disease (35,274 cases, 59,163 controls), and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI ( n max =33,211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer’s disease, (ii) educational attainment and imaging-derived phenotypes, (iii) imaging-derived phenotypes and Alzheimer’s disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the protective effect of education on Alzheimer’s disease risk. Genetically-proxied educational attainment was inversely associated with Alzheimer’s disease (odds ratio per standard deviation increase in genetically-predicted years of schooling = 0.70, 95% confidence interval [CI]: 0.60, 0.80). There was also evidence for positive associations between genetically-predicted educational attainment and four cortical macro-structure metrics (surface area: β=0.30, 95% CI: 0.20, 0.40 volume: β=0.29, 95% CI: 0.20, 0.37 intrinsic curvature: β=0.18, 95% CI: 0.11, 0.25 local gyrification index: β=0.21, 95% CI: 0.11, 0.31), as well as inverse associations with cortical intracellular volume fraction (β=-0.09, 95% CI: − 0.15, −0.03) and white matter hyperintensities volume (β=-0.14, 95% CI: −0.23, −0.05). Genetically-proxied levels of three cortical macro-structure metrics were positively associated with years of education (surface area: β=0.13, 95% CI: 0.10, 0.16 volume: β=0.15, 95% CI: 0.11, 0.19 intrinsic curvature: β=0.12, 95% CI: 0.04, 0.19). We found no evidence of associations between genetically-predicted imaging-derived phenotypes and Alzheimer’s disease. The inverse association of genetically-predicted education with Alzheimer’s disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer’s disease risk, as well as bi-directional causal associations between education and several brain macro- and micro-structure metrics. However, we did not find evidence that these structural markers affect risk of Alzheimer’s disease. The protective effect of education on Alzheimer’s disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.
Publisher: Royal College of Psychiatrists
Date: 07-2015
DOI: 10.1192/BJP.BP.114.150433
Abstract: Depression and borderline personality disorder (BPD) are both thought to be accompanied by alterations in the subjective experience of environmental rewards. We evaluated responses in women to sweet, bitter and neutral tastes (juice, quinine and water): 29 with depression, 17 with BPD and 27 healthy controls. The BPD group gave lower pleasantness and higher disgust ratings for quinine and juice compared with the control group the depression group did not differ significantly from the control group. Juice disgust ratings were related to self-disgust in BPD, suggesting close links between abnormal sensory processing and self-identity in BPD.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.PSYCHRES.2015.04.048
Abstract: Findings on longitudinal change of cognitive performance in schizophrenia are extremely variable in the case of verbal learning and memory, and it is still unclear which dimensions of verbal learning and memory exhibit possible deterioration over the long-term. Our aim was to compare the change in verbal learning and memory in in iduals with schizophrenia 10-20 years after the illness onset and healthy controls during a nine-year follow-up in a general population s le. Our s le included 41 schizophrenia spectrum subjects and 73 controls from the Northern Finland Birth Cohort study 1966. The California Verbal Learning Test (CVLT) was used to estimate the degree of change in verbal learning and memory during a nine-year follow-up from age 34-years to 43- years. Both cases and controls deteriorated. There was statistically significant decline in two out of 20 CVLT items among cases and in 13 out of 20 CVLT items among controls. With the exception of two variables, the decline in verbal learning and memory over nine years was not significantly larger in cases. We conclude that during midlife verbal learning and memory in schizophrenia mostly declines in a normative fashion with aging at the same rate as the general population.
Publisher: Research Square Platform LLC
Date: 26-05-2022
DOI: 10.21203/RS.3.RS-1677052/V1
Abstract: Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical s le of people with FEP. We developed and externally validated two risk prediction models to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts in forced-entry logistic regression models. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (forced-entry: C 0.70 95%CI 0.63,0.76 LASSO: 0.69 95%CI 0.63,0.77). At external validation, discrimination performance reduced (forced-entry: 0.63 0.58,0.69 LASSO: 0.64 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the in idual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.SCHRES.2018.05.013
Abstract: Cross-sectional studies have suggested inhalant use is associated with psychosis. This association was examined in a longitudinal study accounting for other substance use and potential confounders. We used a prospective s le (N = 6542) from the Northern Finland Birth Cohort 1986. Self-report questionnaires on substance use and psychotic experiences were completed when the cohort members were 15-16 years old. Inhalant use was categorized into four groups (never, once, 2-4 times, 5 times or more). Subsequent psychosis diagnoses (ICD-10) until age 30 years were obtained from national registers. Cox regression analysis was used to examine the association between adolescent inhalant use and risk of psychosis. During the observation period 124 in iduals were diagnosed with incident psychosis. Overall, there were 225 (3.4%) subjects with any inhalant use, 18 (8.0%) of whom were diagnosed with psychosis during the follow up. Of non-inhalant users (n = 6317) 106 (1.7%) were diagnosed with psychosis. Compared to non-users, those using inhalants had increased risk of incident psychosis with most frequent inhalant use associated with the greatest risk (unadjusted HR = 9.46 3.86-23.20). After adjusting for baseline psychotic experiences, other substance use, comorbid mental disorder and parental substance abuse, the increased risk of psychosis persisted (HR = 3.06 1.05-8.95). Furthermore, a dose-response effect between inhalant use and risk of psychosis was identified (OR = 2.34 1.83-2.99). Inhalant use in adolescence was independently associated with incident psychosis. The adverse health outcomes associated with adolescent inhalant use provide compelling reasons for implementation of policies to reduce the use of volatile substances in adolescents.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2021
DOI: 10.1186/S40359-021-00565-Y
Abstract: The COVID-19 pandemic has led to dramatic social and economic changes in daily life. First studies report an impact on mental health of the general population showing increased levels of anxiety, stress and depression. In this study, we compared the impact of the pandemic on two culturally and economically similar European countries: the UK and Germany. Participants (UK = 241, German = 541) completed an online-survey assessing COVID-19 exposure, impact on financial situation and work, substance and media consumption, mental health using the Symptom-Check-List-27 (SCL-27) and the Schizotypal Personality Questionnaire. We found distinct differences between the two countries. UK responders reported a stronger direct impact on health, financial situation and families. UK responders had higher clinical scores on the SCL-27, and higher prevalence. Interestingly, German responders were less hopeful for an end of the pandemic and more concerned about their life-stability. As 25% of both German and UK responders reported a subjective worsening of the general psychological symptoms and 20–50% of German and UK responders reached the clinical cut-off for depressive and dysthymic symptoms as well as anxieties, it specifically shows the need for tailored intervention systems to support large proportions of the general public.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2008
Publisher: American Psychiatric Association Publishing
Date: 1994
Abstract: The question of whether prenatal exposure to influenza epidemics is associated with an increased risk of later schizophrenia remains controversial. The authors examined this relationship, using data on the dates of birth and gender of 3,827 schizophrenic patients born in England and Wales between 1938 and 1965 and first admitted to hospitals in the 1980s, the numbers of live births between 1938 and 1965, and the numbers of deaths attributed to influenza between 1937 and 1965. The analysis showed that females, but not males, exposed to influenza epidemics 5 months before birth had a significantly greater rate of adult schizophrenia.
Publisher: Royal College of Psychiatrists
Date: 08-2005
Abstract: Subtle motor, emotional, cognitive and behavioural abnormalities are often present in apparently healthy in iduals who later develop schizophrenia, suggesting that some aspects of causation are established before overt psychosis. To outline the development of schizophrenia. We drew on evidence from The Northern Finland 1966 Birth Cohort supplemented by selected findings from other relevant literature. The main known risk factors in development of schizophrenia are genetic causes, pregnancy and delivery complications, slow neuromotor development, and deviant cognitive and academic performance. However, their effect size and predictive power are small. No powerful risk factor, premorbid sign or risk indicator has been identified that is useful for the prediction of schizophrenia in the general population.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.SCHRES.2014.11.003
Abstract: The central executive network controls and manages high-level cognitive functions. Abnormal activation in the central executive network has been related to psychosis and schizophrenia but it is not established how this applies to people with familial risk for psychosis (FR). We conducted a resting-state functional MRI (R-fMRI) in 72 (29 males) young adults with a history of psychosis in one or both parents (FR) but without psychosis themselves, and 72 (29 males) similarly healthy control subjects without parental psychosis. Both groups in the Oulu Brain and Mind Study were drawn from the Northern Finland Birth Cohort 1986. Participants were 20-25years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data pre-processing was conducted using independent component analysis with 30 and 70 components. A dual regression technique was used to detect between-group differences in the central executive network with p<0.05 threshold corrected for multiple comparisons. FR participants demonstrated statistically significantly lower activity compared to control subjects in the right inferior frontal gyrus, a key area of central executive network corresponding to Brodmann areas 44 and 45, known as Broca's area. The volume of the lower activation area with 30 components was 896mm(3) and with 70 components was 1151mm(3). The activity of the central executive network differed in the right inferior frontal gyrus between FR and control groups. This suggests that abnormality of the right inferior frontal gyrus may be a central part of vulnerability for psychosis.
