Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Dimensional profiling of psychopathology in children and adolescents based on the K-SADS-PL and an analysis of the construct validity of two ADHD symptom dimensions.

OBJECTIVES: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification. METHODS: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls). RESULTS: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale. CONCLUSIONS: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.

Effects of methylphenidate on mismatch negativity and P3a amplitude of initially psychostimulant-naïve, adult ADHD patients.

BACKGROUND: Deficient information processing in ADHD theoretically results in sensory overload and may underlie the symptoms of the disorder. Mismatch negativity (MMN) and P3a amplitude reflect an individual's detection and subsequent change in attention to stimulus change in their environment. Our primary aim was to explore MMN and P3a amplitude in adult ADHD patients and to examine the effects of methylphenidate (MPH) on these measures. METHODS: Forty initially psychostimulant-naïve, adult ADHD patients without comorbid ASD and 42 matched healthy controls (HC) were assessed with an MMN paradigm at baseline. Both groups were retested after 6 weeks, in which patients were treated with MPH. RESULTS: Neither significant group differences in MMN nor P3a amplitude were found at baseline. Although 6-week MPH treatment significantly reduced symptomatology and improved daily functioning of the patients, it did not significantly affect MMN amplitude; however, it did significantly reduce P3a amplitude compared to the HC. Furthermore, more severe ADHD symptoms were significantly associated with larger MMN amplitudes in the patients, both at baseline and follow-up. CONCLUSION: We found no evidence for early information processing deficits in patients with ADHD, as measured with MMN and P3a amplitude. Six-week treatment with MPH decreased P3a but not MMN amplitude, although more severe ADHD-symptoms were associated with larger MMN amplitudes in the patients. Given that P3a amplitude represents an important attentional process and that glutamate has been linked to both ADHD and MMN amplitude, future research should investigate augmenting MPH treatment of less responsive adults with ADHD with glutamatergic antagonists.

Clustering of antipsychotic-naïve patients with schizophrenia based on functional connectivity from resting-state electroencephalography.

Schizophrenia is associated with aberrations in the Default Mode Network (DMN), but the clinical implications remain unclear. We applied data-driven, unsupervised machine learning based on resting-state electroencephalography (rsEEG) functional connectivity within the DMN to cluster antipsychotic-naïve patients with first-episode schizophrenia. The identified clusters were investigated with respect to psychopathological profile and cognitive deficits. Thirty-seven antipsychotic-naïve, first-episode patients with schizophrenia (mean age 24.4 (5.4); 59.5% males) and 97 matched healthy controls (mean age 24.0 (5.1); 52.6% males) underwent assessments of rsEEG, psychopathology, and cognition. Source-localized, frequency-dependent functional connectivity was estimated using Phase Lag Index (PLI). The DMN-PLI was factorized for each frequency band using principal component analysis. Clusters of patients were identified using a Gaussian mixture model and neurocognitive and psychopathological profiles of identified clusters were explored. We identified two clusters of patients based on the theta band (4-8 Hz), and two clusters based on the beta band (12-30 Hz). Baseline psychopathology could predict theta clusters with an accuracy of 69.4% (p = 0.003), primarily driven by negative symptoms. Five a priori selected cognitive functions conjointly predicted the beta clusters with an accuracy of 63.6% (p = 0.034). The two beta clusters displayed higher and lower DMN connectivity, respectively, compared to healthy controls. In conclusion, the functional connectivity within the DMN provides a novel, data-driven means to stratify patients into clinically relevant clusters. The results support the notion of biological subgroups in schizophrenia and endorse the application of data-driven methods to recognize pathophysiological patterns at earliest stage of this syndrome.

Effects of methylphenidate on subjective sleep parameters in adults with ADHD: a prospective, non-randomized, non-blinded 6-week trial.

