Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment.

Cognitive deficits are a core feature of schizophrenia, account for much of the impaired functioning associated with the disorder and are not responsive to existing treatments. In this review, we first describe the clinical presentation and natural history of these deficits. We then consider aetiological factors, highlighting how a range of similar genetic and environmental factors are associated with both cognitive function and schizophrenia. We then review the pathophysiological mechanisms thought to underlie cognitive symptoms, including the role of dopamine, cholinergic signalling and the balance between GABAergic interneurons and glutamatergic pyramidal cells. Finally, we review the clinical management of cognitive impairments and candidate novel treatments.

White matter deficits in schizophrenia are global and don't progress with age.

INTRODUCTION: Diffusion tensor imaging has revealed differences in all examined white matter tracts in schizophrenia, with a range of explanations for why this may be. The distribution and timing of differences may help explain their origin; however, results are usually dependent on the analytical method. We therefore sought to examine the extent of differences and their relationship with age using two different methods. METHODS: A combined voxel-based whole-brain study and a tract-based spatial-statistics study of 104 patients with schizophrenia and 200 matched healthy controls, aged between 17 and 63 years. RESULTS: Fractional anisotropy was reduced throughout the brain in both analyses. The relationship of fractional anisotropy with age differed between patients and controls, with controls showing the gentle fractional anisotropy decline widely noted but patients showing an essentially flat relationship: younger patients had lower fractional anisotropy than controls, but the difference disappeared with age. Mean diffusivity was widely increased in patients. CONCLUSION: Reduction in fractional anisotropy and increase in mean diffusivity would be consistent with global disruption in myelination; the relationship with age would suggest this is present already at the onset of their illness, but does not progress.

Duration of untreated psychosis and need for admission in patients who engage with mental health services in the prodromal phase.

BACKGROUND: It is unknown whether prodromal services improve outcomes in those who go on to develop psychosis, and whether these patients are demographically different from the overall first-episode population. AIMS: To compare sociodemographic features, duration of untreated psychosis, hospital admission and frequency of compulsory treatment in the first year after the onset of psychosis in patients who present to prodromal services with patients who did not present to services until the first episode of psychosis. METHOD: We compared two groups of patients with first-episode psychosis: one who made transition after presenting in the prodromal phase and the other who had presented with a first episode. RESULTS: The patients who had presented before the first episode were more likely to be employed and less likely to belong to an ethnic minority group. They had a shorter duration of untreated psychosis, and were less likely to have been admitted to hospital and to have required compulsory treatment. CONCLUSIONS: Patients who develop psychosis after being engaged in the prodromal phase have a better short-term clinical outcome than patients who do not present until the first episode. Patients who present during first episodes may be more likely to have sociodemographic features associated with relatively poor outcomes.

Road work on memory lane--functional and structural alterations to the learning and memory circuit in adults born very preterm.