Publisher: Cambridge University Press (CUP)
Date: 29-03-2011
DOI: 10.1017/S0033291710000413
Abstract: This article examines a model of how delusions may arise, not just in schizophrenia but also in a number of neurological and psychiatric conditions, through a combination of dysregulated dopamine release from ascending midbrain pathways and reasoning bias. Negative symptoms may also be related to dopamine dysregulation, with the precise mixture of positive and negative symptoms depending on the relative degree of dopamine dysregulation in particular mesocorticolimbic circuits. Evidence for this model is examined, and predictions arising from this model are described.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2018
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.CONB.2010.01.007
Abstract: Learning in a constant environment, and adapting flexibly to a changing one, through changes in reinforcement contingencies or valence-free cues, depends on overlapping circuitry that interconnects the prefrontal cortex (PFC) with the striatum and is subject to several forms of neurochemical modulation. We present evidence from recent studies in animals employing electrophysiological, pharmacological and lesion techniques, and neuroimaging, neuropsychological and pharmacological investigations of healthy humans and clinical patients. Dopamine (DA) neurotransmission in the medial striatum and PFC is critical for basic reinforcement learning and the integration of negative feedback during reversal learning, whilst orbitofrontal 5-hydroxytryptamine (5-HT) likely mediates this type of low level flexibility, perhaps by reducing interference from salient stimuli. The role of prefrontal noradrenaline (NA) in higher order flexibility indexed through attentional set-shifting has recently received significant empirical support, and similar avenues appear promising in the field of task switching.
Publisher: Cambridge University Press (CUP)
Date: 2010
DOI: 10.1016/J.EURPSY.2009.09.006
Abstract: To describe symptom expression and functional outcome in psychotic disorders in relation with temperament traits assessed with the Temperament and Character Inventory (TCI) in a population-based s le. As part of the 31-year follow-up survey of the Northern Finland 1966 Birth Cohort, TCI temperament items were filled in by 4349 members of the cohort. In in iduals with psychotic disorders, also positive and negative symptoms and outcome variables were assessed in a 35-year follow-up. Information of TCI and outcomes were available for altogether 41 in iduals with psychosis. Reward dependence (RD) (rho = −0.45) and Persistence (P) (rho = −0.52) were significantly correlated with Positive and Negative Syndrome Scale (PANSS) negative symptoms. Higher P scores predicted higher social and occupational functioning (as measured by Social and Occupational Functioning Assessment Scale [SOFAS]), and higher Harm avoidance (HA) predicted a higher likelihood of being on a disability pension. Results indicate that understanding of personality dimensions support better understanding of outcome and symptom expressions in psychotic disorders.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Public Library of Science (PLoS)
Date: 30-03-2012
Publisher: Oxford University Press (OUP)
Date: 21-07-2008
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BIOPSYCH.2010.09.043
Abstract: Emotional impairments are important determinants of functional outcome in psychosis, and current treatments are not particularly effective. Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy in iduals and attention and executive function in schizophrenia. We aimed to establish whether modafinil might have a role in the adjuvant treatment of emotional impairments in the first episode of psychosis, when therapeutic endeavor is arguably most vital. Forty patients with a first episode of psychosis participated in a randomized, double-blind, placebo-controlled crossover design study testing the effects of a single dose of 200 mg modafinil on neuropsychological performance. Emotional functions were evaluated with the emotional face recognition test, the affective go-no go task, and the reward and punishment learning test. Visual analogue scales were used throughout the study to assess subjective mood changes. Modafinil significantly improved the recognition of sad facial expressions (z = 2.98, p = .003). In contrast, there was no effect of modafinil on subjective mood ratings, on tasks measuring emotional sensitivity to reward or punishment, or on interference of emotional valence on cognitive function, as measured by the affective go-no go task. Modafinil improves the analysis of emotional face expressions. This might enhance social function in people with a first episode of psychosis.
Publisher: Cambridge University Press (CUP)
Date: 24-04-2020
DOI: 10.1017/S003329171900357X
Abstract: The ‘jumping to conclusions’ (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ. A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva s les from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia. The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn ( B = 0.47, 95% CI −0.21 to 1.16, p = 0.17) whereas IQ PRS ( B = 0.51, 95% CI 0.25–0.76, p 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ ( B = −1.7, 95% CI −2.8 to −0.5, p = 0.006), but did not relate to delusions in patients. Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.
Publisher: Elsevier BV
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 14-10-2020
DOI: 10.1038/S41380-020-00919-9
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Wiley
Date: 18-02-2018
DOI: 10.1111/ACPS.12863
Abstract: Daily smoking has been associated with a greater risk of psychosis. However, we are still lacking studies to adjust for baseline psychotic experiences and other substance use. We examined associations between daily smoking and psychosis risk in a 15-year follow-up while accounting for these covariates in a prospective s le (N = 6081) from the Northern Finland Birth Cohort 1986. Self-report questionnaires on psychotic experiences (PROD-screen), tobacco smoking and other substance use were completed when the cohort members were 15-16 years old. Tobacco smoking was categorized into three groups (non-smokers, 1-9 cigarettes and ≥10 cigarettes/day). Psychosis diagnoses were obtained from national registers until the age of 30 years. Subjects in heaviest smoking category were at increased risk of subsequent psychosis (unadjusted HR = 3.15 95% CI 1.94-5.13). When adjusted for baseline psychotic experiences the association persisted (HR = 2.87 1.76-4.68) and remained significant even after adjustments for multiple known risk factors such as cannabis use, frequent alcohol use, other illicit substance use, parental substance abuse, and psychosis. Furthermore, number of smoked cigarettes increased psychosis risk in a dose-response manner (adjusted OR = 1.05 1.01-1.08). Heavy tobacco smoking in adolescence was associated with a greater risk for psychosis even after adjustment for confounders.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.PSCYCHRESNS.2017.05.009
Abstract: High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 in iduals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.
Publisher: Cambridge University Press (CUP)
Date: 08-2014
DOI: 10.1016/J.EURPSY.2013.11.003
Abstract: Social withdrawal is among the first signs of the prodromal state of psychosis seen in clinical s les. The aim of this prospective study was to find out whether difficulty in making contact with others and social withdrawal precede first episode psychosis in the young general population. The members of the Northern Finland Birth Cohort 1986 ( n = 6274) completed the PROD-screen questionnaire in 2001–2002. The Finnish Hospital Discharge Register was used to detect both new psychotic and non-psychotic disorders requiring hospitalisation during 2003–2008. Twenty-three subjects developed psychosis and 89 developed a non-psychotic mental disorder requiring hospitalisation during the follow-up. Of those who developed psychosis, 35% had reported difficulty or uncertainty in making contact with others and 30% social withdrawal in adolescence. In hospitalised non-psychotic disorder, the corresponding precentages were 10 and 13% and in the control group without hospital-treated mental disorder 9 and 11%. The differences between psychotic and non-psychotic hospitalised subjects ( P 0.01) as well as controls ( P 0.001) were statistically significant regarding difficulty or uncertainty in making contact with others. In this general population-based s le self-reported difficulty or uncertainty in making contact with others in adolescence preceded psychosis specifically compared to hospitalised non-psychotic mental disorders and controls.
Publisher: Elsevier BV
Date: 2017
Publisher: Royal College of Psychiatrists
Date: 02-2004
DOI: 10.1192/PB.28.2.40
Abstract: We conducted a pilot study to determine patients' views on receiving a copy of the assessment letter sent to their general practitioner and to determine how psychiatrists' letter writing practice would be altered in the knowledge that patients would receive copies of such letters. Seventy-six consecutive new outpatients received copies of the initial assessment letter sent to general practitioners. Patients were asked to complete a short questionnaire on how the practice affected them. For each letter, psychiatrists were asked to provide details of anything of importance that had been omitted from the letter that in their normal practice they would have included. There was a broad range of responses on how patients felt about the letters. Only two patients found the letters unhelpful, and 83% expressed a positive desire to continue receiving letters, even though initially 18% found the letter distressing. For 56 out of 76 patients, psychiatrists stated that they composed and sent out the letter to the GP in accordance with their usual practice and copied the letter to the patient in an unaltered form. For 17 patients, the psychiatrist stated that some information he/she would usually have included in the GP letter was omitted in the copy the patient received. In a further 3 cases, the psychiatrist sent no letter to the patient. Patients found it helpful to receive copies of their assessment letters. Psychiatrists might require training and reassurance about this policy before implementation.
Publisher: BMJ
Date: 03-2023
DOI: 10.1136/BMJOPEN-2022-067944
Abstract: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis. A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg max 800 mg) or normal saline. Psychiatric measures and blood s les will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6 .7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis. The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010 IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means. ISRCTN23256704 .
Publisher: Oxford University Press (OUP)
Date: 03-2014
Publisher: Cambridge University Press (CUP)
Date: 23-12-2011
DOI: 10.1017/S0033291710002461
Abstract: Early Intervention in Psychosis Services (EIS) for young people in England experiencing first-episode psychosis (FEP) were commissioned in 2002, based on an expected incidence of 15 cases per 100 000 person-years, as reported by schizophrenia epidemiology in highly urban settings. Unconfirmed reports from EIS thereafter have suggested higher than anticipated rates. The aim of this study was to compare the observed with the expected incidence and delineate the clinical epidemiology of FEP using epidemiologically complete data from the CAMEO EIS, over a 6-year period in Cambridgeshire, for a mixed rural–urban population. A population-based study of FEP (ICD-10, F10–39) in people aged 17–35 years referred between 2002 and 2007 the denominator was estimated from mid-year census statistics. Sociodemographic variation was explored by Poisson regression. Crude and directly standardized rates (for age, sex and ethnicity) were compared with pre-EIS rates from two major epidemiological FEP studies conducted in urban English settings. A total of 285 cases met FEP diagnoses in CAMEO, yielding a crude incidence of 50 per 100 000 person-years [95% confidence interval (CI) 44.5–56.2]. Age- and sex-adjusted rates were raised for people from black ethnic groups compared with the white British [incidence rate ratio (IRR) 2.1, 95% CI 1.1–3.8]. Rates in our EIS were comparable with pre-EIS rates observed in more urban areas after age, sex and ethnicity standardization. Our findings suggest that the incidence observed in EIS is far higher than originally anticipated and is comparable to rates observed in more urban settings prior to the advent of EIS. Sociodemographic variation due to ethnicity and other factors extend beyond urban populations. Our results have implications for psychosis aetiology and service planning.