OBJECTIVE: Methylphenidate is a first-line treatment for ADHD; its contribution to sleep problems in adult ADHD is currently unclear. This study investigates (a) subjective sleep disturbances in a group of initially stimulant medication-naïve adults with ADHD and (b) reported changes in sleep problems after 6 weeks of methylphenidate treatment. METHOD: A prospective, non-randomized, non-blinded, 6-week follow-up study utilising a self-report measure. RESULTS: We found (1) a large difference in reported sleep quality between methylphenidate medication-naïve patients and controls at baseline, (2) a marked improvement in patients after methylphenidate medication, and (3) largest improvement for patients with the poorest reported sleep at baseline. CONCLUSION: The study indicates that treatment with methylphenidate increases subjective sleep quality for at least some adults with ADHD.

Heritability of specific cognitive functions and associations with schizophrenia spectrum disorders using CANTAB: a nation-wide twin study.

BACKGROUND: Many cognitive functions are under strong genetic control and twin studies have demonstrated genetic overlap between some aspects of cognition and schizophrenia. How the genetic relationship between specific cognitive functions and schizophrenia is influenced by IQ is currently unknown. METHODS: We applied selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to examine the heritability of specific cognitive functions and associations with schizophrenia liability. Verbal and performance IQ were estimated using The Wechsler Adult Intelligence Scale-III and the Danish Adult Reading Test. In total, 214 twins including monozygotic (MZ = 32) and dizygotic (DZ = 22) pairs concordant or discordant for a schizophrenia spectrum disorder, and healthy control pairs (MZ = 29, DZ = 20) were recruited through the Danish national registers. Additionally, eight twins from affected pairs participated without their sibling. RESULTS: Significant heritability was observed for planning/spatial span (h2 = 25%), self-ordered spatial working memory (h2 = 64%), sustained attention (h2 = 56%), and movement time (h2 = 47%), whereas only unique environmental factors contributed to set-shifting, reflection impulsivity, and thinking time. Schizophrenia liability was associated with planning/spatial span (rph = -0.34), self-ordered spatial working memory (rph = -0.24), sustained attention (rph = -0.23), and set-shifting (rph = -0.21). The association with planning/spatial span was not driven by either performance or verbal IQ. The remaining associations were shared with performance, but not verbal IQ. CONCLUSIONS: This study provides further evidence that some cognitive functions are heritable and associated with schizophrenia, suggesting a partially shared genetic etiology. These functions may constitute endophenotypes for the disorder and provide a basis to explore genes common to cognition and schizophrenia.

Differential effects of age at illness onset on verbal memory functions in antipsychotic-naïve schizophrenia patients aged 12-43 years.

BACKGROUND: The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition. METHODS: The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12-43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates. RESULTS: There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs. CONCLUSIONS: Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

PURPOSE/BACKGROUND: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). METHODS/PROCEDURES: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. FINDINGS/RESULTS: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. IMPLICATIONS/CONCLUSIONS: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Global fractional anisotropy predicts transition to psychosis after 12 months in individuals at ultra-high risk for psychosis.

OBJECTIVE: Psychosis spectrum disorders are associated with cerebral changes, but the prognostic value and clinical utility of these findings are unclear. Here, we applied a multivariate statistical model to examine the predictive accuracy of global white matter fractional anisotropy (FA) for transition to psychosis in individuals at ultra-high risk for psychosis (UHR). METHODS: 110 UHR individuals underwent 3 Tesla diffusion-weighted imaging and clinical assessments at baseline, and after 6 and 12 months. Using logistic regression, we examined the reliability of global FA at baseline as a predictor for psychosis transition after 12 months. We tested the predictive accuracy, sensitivity and specificity of global FA in a multivariate prediction model accounting for potential confounders to FA (head motion in scanner, age, gender, antipsychotic medication, parental socioeconomic status and activity level). In secondary analyses, we tested FA as a predictor of clinical symptoms and functional level using multivariate linear regression. RESULTS: Ten UHR individuals had transitioned to psychosis after 12 months (9%). The model reliably predicted transition at 12 months (χ2  = 17.595, p = 0.040), accounted for 15-33% of the variance in transition outcome with a sensitivity of 0.70, a specificity of 0.88 and AUC of 0.87. Global FA predicted level of UHR symptoms (R2  = 0.055, F = 6.084, p = 0.016) and functional level (R2  = 0.040, F = 4.57, p = 0.036) at 6 months, but not at 12 months. CONCLUSION: Global FA provided prognostic information on clinical outcome and symptom course of UHR individuals. Our findings suggest that the application of prediction models including neuroimaging data can inform clinical management on risk for psychosis transition.