Very preterm (VPT) birth is considered a risk factor not only for neurological impairment, but also for reduced function in several cognitive domains in childhood and later in life. Individuals who were born VPT are more likely to demonstrate learning and memory difficulties compared to term-born controls. These problems contribute to more VPT-born children repeating grades and underachieving in school. This, in turn, affects their prospects in adult life. Here we aimed to 1) study how the VPT-born adult brain functionally recruited specific areas during learning, i.e. encoding and recall across four repeated blocks of verbal stimuli, and to investigate how these patterns of activation differed from term-born subjects; and 2) probe the microstructural differences of white-matter tracts connecting these areas to other parts of the learning and memory network. To investigate these functional-structural relationships we analyzed functional and diffusion-weighted MRI. Functional-MRI and a verbal paired associate learning (VPAL) task were used to extract Blood Oxygenation Level Dependent (BOLD) activity in 21 VPT-born adults (<33 weeks of gestation) (mean age: 19.68 years ± 0.85; IQ: 99.86 ± 11.20) and 10 term-born controls (mean age: 19.87 years ± 2.04; IQ: 108.9 ± 13.18). Areas in which differences in functional activation were observed between groups were used as seed regions for tractography. Fractional anisotropy (FA) of the tract-skeleton was then compared between groups on a voxel-wise basis. Results of functional MRI analysis showed a significantly different pattern of activation between groups during encoding in right anterior cingulate-caudate body, and during retrieval in left thalamus, hippocampus and parts of left posterior parahippocampal gyrus. The number of correctly recalled word pairs did not statistically differ between individuals who were born VPT and controls. The VPT-born group was found to have reduced FA in tracts passing through the thalamic/hippocampal region that was differently activated during the recall condition, with the hippocampal fornix, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus particularly affected. Young adults who were born very preterm display a strikingly different pattern of activation during the process of learning in key structures of the learning and memory network, including anterior cingulate and caudate body during encoding and thalamus/parahippocampal gyrus during cued recall. Altered activation in thalamus/parahippocampal gyrus may be explained by reduced connections between these areas and the hippocampus, which may be a direct consequence of neonatal hypoxic/ischemic injury. These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions, at least when the cognitive load remains relatively low, as ex-preterm young adults displayed unimpaired performance in completing the verbal paired associate learning task.

Abnormal effective connectivity and psychopathological symptoms in the psychosis high-risk state.

BACKGROUND: Recent evidence has revealed abnormal functional connectivity between the frontal and parietal brain regions during working memory processing in patients with schizophrenia and first-episode psychosis. However, it still remains unclear whether abnormal frontoparietal connectivity during working memory processing is already evident in the psychosis high-risk state and whether the connection strengths are related to psychopathological outcomes. METHODS: Healthy controls and antipsychotic-naive individuals with an at-risk mental state (ARMS) performed an n-back working memory task while undergoing functional magnetic resonance imaging. Effective connectivity between frontal and parietal brain regions during working memory processing were characterized using dynamic causal modelling. RESULTS: Our study included 19 controls and 27 individuals with an ARMS. In individuals with an ARMS, we found significantly lower task performances and reduced activity in the right superior parietal lobule and middle frontal gyrus than in controls. Furthermore, the working memory-induced modulation of the connectivity from the right middle frontal gyrus to the right superior parietal lobule was significantly reduced in individuals with an ARMS, while the extent of this connectivity was negatively related to the Brief Psychiatric Rating Scale total score. LIMITATIONS: The modest sample size precludes a meaningful subgroup analysis for participants with a later transition to psychosis. CONCLUSION: This study demonstrates that abnormal frontoparietal connectivity during working memory processing is already evident in individuals with an ARMS and is related to psychiatric symptoms. Thus, our results provide further insight into the pathophysiological mechanisms of the psychosis high-risk state by linking functional brain imaging, computational modelling and psychopathology.

Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study.

Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using (18)F-dihydroxyphenyl-L-alanine ((18)F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that (18)F-dihydroxyphenyl-L-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral (18)F-dihydroxyphenyl-L-alanine uptake was positively related with the severity of symptoms (r = 0.39, P = 0.035) in patients. However, whereas nigral and striatal (18)F-dihydroxyphenyl-L-alanine uptake were positively related in control subjects (r = 0.63, P < 0.001), this was not the case in patients (r = 0.30, P = 0.11). These findings indicate that elevated dopamine synthesis capacity is seen in the nigral origin of dopamine neurons as well as their striatal terminals in schizophrenia, and is linked to symptom severity in patients.

Translating neuroimaging findings into psychiatric practice.

Although translational medicine has become a priority for medical science, advances in neuroscience have failed to be translated for the benefit of patients. In populations at high risk of psychosis, neuroimaging could stratify those mostly likely to develop psychosis. This is an example of potentially translatable psychiatry.

Data-Driven Taxonomy for Antipsychotic Medication: A New Classification System.