Publisher: Royal College of Psychiatrists
Date: 06-2008
DOI: 10.1192/BJP.BP.107.045740
Abstract: Recent interest has focused on the association between cannabis use and risk of psychosis. In the largest unselected population-based study on this topic to date, we examined cannabis use and prodromal symptoms of psychosis at age 15-16 years among 6330 adolescents. Those who had tried cannabis (n=352 5.6% of the total s le) were more likely to present three or more prodromal symptoms even after controlling for confounders including previous behavioural symptoms (OR=2.23 95% CI 1.70-2.94). A dose-response effect was seen. We conclude that cannabis use is associated with prodromal symptoms of psychosis in adolescence.
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1460-9568.2009.06782.X
Abstract: Social reward dependence (RD) in humans is a stable pattern of attitudes and behaviour hypothesized to represent a favourable disposition towards social relationships and attachment as a personality dimension. It has been theorized that this long-term disposition to openness is linked to the capacity to process primary reward. Using brain structure measures from magnetic resonance imaging, and a measure of RD from Cloninger's temperament and character inventory, a self-reported questionnaire, in 41 male subjects s led from a general population birth cohort, we investigated the neuro-anatomical basis of social RD. We found that higher social RD in men was significantly associated with increased gray matter density in the orbitofrontal cortex, basal ganglia and temporal lobes, regions that have been previously shown to be involved in processing of primary rewards. These findings provide evidence for a brain structural disposition to social interaction, and that sensitivity to social reward shares a common neural basis with systems for processing primary reward information.
Publisher: Springer Science and Business Media LLC
Date: 28-12-2015
DOI: 10.1038/NPP.2015.370
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.SCHRES.2015.01.039
Abstract: Social interaction requires mirroring to other people's mental state. Psychotic disorders have been connected to social interaction and emotion recognition impairment. We compared the brain activity between young adults with familial risk for psychosis (FR) and matched controls during visual exposure to emotional facial expression. We also investigated the role of the amygdala, the key region for social interaction and emotion recognition. 51 FR and 52 control subjects were drawn from the Northern Finland 1986 Birth Cohort (Oulu Brain and Mind Study). None of the included participants had developed psychosis. The FR group was defined as having a parent with psychotic disorder according to the Finnish Hospital Discharge Register. Participants underwent functional MRI (fMRI) using visual presentation of dynamic happy and fearful facial expressions. FMRI data were processed to produce maps of activation for happy and fearful facial expression, which were then compared between groups. Two spherical regions of interest (ROIs) in the amygdala were set to extract BOLD responses during happy and fearful facial expression. BOLD responses were then compared with subjects' emotion recognition, which was assessed after fMRI. Psychophysiological interaction (PPI) for the left and right amygdala during happy and fearful facial expression was conducted using the amygdala as seed regions. FR subjects had increased activity in the left premotor cortex and reduced deactivation of medial prefrontal cortex structures during happy facial expression. There were no between-group differences during fearful facial expression. The FR group also showed a statistically significant linear correlation between mean amygdala BOLD response and facial expression recognition. PPI showed that there was a significant negative interaction between the amygdala and the dorsolateral prefrontal cortex (dlPFC) and superior temporal gyrus in FR subjects. Increased activations by positive valence in FR were in brain regions crucial to emotion recognition and social interaction. Increased activation of the premotor cortex may serve as a compensatory mechanism as FR subjects may have to exert more effort on processing the stimuli, as has been found earlier in schizophrenia. Failure to deactivate PFC structures may imply error in the default mode network. Abnormal PFC function in FR was also suggested by PPI, as the dlPFC showed decreased functional connectivity with the amygdala in the FR group. This may indicate that in FR subjects the amygdala have to take a greater role in emotion recognition and social functioning. This inference was supported by our discovery of statistically significant correlations between the amygdala BOLD response and emotion recognition in the FR group but not in controls.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.20122424
Abstract: All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a erse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T structural magnetic resonance (MR) imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK n = 22 Shanghai) and without (n = 43 UK n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS) from MR images and constructed cortical folding covariance matrices organized by large-scale networks. In both ethnic groups, we replicated a significantly shorter left PCS in patients with hallucinations compared to those without, and healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.SCHRES.2014.06.035
Abstract: The association between the course of cognition and long-term antipsychotic medication in schizophrenia remains unclear. We analysed the association between cumulative lifetime antipsychotic medication dose and change of verbal learning and memory during a 9-year follow-up. Forty schizophrenia subjects and 73 controls from the Northern Finland Birth Cohort 1966 were assessed by California Verbal Learning Test (CVLT) at the ages of 34 and 43 years. Data on the lifetime antipsychotic doses in chlorpromazine equivalents were collected. The association between antipsychotic dose-years and baseline performance and change in CVLT was analysed, controlling for baseline performance, gender, age of onset and severity of illness. Higher antipsychotic dose-years by baseline were significantly associated with poorer baseline performance in several dimensions of verbal learning and memory, and with a larger decrease in short-delay free recall during the follow-up (p=0.031). Higher antipsychotic dose-years during the follow-up were associated with a larger decrease of immediate free recall of trials 1-5 during the follow-up (p=0.039). Compared to controls, decline was greater in some CVLT variables among those using high-doses, but not among those using low-doses. This is the first report of an association between cumulative lifetime antipsychotic use and change in cognition in a long-term naturalistic follow-up. The use of high doses of antipsychotics may be associated with a decrease in verbal learning and memory in schizophrenia years after illness onset. The results do not support the view that antipsychotics in general prevent cognitive decline or promote cognitive recovery in schizophrenia.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.SCHRES.2012.11.020
Abstract: The default mode network (DMN) is active in the brain at rest and de-activated during cognitive tasks. Abnormal function in the DMN has been reported in people with schizophrenia but it is not known whether this applies also to people with a familial risk for psychosis (FR). We compared the activity of the DMN between FR participants and controls. We conducted a resting state functional MRI (R-fMRI) in 72 young adults without psychosis and with a history of psychosis in one or both parents (FR group) and 72 age matched controls without parental psychosis, and without current psychosis or a current prodromal syndrome. Both groups were drawn from the Northern Finland Birth Cohort 1986 (Oulu Brain and Mind study). Parental psychosis was established using the Finnish hospital discharge register. We pre-processed R-fMRI data using independent component analysis followed by a dual regression approach to assess differences between the groups. The FR vs. Control group differences were assessed using non-parametric permutation tests utilizing threshold-free cluster enhancement and correcting for multiple comparisons (p<0.05). FR participants demonstrated significantly lower activity compared with controls in the posterior cingulate cortex, the central node of the DMN. The size of the region was 41 mm(3). The activity of the DMN differed between FR and control groups. This suggests that familial risk for psychotic disorders may be mediated through genetic effects on connectivity in the posterior cingulate cortex.
Publisher: Wiley
Date: 27-01-2011
DOI: 10.1111/J.1751-7893.2010.00254.X
Abstract: Much research has begun to focus on the identification of people who are at high risk of developing psychosis, and clinical services have been initiated for this population. However, only a small number of studies have reported on the efficacy of interventions for preventing or delaying the onset of psychosis. The results of prior work suggest that cognitive therapy (CT) may be an effective, well-tolerated treatment. We report on the rationale and design for a large-scale, multi-site randomized, controlled trial of CT for people who are assessed to be at high risk of psychosis because of either state or state-plus-trait risk factors. The study employs a single-blind design in which all participants receive frequent mental-state monitoring, which will efficiently detect transition to psychosis, and half are randomized to weekly sessions of CT for up to 6 months. Participants will be followed-up for a minimum of 12 months and to a maximum of 2 years. We report the characteristics of the final s le at baseline (n=288). Our study aimed to expand the currently limited evidence base for best practice in interventions for in iduals at high risk of psychosis.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Springer Science and Business Media LLC
Date: 07-08-2007
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: American Psychiatric Association Publishing
Date: 2010
DOI: 10.1176/APPI.AJP.2009.09010133
Abstract: Maternal depression is relatively common during pregnancy. The authors examined whether maternal antenatal depressed mood increased the risk of schizophrenia and other psychoses among offspring with and without a familial history of psychosis. In the Northern Finland 1966 birth cohort, mothers of 12,058 children were asked at mid-gestation at the antenatal clinic if they felt depressed. The offspring were followed for over 30 years, and subsequent schizophrenia and other psychoses were detected using the Finnish Hospital Discharge Register, which was also used for identifying psychosis in the parents. Familial risk for psychosis was considered as a genetic risk factor and mothers' depressed mood as an environmental or genetic risk factor. The risk for schizophrenia was higher in the offspring with both maternal depressed mood during pregnancy and parental psychosis (OR=9.4, 95% CI=4.2-20.9 adjusted for sex and perinatal complications) than in those with a depressed mother but without parental psychosis (OR=1.0, 95% CI=0.6-1.8) or those without maternal depression and with a psychotic parent (OR=2.6, 95% CI=1.2-5.4). The reference group was birth cohort members without maternal antenatal depression and without parental psychosis. Maternal depressed mood during pregnancy per se is unlikely to increase the risk for schizophrenia in the offspring but may affect subjects with a family history for psychosis. This finding could be an ex le of a gene-environment or possibly a gene-gene interaction in the development of schizophrenia. Mothers' antenatal depression may act as additive factor for subjects vulnerable to schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2023
Publisher: Springer Science and Business Media LLC
Date: 21-09-2018
DOI: 10.1038/S41398-018-0250-3
Abstract: Abnormal salience processing has been suggested to contribute to the formation of positive psychotic symptoms in schizophrenia and related conditions. Previous research utilising reward learning or anticipation paradigms has demonstrated cortical and subcortical abnormalities in people with psychosis, specifically in the prefrontal cortex, the dopaminergic midbrain and the striatum. In these paradigms, reward prediction errors attribute motivational salience to stimuli. However, little is known about possible abnormalities across different forms of salience processing in psychosis patients, and whether any such abnormalities involve the dopaminergic midbrain. The aim of our study was, therefore, to investigate possible alterations in psychosis in neural activity in response to various forms of salience: novelty, negative emotion, targetness (task-driven salience) and rareness/deviance. We studied 14 antipsychotic naïve participants with first episode psychosis, and 37 healthy volunteers. During fMRI scanning, participants performed a visual oddball task containing these four forms of salience. Psychosis patients showed abnormally reduced signalling in the substantia nigra/ventral tegmental area (SN/VTA) for novelty, negative emotional salience and targetness reduced striatal and occipital (lingual gyrus) signalling to novelty and negative emotional salience, reduced signalling in the amygdala, anterior cingulate cortex and parahippocamal gyrus to negative emotional salience, and reduced cerebellar signalling to novelty and negative emotional salience. Our results indicate alterations of several forms of salience processing in patients with psychosis in the midbrain SN/VTA, with additional subcortical and cortical regions also showing alterations in salience signalling, the exact pattern of alterations depending on the form of salience in question.