Fish Oil Supplementation in Pregnancy and Neurodevelopment in Childhood-A Randomized Clinical Trial.

A double-blind randomized controlled trial of n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation or matching placebo during third trimester of pregnancy was conducted within the COPSAC2010 mother-child cohort consisting of 736 women and their children. The objective was to determine if maternal n-3 LCPUFA pregnancy supplementation affects offspring neurodevelopment until 6 years. Neurodevelopment was evaluated in 654 children assessing age of motor milestone achievement, language development, cognitive development, general neurodevelopment, and emotional and behavioral problems. Maternal n-3 LCPUFA supplementation during pregnancy improved early language development and reduced the impact of emotional and behavioral problems. The n-3 LCPUFA supplementation was in boys associated with the earlier achievement of gross motor milestones, improved cognitive development, and a reduced impact of emotional and behavioral problems.

Do young adolescents with first-episode psychosis or ADHD show sensorimotor gating deficits?

BACKGROUND: Early identification is important for patients with early-onset schizophrenia (SZ). Assessment of (candidate) endophenotypic markers for SZ, such as prepulse inhibition of the startle reflex (PPI), may help distinguish between the early-onset SZ and other psychiatric disorders. We explored whether PPI deficits usually seen in adult-onset SZ are present in young adolescents with either early-onset psychosis or attention deficit/hyperactivity disorder (ADHD). METHODS: Twenty-five adolescents with first-episode, non-affective psychosis (FEP), 28 adolescents with ADHD and 43 healthy controls (HC), aged 12-17 years, were assessed with an auditory PPI paradigm. RESULTS: No significant group differences were found in PPI. However, when the FEP group was divided into those already diagnosed with SZ (n = 13) and those without (N-SZ) (n = 12), and all four groups (SZ, N-SZ, ADHD and HC) were compared on percentage PPI in the 85/60 trials, significantly less PPI was found in patients with SZ than in the HC as well as the ADHD group. No significant group differences were found in explorative analyses on the other trial types. Additionally, startle magnitude was significantly higher in SZ than in N-SZ patients. CONCLUSION: Young adolescents with SZ showed sensorimotor gating deficits similar to those usually found in adults with SZ and had larger startle magnitude than patients with other types of non-affective early-onset psychosis. No sensorimotor gating deficits were found in adolescents with ADHD. Our findings support the theory that deficient PPI is endophenotypic for SZ.

Cognitive reserve attenuates age-related cognitive decline in the context of putatively accelerated brain ageing in schizophrenia-spectrum disorders.

BACKGROUND: In schizophrenia, relative stability in the magnitude of cognitive deficits across age and illness duration is inconsistent with the evidence of accelerated deterioration in brain regions known to support these functions. These discrepant brain-cognition outcomes may be explained by variability in cognitive reserve (CR), which in neurological disorders has been shown to buffer against brain pathology and minimize its impact on cognitive or clinical indicators of illness. METHODS: Age-related change in fluid reasoning, working memory and frontal brain volume, area and thickness were mapped using regression analysis in 214 individuals with schizophrenia or schizoaffective disorder and 168 healthy controls. In patients, these changes were modelled as a function of CR. RESULTS: Patients showed exaggerated age-related decline in brain structure, but not fluid reasoning compared to controls. In the patient group, no moderation of age-related brain structural change by CR was evident. However, age-related cognitive change was moderated by CR, such that only patients with low CR showed evidence of exaggerated fluid reasoning decline that paralleled the exaggerated age-related deterioration of underpinning brain structures seen in all patients. CONCLUSIONS: In schizophrenia-spectrum illness, CR may negate ageing effects on fluid reasoning by buffering against pathologically exaggerated structural brain deterioration through some form of compensation. CR may represent an important modifier that could explain inconsistencies in brain structure - cognition outcomes in the extant literature.