BACKGROUND: Globally, there are more than 25 licensed antipsychotic medications. Antipsychotics are commonly described as either typical or atypical, but this dichotomous classification does not reflect the diversity of their pharmacological and clinical profiles. There is a need for a data-driven antipsychotic classification scheme suitable for clinicians and researchers that maps onto both pharmacological and clinical effects. Receptor affinity provides one starting point for such a scheme. METHODS: We analyzed affinities of 27 antipsychotics for 42 receptors from 3325 in vitro receptor binding studies. We used a clustering algorithm to group antipsychotics based on receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced clinical effects quantified according to an umbrella review of clinical trial and treatment guideline data. RESULTS: Clustering resulted in 4 groups of antipsychotics. The predominant receptor affinity and clinical effect "fingerprints" of these 4 groups were defined as follows: group 1, muscarinic (M2-M5) receptor antagonism (cholinergic and metabolic side effects); group 2, dopamine (D2) partial agonism and adrenergic antagonism (overall low side-effect burden); group 3, serotonergic and dopaminergic antagonism (overall moderate side-effect burden); and group 4, dopaminergic antagonism (extrapyramidal side effects and hyperprolactinemia). Groups 1 and 4 were more efficacious than groups 2 and 3. The classification was shown to predict out-of-sample clinical effects of individual drugs. CONCLUSIONS: A receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences. This approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development.

BACKGROUND: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. METHODS: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). FINDINGS: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. INTERPRETATION: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. FUNDING: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment.

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks' naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

Multivariate pattern classification reveals differential brain activation during emotional processing in individuals with psychosis proneness.

Among the general population, individuals with subthreshold psychotic-like experiences, or psychosis proneness (PP), can be psychometrically identified and are thought to have a 10-fold increased risk of psychosis. They also show impairments in measures of emotional functioning parallel to schizophrenia. Whilst previous studies have revealed altered brain activation in patients with schizophrenia during emotional processing, it is unclear whether these alterations are also expressed in individuals with high PP. Here we used Support Vector Machine (SVM) to perform multivariate pattern classification based on brain activation during emotional processing in 20 individuals with high PP and 20 comparison subjects (low PP). In addition, we performed a standard univariate analysis based on the General Linear Model (GLM) on the same data for comparison. The experimental task involved passively viewing negative and neutral pictures from the International Affective Picture System (IAPS). SVM allowed classification of the two groups with statistically significant accuracy (p=0.017) and identified group differences within an emotional circuitry including the amygdala, insula, anterior cingulate and medial prefrontal cortex. In contrast, the standard univariate analysis did not detect any significant between-group differences. Our results reveal a distributed and subtle set of alterations in brain function within the emotional circuitry of individuals with high PP, providing neurobiological support for the notion of dysfunctional emotional circuitry in this group. In addition, these alterations are best detected using a multivariate approach rather than standard univariate methods. Further application of this approach may aid in characterising people at clinical and genetic risk of developing psychosis.

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency.

BACKGROUND: The D-Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D-amino acid oxidase (DAO), which metabolizes D-serine, a co-agonist of NMDA-type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. AIMS: To examine the influence of G72 variation on brain function in the healthy population. METHOD: Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task-dependent functional connectivity during word generation was compared between different rs746187 genotypes. RESULTS: G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task-dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). CONCLUSIONS: Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D-amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis.

Sexual dysfunction in people with prodromal or first-episode psychosis.