Publisher: Cold Spring Harbor Laboratory
Date: 13-06-2019
DOI: 10.1101/668939
Abstract: Schizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning. We administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls ( n = 29, F|M=0.81), At Risk Mental State for psychosis (ARMS, n = 23, F|M=0.35) and FEP (First-episode psychosis, n = 26, F|M=0.18). Study 2 included healthy adolescents ( n = 735, F|M= 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated. Patients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology. Reinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy in iduals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1038/S41467-021-21280-7
Abstract: Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) in iduals identify 8 independent and significant loci for PUD at, or near, genes MUC1 , MUC6, FUT2 , PSCA , ABO , CDX2, GAST and CCKBR . There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
Publisher: BMJ
Date: 23-04-2015
Publisher: Cold Spring Harbor Laboratory
Date: 09-2020
DOI: 10.1101/2020.08.27.20182980
Abstract: The COVID-19 pandemic has led to dramatic social and economic changes in daily life. First studies report an impact on mental health of the general population showing increased levels of anxiety, stress and depression. In this study, we compared the impact of the pandemic on two culturally and economically similar European countries: the UK and Germany. Participants (UK=241, German=541) completed an online-survey assessing COVID-19 exposure, impact on financial situation and work, substance and media consumption, mental health using the tSymptom-Check-List-27 (SCL-27) and the Schizotypal Personality Questionnaire. We found distinct differences between the two countries. UK responders reported a stronger direct impact on health, financial situation and families. UK responders had higher clinical scores on the SCL-27, and higher prevalence. Interestingly, German responders were less hopeful for an end of the pandemic and more concerned about their life-stability. As 25% of both German and UK responders reported a subjective worsening of the general psychological symptoms and 20-50% of German and UK responders reached the clinical cut-off for depressive and dysthymic symptoms as well as anxieties, it specifically shows the need for tailored intervention systems to support large proportions of the general public.
Publisher: S. Karger AG
Date: 20-11-2009
DOI: 10.1159/000260044
Abstract: i Background/Aims: /i Cluster analysis has had limited success in establishing whether there are subtypes of schizophrenia. Grade of membership (GoM) analysis is a multivariate statistical technique which has advantages when, as in schizophrenia, in iduals conforming to pure types are uncommon and mixed forms are frequent. i Methods: /i GoM analysis was applied to 118 chronic schizophrenic patients. The patients were of all clinical subtypes, including 13 with simple schizophrenia. Both current and ‘lifetime’ symptoms were assessed, and two different rating systems were used. i Results: /i Specifying 3 pure types resulted in robust findings across analyses. One pure type corresponded to paranoid schizophrenia, one to simple schizophrenia and the third combined elements of hebephrenic and catatonic schizophrenia. Specifying 4 pure types split the original 3 pure types in ways which were not clinically intuitive. i Conclusion: /i GoM analysis ides schizophrenia into subtypes along conventional lines, with the proviso that hebephrenic and catatonic schizophrenic patients are not separable, at least in the chronic stage of the illness.
Publisher: Oxford University Press (OUP)
Date: 02-11-2018
Abstract: Psychotic experiences may be understood as altered information processing due to aberrant neural computations. A prominent ex le of such neural computations is the computation of prediction errors (PEs), which signal the difference between expected and experienced events. Among other areas showing PE coding, hippoc al-prefrontal-striatal neurocircuits play a prominent role in information processing. Dysregulation of dopaminergic signaling, often secondary to psychosocial stress, is thought to interfere with the processing of biologically important events (such as reward prediction errors) and result in the aberrant attribution of salience to irrelevant sensory stimuli and internal representations. Bayesian hierarchical predictive coding offers a promising framework for the identification of dysfunctional neurocomputational processes and the development of a mechanistic understanding of psychotic experience. According to this framework, mismatches between prior beliefs encoded at higher levels of the cortical hierarchy and lower-level (sensory) information can also be thought of as PEs, with important consequences for belief updating. Low levels of precision in the representation of prior beliefs relative to sensory data, as well as dysfunctional interactions between prior beliefs and sensory data in an ever-changing environment, have been suggested as a general mechanism underlying psychotic experiences. Translating the promise of the Bayesian hierarchical predictive coding into patient benefit will come from integrating this framework with existing knowledge of the etiology and pathophysiology of psychosis, especially regarding hippoc al-prefrontal-striatal network function and neural mechanisms of information processing and belief updating.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Cold Spring Harbor Laboratory
Date: 27-11-2017
DOI: 10.1101/225938
Abstract: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. In this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. We studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses group differences were examined in anterior cingulate and nucleus accumbens regions of interest. There were no significant group, drug or interaction effects in number of correct choices computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial ⍰ 2 =0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial ⍰ 2 =0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial ⍰ 2 =0.26, 1-β error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.PEDIATRNEUROL.2010.07.002
Abstract: Previous studies have indicated that preterm birth and low birth weight are associated with structural brain abnormalities and neurocognitive deficits in childhood and adolescence, although very few studies have included follow-up in adulthood. Here we assessed the effect of preterm delivery (524 subjects mean 34.6 weeks, S.D. = 1.7) or low birth weight (366 subjects mean 2159 g, S.D. = 303) on educational and occupational outcomes at age 31 years in the Northern Finland 1966 Birth Cohort, along with 10,132 term, normal birth weight control subjects. Cognitive tests and brain morphology using magnetic resonance imaging were assessed at age 33-35 years in a subset of the cohort (9 subjects 95 controls). The preterm or low birth weight subjects had slightly lower school ratings and lower educational levels in adulthood, and they performed worse in verbal learning. The low birth weight subjects were less likely to be employed. There were no mean differences in the magnetic resonance imaging tissue segmentation analysis of the brain. In conclusion, although there were no overall changes in brain morphology in the preterm or low birth weight group, there was evidence for slightly poorer educational and occupational careers and cognitive capacity, which may reflect functional disruption not evident in structure.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2019
DOI: 10.1038/S41398-019-0635-Y
Abstract: Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson’s Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest diffusion tensor imaging (DTI) measures of white matter tract integrity and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h 2 SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder but not with obsessive compulsive disorder or Parkinson’s Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2021
DOI: 10.1101/2021.02.04.21251136
Abstract: Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, an archetypal inflammatory marker, as a potential mediator for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated significant reciprocal relationships between lifetime smoking and both depression (OR Smk-Dep = 2.01, 95% CI 1.71-2.37, p 0.001 O R Dep-Smk = 1.09, 95% CI 1.06-1.13, p 0.001) and CRP levels (OR Smk-CRP = 1.40, 95% CI 1.21-1.55, p 0.001 OR CRP-Smk = 1.03, 95% CI 1.02-1.05, p 0.001). These significant and positive associations were also supported by the majority of the robust MR methods performed. The reciprocal relationships between CRP levels (using genetic instruments for CRP) and depression were not significant (OR CRP-Dep = 1.01, 95% CI 0.99-1.04 OR Dep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to inflammation or when we adjusted the analysis by CRP-levels in multivariable analysis. Our study supports potential causal associations between lifetime smoking and depression, as well as between lifetime smoking and CRP levels, but not between CRP and depression. No evidence was found that CRP mediates the relationship between smoking and depression.
Publisher: Frontiers Media SA
Date: 2009
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2021
DOI: 10.1101/2021.08.31.21262937
Abstract: Cognitive impairments in psychosis are one of the strongest predictors of functional decline. Cortico-striatal dysfunction may contribute to both psychosis and cognitive impairment in psychotic illnesses. The decision-making processes underlying goal-directed action and serial reversal learning can be measured and are sensitive to changes reflecting cortico-striatal dysfunction. As such, changes in decision-making performance may assist with predicting functional decline in people with psychosis. We assessed decision-making processes in healthy controls (N=34), and those with early psychosis (N=15) and persistent psychosis (N=45). We subclassified subjects based on intact/impaired goal-directed action. Compared with healthy controls ( %), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with persistent psychosis were less deterministic in their decision-making. Those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. In contrast, the early psychosis group included a lower proportion of in iduals with impaired goal-directed action (20%) and displayed a different cognitive phenotype from those with persistent psychosis. These findings suggest prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis while those with early psychosis have relatively intact decision-making processes compared to healthy controls. It is unclear if there is a progressive decline in decision-making processes in some in iduals with psychosis or if the presence of decision-making processes in early psychosis is predictive of a persistent trajectory of illness.