Measuring movements in adolescents with psychosis using the Microsoft Kinect sensor: a pilot study exploring a new tool for assessing aspects of antipsychotic-induced parkinsonism.

BACKGROUND: The assessment of motor disturbances in antipsychotic-treated adolescent patients is often limited to the use of observer-based rating scales with interobserver variability. The objectives of this pilot study were to measure movement patterns associated with antipsychotic-induced parkinsonism in young patients with psychosis and initiating/treated with antipsychotics, using a computer application connected with the Microsoft Kinect sensor (Motorgame). METHOD: All participants were assessed by neurological examination, clinical side effect rating scales (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, Barnes Akathisia Rating Scale, Simpson Angus Scale (SAS), and Abnormal Involuntary Movement Scale), and the Motorgame. Furthermore, speed of information processing and motor speed with subtests from the Brief Assessment of Cognition in Schizophrenia test battery was assessed. RESULTS: We included 21 adolescents with first-episode psychosis (62% treated with antipsychotics; males 38%; mean age 16 ± 1.4 years) and 69 healthy controls (males 36%; mean age 16 ± 1.5 years). Prolonged time of motor performance (TOMP) in the Motorgame was associated with higher SAS scores for arm dropping (p = .009). A consistent practice effect was detected (p < .001). We found no significant associations between TOMP and age, height, body weight, sex, antipsychotic dosage, or information processing speed. CONCLUSIONS: We found an uncorrected significant association between prolonged TOMP and shoulder bradykinesia. The Motorgame was found useful in assessing parkinsonian symptoms in early-onset psychosis and accepted by participants. Future studies of larger cohorts, including patients with high scores in clinical motor side effect scales, are required to establish solid validity of the novel test.

Widespread higher fractional anisotropy associates to better cognitive functions in individuals at ultra-high risk for psychosis.

In schizophrenia patients, cognitive functions appear linked to widespread alterations in cerebral white matter microstructure. Here we examine patterns of associations between regional white matter and cognitive functions in individuals at ultra-high risk for psychosis. One hundred and sixteen individuals at ultra-high risk for psychosis and 49 matched healthy controls underwent 3 T magnetic resonance diffusion-weighted imaging and cognitive assessments. Group differences on fractional anisotropy were tested using tract-based spatial statistics. Group differences in cognitive functions, voxel-wise as well as regional fractional anisotropy were tested using univariate general linear modeling. Multivariate partial least squares correlation analyses tested for associations between patterns of regional fractional anisotropy and cognitive functions. Univariate analyses revealed significant impairments on cognitive functions and lower fractional anisotropy in superior longitudinal fasciculus and cingulate gyrus in individuals at ultra-high risk for psychosis. Partial least squares correlation analysis revealed different associations between patterns of regional fractional anisotropy and cognitive functions in individuals at ultra-high risk for psychosis compared to healthy controls. Widespread higher fractional anisotropy was associated with better cognitive functioning for individuals at ultra-high risk for psychosis, but not for the healthy controls. Furthermore, patterns of cognitive functions were associated with an interaction-effect on regional fractional anisotropy in fornix, medial lemniscus, uncinate fasciculus, and superior cerebellar peduncle. Aberrant associations between patterns of cognitive functions to white matter may be explained by dysmyelination.