BACKGROUND: Sexual dysfunction is common in psychotic disorder but it is not clear whether it is intrinsic to the development of the illness or secondary to other factors. AIMS: To compare sexual function in people at ultra-high risk (UHR) of a psychotic disorder, patients with first-episode psychosis predominantly taking antipsychotic drugs and healthy volunteers. METHOD: Sexual function was assessed in a UHR group (n = 31), a group with first-episode psychosis (n = 37) and a matched control group of healthy volunteers (n = 56) using the Sexual Function Questionnaire. RESULTS: There was a significant effect of group on sexual function (P<0.001). Sexual dysfunction was evident in 50% of the UHR group, 65% of first-episode patients and 21% of controls. Within the UHR group, sexual dysfunction was more marked in those who subsequently developed psychosis than in those who did not. Across all groups the severity of sexual dysfunction was correlated with the severity of psychotic symptoms (P<0.001). Within the first-episode group there was no significant difference in sexual dysfunction between patients taking prolactin-raising v. prolactin-sparing antipsychotics. CONCLUSIONS: Sexual dysfunction is present prior to onset of psychosis, suggesting it is intrinsic to the development of illness unlikely to be related to the prolactin-raising properties of antipsychotic medication.

Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder.

BACKGROUND: Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses. METHODS: 104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis. RESULTS: During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls. CONCLUSIONS: In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

White matter defects in first episode psychosis patients: a voxelwise analysis of diffusion tensor imaging.

OBJECTIVE: Disruptions in white matter structure have consistently been shown in schizophrenia--but mainly in patients in whom the illness is well-established. In order to determine whether white matter abnormalities are present at illness onset, and to minimise the potentially confounding effects of chronic illness and treatment, we used diffusion tensor imaging to study a large cohort of first episode psychotic patients who were medication-naive. METHODS: Sixty two first episode patients and 54 controls matched on age, sex, years of education and laterality index underwent diffusion tensor imaging. Data were acquired on a GE Signa NVi 1.5 Tesla System. Fractional anisotropy maps were generated on a voxel-by-voxel basis. An optimized voxel-based morphometry technique was conducted with two-stage registration approach. Group differences were examined using a non-parametric statistical method. RESULTS: The voxelwise analysis revealed four clusters where fractional anisotropy values were significantly lower in patients than controls. These were localised bilaterally to regions of white matter corresponding to superior and inferior longitudinal fasciculus, forceps major, anterior and superior thalamic radiation and corpus callosum. CONCLUSIONS: Reductions in white matter integrity are present early in the course of the schizophrenia and localised in fascicule that connect brain regions implicated in the disorder.

The very preterm brain in young adulthood: the neural correlates of verbal paired associate learning.

OBJECTIVE: To determine whether preterm birth influences functional neuronal development in adulthood. STUDY DESIGN: We evaluated adults born very preterm (VPT; < 33 weeks of gestation) using a verbal paired-associate learning task within a functional magnetic resonance imaging paradigm. Hippocampi and parahippocampal gyri gray matter volumes were also quantified. RESULTS: Despite similar task performance compared with control participants, VPT adults showed increased brain activation in the left parahippocampal and precentral gyri during Encoding, and in the precentral gyrus during Recall. Very preterm participants also had decreased gray matter volume in the left and right hippocampi yet increased gray matter in the left parahippocampal gyrus. In VPT participants alone, activation in the left parahippocampal gyrus during Encoding (VPT>control participants) was positively associated with gray matter volume in the left parahippocampal gyrus, with VPT participants with the youngest gestational age (eg, born 28 weeks or less) having both increased gray matter and functional activation in this region. These results may reflect the process of neural reorganization after early brain injury. CONCLUSION: Preterm birth leads to functional neuronal differences in adulthood, which are meditated by both structural variations in task-specific regions, and gestational age.

Thalamic neurochemical abnormalities in individuals with prodromal symptoms of schizophrenia - relationship to auditory event-related potentials.

Thalamic neurochemical abnormalities may underlie psychotic symptoms and auditory event-related potential (ERP) abnormalities in schizophrenia. We investigated this hypothesis in subjects at risk of psychosis using magnetic resonance spectroscopy and electroencephalography (EEG). Reduced thalamic glutamate plus glutamine and N-acetyl aspartate levels were associated with abnormal frontal ERPs, supporting a thalamic basis for filtering impairments.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: multiple-domain deficits and longitudinal evaluation.

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n=70) recruited from the same area of São Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time.