Publisher: Informa UK Limited
Date: 08-2012
DOI: 10.1080/13803395.2012.668875
Abstract: The California Verbal Learning Test and structural brain imaging were administered to 57 subjects with schizophrenia spectrum disorders and 94 controls in a general population s le. Cases had lower semantic cluster scores. Poorer verbal memory strategies were associated with longer duration of illness and heavier use of antipsychotic medication. After controlling for duration of illness, sex, and total gray matter, poorer verbal memory was associated with lower gray matter volume in the cingulate cortex, juxtapositional lobule, right superior temporal gyrus, and precuneus. After controlling for use of antipsychotic medication, there was an association between higher serial clustering and smaller anterior cingulate gyrus and larger intracalcarine cortex.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.SCHRES.2010.08.016
Abstract: Duration of untreated psychosis (DUP) has been linked with poor prognosis and changes in the brain structure in schizophrenia at least at the beginning of the disease, but it is still unknown whether DUP relates to brain morphometry in the longer term. Our aim was to analyze the relation between DUP and the brain structure in schizophrenia in the general population, after several years of illness. Brains of subjects with psychosis from the Northern Finland 1966 Birth Cohort (NFBC 1966) were scanned with MRI during 1999-2001 after an 11-year follow-up. DUP was assessed from medical records and regressed against global and local tissue density measurements. The brain morphometric and the DUP information were available for 46 subjects with DSM-III-R schizophrenia. The DUP did not correlate with volumes of the total gray or white matter or the cerebrospinal fluid. The length of DUP associated positively with reduced densities of the right limbic area and the right hippoc us. Long DUP was slightly associated with reductions of gray matter densities in the limbic area and especially the hippoc us after several years follow-up, supporting the hypothesis that, compared to short DUP, long DUP might be a marker of different disease trajectories including subtle morphometric changes.
Publisher: Royal College of Psychiatrists
Date: 04-2004
Abstract: Cognitive impairment is well established in schizophrenia but its relationship to the course of the illness remains incompletely understood. Here we document two patients with schizophrenia who underwent neuropsychological testing while chronically unwell, and this was repeated after improvement took place. Both patients showed significant recovery of general intellectual function, accompanied by improvements in some but not all areas of neuropsychological function: executive function remained particularly impaired.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.EURONEURO.2019.10.002
Abstract: Previous research in patients with psychotic disorder has shown widespread abnormalities in brain activation during reward anticipation. Research at the level of subclinical psychotic experiences in in iduals unexposed to antipsychotic medication is limited with inconclusive results. Therefore, brain activation during reward anticipation was examined in a larger s le of in iduals with subclinical psychotic experiences (PE). Participants in the PE-group were included based on CAPE scores. A s le of emerging adults aged 16-26 years (n = 47) with PE and healthy controls (HC) (n = 40) underwent fMRI scanning. The Monetary Incentive Delay task was conducted with cues related to win, loss or neutral conditions. fMRI nonparametric tests were used to examine the reward versus neutral cue contrast. A significant main effect of the large win (€3.00) > neutral contrast was found in both groups showing activation in many brain areas, including classic reward regions. Whole brain analysis on the group comparison regarding the large win > neutral contrast showed significantly decreased activation in the right insula, putamen and supramarginal gyrus in the PE-group compared to controls. There was no group difference in the hypothesized reward-related region. Decreased activation in the right insula, putamen and supramarginal gyrus during reward anticipation in in iduals with PE may be consistent with altered processing of sensory information, related to decreased emotional valuing and motivational tendencies and/or altered motor-cognitive processes. The absence of group differences in striatal activation suggests that activation here is intact in the earliest stages of psychosis and may exhibit progressive deterioration in as the disease develops.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2015
DOI: 10.1038/TP.2015.26
Abstract: Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with in iduals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N -methyl- D -aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2010
Publisher: Oxford University Press (OUP)
Date: 19-04-2010
Publisher: Cambridge University Press (CUP)
Date: 09-2017
DOI: 10.1016/J.EURPSY.2017.06.004
Abstract: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance ( P = 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition ( P = 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia.
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2019
DOI: 10.1101/19010512
Abstract: Current research does not provide a clear explanation for why some patients with Parkinson’s Disease (PD) develop psychotic symptoms. In the field of schizophrenia research the ‘aberrant salience hypothesis’ of psychosis has been influential. According to the theory, dopaminergic dysregulation leads to the inappropriate attribution of salience to otherwise irrelevant or non-informative stimuli, allowing for the formation of hallucinations and delusions. This theory has not yet been extensively investigated in the context of psychosis in PD. We investigated salience processing in 14 PD patients with a history of psychotic symptoms, 23 PD patients without psychotic symptoms and 19 healthy controls. All patients received dopaminergic medication. We examined emotional salience using a visual oddball fMRI paradigm (Bunzeck and Düzel, 2006) that previously has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow as assessed with arterial spin labelling fMRI. We found significant differences between patient groups in brain responses to emotional salience. PD patients with psychotic symptoms revealed senhanced brain responses in the striatum, the hippoc us and the amygdala compared to PD patients without psychotic symptoms. PD patients with psychotic symptoms also showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores. Furthermore, our data provide a first indication for dysfunctional top-down processes, measured in a ‘jumping to conclusions’ bias. Our study suggests that enhanced signalling in the striatum, hippoc us and amygdala together with deficient top-down cognitive regulations is associated with the development of psychotic symptoms in PD which is similar to that proposed in the ‘aberrant salience hypothesis’ of psychosis in schizophrenia.
Publisher: Oxford University Press (OUP)
Date: 2005
DOI: 10.1093/BMB/LDH046
Abstract: Schizophrenia is an aetiologically heterogeneous syndrome that usually becomes overtly manifest in adolescence and early adulthood, but in many cases subtle impairments in neurointegrative function are present from birth hence it is considered to be a disorder with a neurodevelopmental component. The strongest risk factor that has been identified is familial risk with genetic loading. Other risk factors include pregnancy and delivery complications, infections during pregnancy, disturbances of early neuromotor and cognitive development and heavy cannabis use in adolescence. Unfortunately, to date it has not been possible to utilize the predictors of the disorder that have been identified in primary preventative interventions in a general population. However, some authors have claimed that in future it might be possible to reduce the risk for developing schizophrenia through general health policy. In clinical settings, it is helpful to map out possible early risk factors, at least familial risk for psychosis, especially in child, adolescent and young adult mental patients. Furthermore, in the future we may have predictive models combining data from genetic factors for schizophrenia, antenatal risk factors, childhood and adolescent development and clinical symptomatology, as well as brain structural and functional abnormalities.
Publisher: Elsevier BV
Date: 2020
Publisher: Cold Spring Harbor Laboratory
Date: 15-12-2017
DOI: 10.1101/225920
Abstract: Jumping to conclusions during probabilistic reasoning is a cognitive bias reliably observed in psychosis, and linked to delusion formation. Although the reasons for this cognitive bias are unknown, one suggestion is that psychosis patients may view s ling information as more costly. However, previous computational modelling has provided evidence that patients with chronic schizophrenia jump to conclusion because of noisy decision making. We developed a novel version of the classical beads-task, systematically manipulating the cost of information gathering in four blocks. For 31 in iduals with early symptoms of psychosis and 31 healthy volunteers, we examined the numbers of ‘draws to decision’ when information s ling had no, a fixed, or an escalating cost. Computational modelling involved estimating a cost of information s ling parameter and a cognitive noise parameter. Overall patients s led less information than controls. However, group differences in numbers of draws became less prominent at higher cost trials, where less information was s led. The attenuation of group difference was not due to floor effects, as in the most costly block participants s led more information than an ideal Bayesian agent. Computational modelling showed that, in the condition with no objective cost to information s ling, patients attributed higher costs to information s ling than controls (Mann-Whiney U=289, p=0.007), with marginal evidence of differences in noise parameter estimates (t=1.86 df=60, p=0.07). In patients, in idual differences in severity of psychotic symptoms were statistically significantly associated with higher cost of information s ling (rho=0.6, p=0.001) but not with more cognitive noise (rho=0.27, p=0.14) in controls cognitive noise predicted aspects of schizotypy (preoccupation and distress associated with delusion-like ideation on the Peters Delusion Inventory). Using a psychological manipulation and computational modelling, we provide evidence that early psychosis patients jump to conclusions because of attributing higher costs to s ling information, not because of being primarily noisy decision makers.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2019
DOI: 10.1101/263020
Abstract: Abnormal salience processing has been suggested to contribute to the formation of positive psychotic symptoms in schizophrenia and related conditions. Previous research utilising reward learning or anticipation paradigms has demonstrated cortical and subcortical abnormalities in people with psychosis, specifically in the prefrontal cortex, the dopaminergic midbrain and the striatum. In these paradigms, reward prediction errors attribute motivational salience to stimuli. However, little is known about possible abnormalities across different forms of salience processing in psychosis patients, and whether any such abnormalities involve the dopaminergic midbrain. The aim of our study was, therefore, to investigate possible alterations in psychosis in neural activity in response to various forms of salience: novelty, negative emotion, targetness (task-driven salience) and rareness/deviance. We studied 14 antipsychotic naïve participants with first episode psychosis, and 37 healthy volunteers. During fMRI scanning, participants performed a visual oddball task containing these four forms of salience. Psychosis patients showed abnormally reduced signalling in the substantia nigra/ventral tegmental area (SN/VTA) for novelty, negative emotional salience and targetness reduced striatal and occipital (lingual gyrus) signalling to novelty and negative emotional salience, reduced signalling in the amygdala, anterior cingulate cortex and parahippocamal gyrus to negative emotional salience, and reduced cerebellar signalling to novelty and negative emotional salience. Our results indicate alterations of several forms of salience processing in patients with psychosis in the midbrain SN/VTA, with additional subcortical and cortical regions also showing alterations in salience signalling, the exact pattern of alterations depending on the form of salience in question.
Publisher: Frontiers Media SA
Date: 26-08-2015
Publisher: Springer Science and Business Media LLC
Date: 06-11-2020
DOI: 10.1038/S41398-020-01075-Y
Abstract: All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a erse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. Sulcal patterns derived from structural magnetic resonance (MR) images can provide a proxy in adulthood for early brain development. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MR imaging from the United Kingdom and Shanghai, China ( n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with ( n = 79 UK n = 22 Shanghai) and without ( n = 43 UK n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS), which have previously been associated with hallucinations in schizophrenia, and constructed cortical folding covariance matrices organized by large-scale functional networks. In both ethnic groups, we demonstrated a significantly shorter left PCS in patients with hallucinations compared to those without, and to healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.
Publisher: Royal College of Psychiatrists
Date: 04-03-2018
DOI: 10.1192/BJP.2017.52
Abstract: The association between cannabis use and the risk of psychosis has been studied extensively but the temporal order still remains controversial. To examine the association between cannabis use in adolescence and the risk of psychosis after adjustment for prodromal symptoms and other potential confounders. The s le ( n = 6534) was composed of the prospective general population-based Northern Finland Birth Cohort of 1986. Information on prodromal symptoms of psychosis and cannabis use was collected using questionnaires at age 15–16 years. Participants were followed up for ICD-10 psychotic disorders until age 30 years using nationwide registers. The risk of psychosis was elevated in in iduals who had tried cannabis five times or more (hazard ratio, (HR) = 6.5, 95% CI 3.0–13.9). The association remained statistically significant even when adjusted for prodromal symptoms, other substance use and parental psychosis (HR = 3.0, 95% CI 1.1–8.0). Adolescent cannabis use is associated with increased risk of psychosis even after adjustment for baseline prodromal symptoms, parental psychosis and other substance use. None.
Publisher: Wiley
Date: 14-06-2017
DOI: 10.1002/HBM.23674
Publisher: Society for Neuroscience
Date: 18-06-2008
Publisher: Cold Spring Harbor Laboratory
Date: 21-10-2019
DOI: 10.1101/811737
Abstract: Genetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 in iduals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs associated with PUD at or near genes MUC1, FUT2, PSCA and CCKBR , for which there are previously established roles in Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-directional causality (the risk of GORD in liability to major depression and the risk of major depression in liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS than between these disorders and IBD is reported. These findings advance understanding the role of genetic variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous system and the gastrointestinal tract.
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 21-03-2006
DOI: 10.1111/J.1469-7610.2005.01450.X
Abstract: The relationship between the age of reaching infant developmental milestones and later intellectual function within the normal population remains unresolved. We hypothesised that the age of learning to stand in infancy would be associated with adult executive function and that the association would be apparent throughout the range of abilities, rather than confined to extremes. The Northern Finland 1966 Birth Cohort is based upon 12,058 live-born children in a geographic and temporally defined population. Information on age at learning to stand without support was obtained at one year. At age 33-35 a random s le of 104 subjects underwent a neuropsychological test battery including tests of executive function (cognitive categorisation), visuo-spatial memory, verbal learning and visual object learning. We investigated associations between developmental data and adult neuropsychological test scores. There was a significant linear relationship between age of learning to stand and adult categorisation: the earlier the attainment of the milestone, the better was the categorisation. No such relationships were observed between infant neurodevelopment and adult cognition in other neuropsychological domains. Even within the normal range of development, early development in the gross motor domain is associated with better adult executive function (in tests of categorisation). Investigation of the determinants and sequelae of normal neural development will facilitate research into a variety of neurodevelopmental disorders.
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.SCHRES.2004.03.008
Abstract: Childhood precursors of schizophrenia include multiple abnormalities of development. Continuities between early and subsequent deviance are poorly characterised. We studied associations among premorbid developmental deviance using data at ages 1 year (learning to stand, walk, and speak, attainment of bladder and bowel control) and 16 years (success at school). Generalised linear modelling was used to examine differential linear associations and trends across adult psychiatric diagnoses. In babies who, as adults, suffered schizophrenia or any psychosis, those who learned to stand latest were also more likely to perform poorly at school in both motor and theoretical domains at age 16 when compared with earlier learners. The effect was independent of genetic and perinatal factors. We conclude that the early developmental deviation in the first year of life is associated with lower school performance at age 16. Developmental continuity among children who develop psychoses was stronger than among normal controls and those hospitalized for nonpsychotic psychiatric disorder. These findings are in line with the hypothesis that a neural diathesis is present during postnatal brain development before schizophrenia. This supports the longitudinal dimension and life span models of schizophrenia.
Publisher: Frontiers Media SA
Date: 08-01-2018
Publisher: Royal College of Psychiatrists
Date: 07-2012
DOI: 10.1192/BJP.BP.111.107789
Abstract: Psychotic symptoms are common in the general population. There is evidence for common mechanisms underlying such symptoms in health and illness (such as the functional role of mesocorticostriatal circuitry in error-dependent learning) and differentiating factors (relating to non-psychotic features of psychotic illness and to social and emotional aspects of psychotic symptoms). Clinicians should be aware that psychotic symptoms in young people are more often associated with common mental disorders such as depression and anxiety than with severe psychotic illness.
Publisher: Oxford University Press (OUP)
Date: 09-2007
DOI: 10.1093/BRAIN/AWM173
Publisher: Cambridge University Press (CUP)
Date: 09-06-2015
DOI: 10.1016/J.EURPSY.2015.04.006
Abstract: Delayed motor development in infancy and family history of psychosis are both associated with increased risk of schizophrenia, but their interaction is largely unstudied. To investigate the association of the age of achieving motor milestones and parental psychosis and their interaction in respect to risk of schizophrenia. We used data from the general population-based prospective Northern Finland Birth Cohort 1966 ( n = 10,283). Developmental information of the cohort members was gathered during regular visits to Finnish child welfare clinics. Several registers were used to determine the diagnosis of schizophrenia among the cohort members and psychosis among the parents. Altogether 152 (1.5%) in iduals had schizophrenia by the age of 46 years, with 23 (15.1%) of them having a parent with psychosis. Cox regression analysis was used in analyses. Parental psychosis was associated ( P 0.05) with later achievement of holding the head up, grabbing an object, and walking without support. In the parental psychosis group, the risk for schizophrenia was increased if holding the head up (hazard ratio [HR]: 2.46 degrees of freedom [df] = 1 95% confidence interval [95% CI]: 1.07–5.66) and touching the thumb with the index finger (HR: 1.84 df = 1 95% CI: 1.11–3.06) was later. In the group without parental psychosis, a delay in the following milestones increased the risk of schizophrenia: standing without support and walking without support. Parental psychosis had an interaction with delayed touching thumb with index finger (HR: 1.87 df = 1 95% CI: 1.08–3.25) when risk of schizophrenia was investigated. Parental psychosis was associated with achieving motor milestones later in infancy, particularly the milestones that appear early in a child's life. Parental psychosis and touching the thumb with the index finger had a significant interaction on risk of schizophrenia. Genetic risk for psychosis may interact with delayed development to raise future risk of schizophrenia, or delayed development may be a marker of other risk processes that interact with genetic liability to cause later schizophrenia.
Publisher: Cambridge University Press (CUP)
Date: 24-07-2018
DOI: 10.1017/S0033291718001794
Abstract: Psychoses, especially schizophrenia, are often preceded by cognitive deficits and psychosis risk states. Altered metabolic profiles have been found in schizophrenia. However, the associations between metabolic profiles and poorer cognitive performance and psychosis risk in the population remain to be determined. Detailed molecular profiles were measured for up to 8976 in iduals from two general population-based prospective birth cohorts: the Northern Finland Birth Cohort 1986 (NFBC 1986) and the Avon Longitudinal Study of Parents and Children (ALSPAC). A high-throughput nuclear magnetic resonance spectroscopy platform was used to quantify 70 metabolic measures at age 15–16 years in the NFBC 1986 and at ages 15 and 17 years in ALSPAC. Psychosis risk was assessed using the PROD-screen questionnaire at age 15–16 years in the NFBC 1986 or the psychotic-like symptoms assessment at age 17 years in ALSPAC. Cognitive measures included academic performance at age 16 years in both cohorts and general intelligence and executive function in ALSPAC. Logistic regression measured cross-sectional and longitudinal associations between metabolic measures and psychosis risk and cognitive performance, controlling for important covariates. Seven metabolic measures, primarily fatty acid (FA) measures, showed cross-sectional associations with general cognitive performance, four across both cohorts (low density lipoprotein diameter, monounsaturated FA ratio, omega-3 ratio and docosahexaenoic acid ratio), even after controlling for important mental and physical health covariates. Psychosis risk showed minimal metabolic associations. FA ratios may be important in marking risk for cognitive deficits in adolescence. Further research is needed to clarify whether these biomarkers could be causal and thereby possible targets for intervention.
Publisher: Royal College of Psychiatrists
Date: 06-2007
DOI: 10.1192/BJP.BP.106.024448
Abstract: Substance use is implicated in the cause and course of psychosis. To characterise substance and alcohol use in an epidemiologically representative treatment s le of people experiencing a first psychotic episode in south Cambridgeshire. Current and lifetime substance use was recorded for 123 consecutive referrals to a specialist early intervention service. Substance use was compared with general population prevalence estimates from the British Crime Survey. Substance use among people with first-episode psychosis was twice that of the general population and was more common in men than women. Cannabis abuse was reported in 51% of patients ( n =62) and alcohol abuse in 43% ( n =53). More than half ( n =68, 55%) had used Class A drugs, and 38% ( n =43) reported polysubstance abuse. Age at first use of cannabis, cocaine, ecstasy and hetamine was significantly associated with age at first psychotic symptom. Substance misuse is present in the majority of people with first-episode psychosis and has major implications for management. The association between age at first substance use and first psychotic symptoms has public health implications.
Publisher: American Medical Association (AMA)
Date: 06-2006
DOI: 10.1001/ARCHPSYC.63.6.611
Abstract: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. Within-subject, randomized, placebo-controlled study. Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.
Publisher: Elsevier BV
Date: 2016
Publisher: American Medical Association (AMA)
Date: 2021
DOI: 10.1001/JAMAPSYCHIATRY.2020.3049
Abstract: Polygenic risk scores (PRS) are predictors of the genetic susceptibilities of in iduals to diseases. All in iduals have DNA risk variants for all common diseases, but genetic susceptibility differences between people reflect the cumulative burden of these. Polygenic risk scores for an in idual are calculated as weighted counts of thousands of risk variants that they carry, where the risk variants and their weights have been identified in genome-wide association studies. Here, we review the underlying basic science of PRS, providing a foundation for understanding the potential clinical utility and limitations of PRS. Polygenic risk scores can be calculated for a wide range of diseases from a saliva or blood s le using genotyping technologies that are inexpensive. While genotyping only needs to be done once for each in idual in their lifetime, the PRS can be recalculated as identification of risk variants improves. On their own, PRS will never be able to establish or definitively predict future diagnoses of common complex conditions because genetic factors only contribute part of the risk, and PRS will only ever capture part of the genetic contributions. Nonetheless, just as clinical medicine uses a multitude of other predictive measures, PRS either on their own or as part of multivariable predictive algorithms could play a role. Utility of PRS in clinical medicine and ethical issues related to their use should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. For different diseases, PRS could have utility in community settings (stratification to better triage people into established screening programs) or could contribute to clinical decision-making for those presenting with symptoms but where formal diagnosis is unclear. In principle, PRS could contribute to treatment choices, but more data are needed to allow development of PRS in this context.
Publisher: American Medical Association (AMA)
Date: 02-2021
DOI: 10.1001/JAMAPSYCHIATRY.2020.3042
Abstract: Polygenic risk scores (PRS) are predictors of the genetic susceptibility to diseases, calculated for in iduals as weighted counts of thousands of risk variants in which the risk variants and their weights have been identified in genome-wide association studies. Polygenic risk scores show promise in aiding clinical decision-making in many areas of medical practice. This review evaluates the potential use of PRS in psychiatry. On their own, PRS will never be able to establish or definitively predict a diagnosis of common complex conditions (eg, mental health disorders), because genetic factors only contribute part of the risk and PRS will only ever capture part of the genetic contribution. Combining PRS with other risk factors has potential to improve outcome prediction and aid clinical decision-making (eg, determining follow-up options for in iduals seeking help who are at clinical risk of future illness). Prognostication of adverse physical health outcomes or response to treatment in clinical populations are of great interest for psychiatric practice, but data from larger s les are needed to develop and evaluate PRS. Polygenic risk scores will contribute to risk assessment in clinical psychiatry as it evolves to combine information from molecular, clinical, and lifestyle metrics. The genome-wide genotype data needed to calculate PRS are inexpensive to generate and could become available to psychiatrists as a by-product of practices in other medical specialties. The utility of PRS in clinical psychiatry, as well as ethical issues associated with their use, should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. Clinical psychiatry has lagged behind other fields of health care in its use of new technologies and routine clinical data for research. Now is the time to catch up.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.NEUROIMAGE.2011.10.007
Abstract: The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2021
DOI: 10.1038/S41380-021-01260-5
Abstract: Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset ( N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large s le of adults from the UK Biobank ( N max = 29,878) who had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed-effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts. Other microstructural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate, and prefrontal cortical areas, insula, and hippoc us. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical, and white matter microstructure may be linked to the genetic mechanisms of schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2021
DOI: 10.1038/S41537-021-00157-0
Abstract: Age plays a crucial role in the performance of schizophrenia vs. controls (SZ-HC) neuroimaging-based machine learning (ML) models as the accuracy of identifying first-episode psychosis from controls is poor compared to chronic patients. Resolving whether this finding reflects longitudinal progression in a disorder-specific brain pattern or a systematic but non-disorder-specific deviation from a normal brain aging (BA) trajectory in schizophrenia would help the clinical translation of diagnostic ML models. We trained two ML models on structural MRI data: an SZ-HC model based on 70 schizophrenia patients and 74 controls and a BA model (based on 561 healthy in iduals, age range = 66 years). We then investigated the two models’ predictions in the naturalistic longitudinal Northern Finland Birth Cohort 1966 (NFBC1966) following 29 schizophrenia and 61 controls for nine years. The SZ-HC model’s schizophrenia-specificity was further assessed by utilizing independent validation (62 schizophrenia, 95 controls) and depression s les (203 depression, 203 controls). We found better performance at the NFBC1966 follow-up (sensitivity = 75.9%, specificity = 83.6%) compared to the baseline (sensitivity = 58.6%, specificity = 86.9%). This finding resulted from progression in disorder-specific pattern expression in schizophrenia and was not explained by concomitant acceleration of brain aging. The disorder-specific pattern’s progression reflected longitudinal changes in cognition, outcomes, and local brain changes, while BA captured treatment-related and global brain alterations. The SZ-HC model was also generalizable to independent schizophrenia validation s les but classified depression as control subjects. Our research underlines the importance of taking account of longitudinal progression in a disorder-specific pattern in schizophrenia when developing ML classifiers for different age groups.
Publisher: Elsevier BV
Date: 02-2016
Publisher: Informa UK Limited
Date: 02-01-2016
DOI: 10.1080/13854046.2015.1128000
Abstract: Several social life events and challenges have an impact on cognitive development. Our goal was to analyze the predictors of change in cognitive performance in early midlife in a general population s le. Additionally, systematic literature review was performed. The study s le was drawn from the Northern Finland Birth Cohort 1966 at the ages of 34 and 43 years. Primary school performance, sociodemographic factors and body mass index (BMI) were used to predict change in cognitive performance measured by the California Verbal Learning Test, Visual Object Learning Test, and Abstraction Inhibition and Working Memory task. Analyses were weighted by gender and education, and p-values were corrected for multiple comparisons using Benjamini-Hochberg procedure (B-H). Male gender predicted decrease in episodic memory. Poor school marks of practical subjects, having no children, and increase in BMI were associated with decrease in episodic memory, though non-significantly after B-H. Better school marks, and higher occupational class were associated with preserved performance in visual object learning. Higher vocational education predicted preserved performance in visual object learning test, though non-significantly after B-H. Likewise, having children predicted decreased performance in executive functioning but non-significantly after B-H. Adolescent cognitive ability, change in BMI and several sociodemographic factors appear to predict cognitive changes in early midlife. The key advantage of present study is the exploration of possible predictors of change in cognitive performance among general population in the early midlife, a developmental period that has been earlier overlooked.
Publisher: American Psychological Association (APA)
Date: 08-2020
DOI: 10.1037/ABN0000494
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.SCHRES.2005.08.016
Abstract: Childhood neuromotor dysfunction is a risk factor for schizophrenia, a disorder in which cognitive deficits are prominent. The relationship between early neurodevelopment and adult cognition in schizophrenia remains unclear. We examined the associations between infant motor development and adult cognitive functions in schizophrenia (n = 61) and the general population (n = 104) in a s le drawn from the The Northern Finland 1966 Birth Cohort. Data on ages of learning to stand and walk with or without support were obtained at age 12 months by health visitor assessment. Neurocognitive measures at age 33-35 included executive function, verbal and visual episodic memory, and visuo-spatial working memory. The schizophrenia group achieved neuromotor milestones later and performed significantly worse than the control group on all measures of cognition. In pooled analyses there were associations between infant motor development and adult cognition in the domains of executive function, verbal learning and visuospatial working memory, but not in visual object learning. The pattern of associations between development and cognition was similar in schizophrenia and the general population. These findings are consistent with the hypothesis that in schizophrenia mild infant motor developmental delay and adult cognitive deficits (at least in some domains) are age dependent manifestations of the same underlying neural process. Thus, they may be better considered as part of a single longitudinal syndrome.
Publisher: Cold Spring Harbor Laboratory
Date: 29-11-2019
DOI: 10.1101/859496
Abstract: Many architectures of deep neural networks have been designed to solve specific biomedical problems, among which segmentation is a critical step to detect and locate the boundaries of the target object from an image. In this paper, we develop a deep learning based framework to automatically segment the paracingulate sulcus (PCS) from the MRI scan and estimate lengths for its segments. The study is the first work on segmentation and characterisation of the PCS, and the model achieves a Dice score of over 0.77 on segmentation, which demonstrates its potential for clinical use to assist human annotation. Moreover, the proposed architecture as a solution can be generalised to other problems where the object has similar patterns.
Publisher: Wiley
Date: 08-2007
DOI: 10.1002/ANA.21120
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.PSCYCHRESNS.2018.08.015
Abstract: The aim of this paper was to investigate differences in brain structure volumes between schizophrenia and affective psychoses, and whether cumulative lifetime antipsychotic or benzodiazepine doses relate to brain morphology in these groups. We conducted two systematic reviews on the topic and investigated 44 schizophrenia cases and 19 with affective psychoses from the Northern Finland Birth Cohort 1966. The association between lifetime antipsychotic and benzodiazepine dose and brain MRI scans at the age of 43 was investigated using linear regression. Intracranial volume, sex, illness severity, and antipsychotic/benzodiazepine doses were used as covariates. There were no differences between the groups in brain structure volumes. In schizophrenia, after adjusting for benzodiazepine dose and symptoms, a negative association between lifetime antipsychotic dose and the nucleus accumbens volume remained. In affective psychoses, higher lifetime benzodiazepine dose associated with larger volumes of total gray matter and hippoc al volume after controlling for antipsychotic use and symptoms. It seems that in addition to antipsychotics, the severity of symptoms and benzodiazepine dose are also associated with brain structure volumes. These results suggest, that benzodiazepine effects should also be investigated also independently and not only as a confounder.
Publisher: Oxford University Press (OUP)
Date: 03-10-2019
Publisher: Wiley
Date: 05-06-2013
DOI: 10.1111/J.1751-7893.2012.00360.X
Abstract: Set within the general population-based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first-degree relative with psychotic illness or due to having experienced psychotic-like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview. Prospectively collected data from earlier follow-ups of this cohort were combined with health register data to categorize subjects as those with familial risk (n = 272), symptomatic risk (n = 117), psychosis (n = 78), attention deficit hyperactivity disorder (ADHD) (n = 103) and a s le of controls (n = 193) drawn randomly from the remaining cohort. The Structured Interview for Prodromal Syndromes (SIPS) was applied to all, 295 participants together with questionnaires measuring psychosis vulnerability and schizotypal traits. There were 29 (10%) current prodromal cases. Criteria for the current prodromal syndrome were fulfilled by 12% of the familial risk group and 19% of the symptomatic risk group, compared with 5% of the ADHD group and 4% of controls. We successfully detected young people with a prodromal psychosis syndrome although relatively few subjects deemed to be at high risk met the full operational criteria according to the SIPS interview. Combining methods from familial, clinical and psychometric high-risk approaches provides a tractable method for studying risk of psychosis in the general population.
Publisher: Royal College of Psychiatrists
Date: 08-2006
DOI: 10.1192/BJP.BP.105.015263
Abstract: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically. To examine the effects of ketamine in healthy people using a structured psychiatric interview. Ketamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms. Ketamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the s le. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers. Ketamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.SCHRES.2007.11.024
Abstract: Delayed neuromotor development carries an increased risk of developing schizophrenia, and some authors have assumed that risk factors for schizophrenia such as delayed development are also prognostic indicators for patients with established illness. In those who do develop schizophrenia, it is not clear if these same early developmental markers influence the outcome of illness. Our aim was to examine the association between infant developmental milestones and a range of outcomes in patients with schizophrenia. Our s le was drawn from Northern Finland 1966 Birth Cohort and included 109 subjects for whom prospectively collected information on age of learning to stand, walk and talk was available and who had developed schizophrenia by the age 35 years. By utilizing national registers we examined outcomes related to service utilization, educational achievement, and occupational status. Age of illness onset was also analyzed. Based on the diagnostic interview, a subgroup of 59 cases was assessed in clinical examinations on functioning and quality of life. Contrary to a widespread assumption within the field of schizophrenia research, later attainment of developmental milestones was not associated with poor outcome. We conclude that risk factors for schizophrenia are not necessarily prognostic factors.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
Publisher: Elsevier BV
Date: 10-2015
Publisher: Cambridge University Press (CUP)
Date: 30-08-2018
Publisher: Wiley
Date: 03-2017
DOI: 10.1002/HUP.2574
Abstract: The association between long-term antipsychotic treatment and changes in brain structure in schizophrenia is unclear. Our aim was to conduct a systematic review and a meta-analysis on long-term antipsychotic effects on brain structures in schizophrenia focusing on studies with at least 2 years of follow-up between MRI scans. Studies were systematically collected using 4 databases, and we also contacted authors for unpublished data. We calculated correlations between antipsychotic dose and/or type and brain volumetric changes and used random effect meta-analysis to study correlations by brain area. Thirty-one publications from 16 s les fulfilled our inclusion criteria. In meta-analysis, higher antipsychotic exposure associated statistically significantly with parietal lobe decrease (studies, n = 4 r = -.14, p = .013) and with basal ganglia increase (n = 4 r = .10, p = .044). Most of the reported correlations in the original studies were statistically nonsignificant. There were no clear differences between typical and atypical exposure and brain volume change. The studies were often small and highly heterogeneous in their methods and seldom focused on antipsychotic medication and brain changes as the main subject. Antipsychotic medication may associate with brain structure changes. More long-term follow-up studies taking into account illness severity measures are needed to make definitive conclusions.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2023
DOI: 10.1038/S41531-023-00522-Z
Abstract: Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson’s disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter s le containing 722 participants: 146 patients with first episode psychosis, FEP 106 in iduals in at-risk mental state for developing psychosis, ARMS 145 healthy controls matching FEP and ARMS, Con-Psy 92 PD patients with psychotic symptoms, PDP 145 PD patients without psychotic symptoms, PDN 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2008
Publisher: Wiley
Date: 15-08-2005
Publisher: Frontiers Media SA
Date: 26-02-2015
Publisher: Cold Spring Harbor Laboratory
Date: 17-02-2021
DOI: 10.1101/2021.02.15.21251726
Abstract: Studies reported a strong impact on mental health during the first wave of the COVID-19 pandemic in March–June, 2020. In this study, we assessed the impact of the pandemic on mental health in general and on schizoptypal traits in two independent general population s les of the UK (May s le N: 239, October s le N: 126 participation at both timepoints: 21) and in two independent general population s les of Germany (May s le N: 543, October s le N: 401 participation at both timepoints: 100) using online surveys. Whereas general psychological symptoms (global symptom index, GSI) and percentage of responders above clinical cut-off for further psychological investigation were higher in the May s le compared to the October s le, schizotypy scores (Schizotypal Personality Questionnaire) were higher in the October s le. We investigated potential associations, using general linear regression models (GLM). For schizotypy scores, we found that loneliness, use of drugs, and financial burden were more strongly corrected with schizotypy in the October compared to the May s le. We identified similar associations for GSI, as for schizotypy scores, in the May and October s les. We furthermore found that living in the UK was related to higher schizotypal scores or GSI. However, in idual estimates of the GLM are highly comparable between the two countries. In conclusion, this study shows that while the general psychological impact is lower in the October than the May s le, potentially showing a normative response to an exceptional situation schizotypy scores are higher at the second timepoint, which may be due to a stronger impact of estimates of loneliness, drug use, and financial burden. The ongoing, exceptional circumstances within this pandemic might increase the risk for developing psychosis in some in iduals. The development of general psychological symptoms and schizotypy scores over time requires further attention and investigation.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.SCHRES.2015.10.010
Abstract: The cerebellum plays a critical role in cognition and behavior. Altered function of the cerebellum has been related to schizophrenia and psychosis but it is not known how this applies to spontaneous resting state activity in young people with familial risk for psychosis. We conducted resting-state functional MRI (R-fMRI) in 72 (29 male) young adults with a history of psychosis in one or both parents (FR) but without their own psychosis, and 72 (29 male) similarly healthy control subjects without parental psychosis. Both groups in the Oulu Brain and Mind Study were drawn from the Northern Finland Birth Cohort 1986. Participants were 20-25 years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data pre-processing was conducted using independent component analysis with 30 and 70 components. A dual regression technique was used to detect between-group differences in the cerebellum with p<0.05 threshold corrected for multiple comparisons. FR participants demonstrated statistically significantly increased activity compared to control subjects in the anterior lobe of the right cerebellum in the analysis with 70 components. The volume of the increased activity was 73 mm(3). There was no difference between the groups in the analysis with 30 components. The finding suggests that increased activity of the anterior lobe of the right cerebellum may be associated with increased vulnerability to psychosis. The finding is novel, and needs replication to be confirmed.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2020
DOI: 10.1038/S41380-020-0803-8
Abstract: 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 in iduals 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.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2019
Publisher: Frontiers Media SA
Date: 11-07-2017
Publisher: Informa UK Limited
Date: 06-01-2011
Publisher: Oxford University Press (OUP)
Date: 12-02-2010
Publisher: Public Library of Science (PLoS)
Date: 26-06-2015
Publisher: Oxford University Press (OUP)
Date: 31-10-2022
Abstract: Higher educational attainment is observationally associated with lower risk of Alzheimer’s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer’s disease may be mediated via increased brain reserve. We used two-s le Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer’s disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer’s disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer’s disease (ii) educational attainment and imaging-derived phenotypes and (iii) imaging-derived phenotypes and Alzheimer’s disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer’s disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer’s disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40) volume 0.29 (95% confidence interval 0.20, 0.37) intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25) local gyrification index 0.21 (95% confidence interval 0.11, 0.31)] and inverse associations with cortical intracellular volume fraction [−0.09 (95% confidence interval −0.15, −0.03)] and white matter hyperintensities volume [−0.14 (95% confidence interval −0.23, −0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16) 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer’s disease. The inverse association of genetically predicted educational attainment with Alzheimer’s disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer’s disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer’s disease. The protective effect of education on Alzheimer’s disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Graham Murray.