Cortical structures and their clinical correlates in antipsychotic-naïve schizophrenia patients before and after 6 weeks of dopamine D2/3 receptor antagonist treatment.

BACKGROUND: Schizophrenia has been associated with changes in both cortical thickness and surface area, but antipsychotic exposure, illness progression and substance use may confound observations. In antipsychotic-naïve schizophrenia patients, we investigated cortical thickness and surface area as well as mean curvature before and after monotherapy with amisulpride, a relatively selective dopamine D2/3 receptor antagonist. METHODS: Fifty-six patients and 59 matched healthy controls (HCs) underwent T1-weighted 3T magnetic resonance imaging. Forty-one patients and 51 HCs were re-scanned. FreeSurfer-processed baseline, follow-up values and symmetrized percentage changes (SPC) in cortical structures were analysed using univariate analysis of variance. Clinical measures comprised psychopathology ratings, assessment of functioning and tests of premorbid and current intelligence. We applied false discovery rate correction to account for multiple comparisons. RESULTS: At baseline, groups did not differ in cortical thickness or surface area; however, curvature in the left hemisphere was higher in patients (p = 0.015). In both patients and HCs, higher curvature was associated with lower premorbid (p = 0.009) and current intelligence (p 0.43). Cortical thickness SPC was negatively associated with symptom improvement (p = 0.002). CONCLUSIONS: Schizophrenia appears associated with subtle, yet clinically relevant aberrations in cortical structures. Mean curvature holds promise as a sensitive supplement to cortical thickness and surface area to detect complex structural brain abnormalities.

Associations between P3a and P3b amplitudes and cognition in antipsychotic-naïve first-episode schizophrenia patients.

BACKGROUND: Cognitive deficits are already present in early stages of schizophrenia. P3a and P3b event-related potentials (ERPs) are believed to underlie the processes of attention and working memory (WM), yet limited research has been performed on the associations between these parameters. Therefore, we explored possible associations between P3a/b amplitudes and cognition in a large cohort of antipsychotic-naïve, first-episode schizophrenia (AN-FES) patients and healthy controls (HC). METHODS: Seventy-three AN-FES patients and 93 age- and gender-matched HC were assessed for their P3a/b amplitude with an auditory oddball paradigm. In addition, subjects performed several subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: AN-FES patients had significantly reduced P3a/b amplitudes, as well as significantly lower scores on all cognitive tests compared with HC. Total group correlations revealed positive associations between P3b amplitude and WM and sustained attention and negative associations with all reaction time measures. These associations appeared mainly driven by AN-FES patients, where we found a similar pattern. No significant associations were found between P3b amplitude and cognitive measures in our HC. P3a amplitude did not correlate significantly with any cognitive measures in either group, nor when combined. CONCLUSIONS: Our results provide further evidence for P3a/b amplitude deficits and cognitive deficits in AN-FES patients, which are neither due to antipsychotics nor to disease progress. Furthermore, our data showed significant, yet weak associations between P3b and cognition. Therefore, our data do not supply evidence for deficient P3a/b amplitudes as direct underlying factors for cognitive deficits in schizophrenia.

Visual attention in adults with attention-deficit/hyperactivity disorder before and after stimulant treatment.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder which frequently persists into adulthood. The primary goal of the current study was to (a) investigate attentional functions of stimulant medication-naïve adults with ADHD, and (b) investigate the effects of 6 weeks of methylphenidate treatment on these functions. METHODS: The study was a prospective, non-randomized, non-blinded, 6-week follow-up design with 42 stimulant medication-naïve adult patients with ADHD, and 42 age and parental education-matched healthy controls. Assessments included measures of visual attention, based on Bundesen's Theory of Visual Attention (TVA), which yields five precise measures of aspects of visual attention; general psychopathology; ADHD symptoms; dyslexia screening; and estimates of IQ. RESULTS: At baseline, significant differences were found between patients and controls on three attentional parameters: visual short-term memory capacity, threshold of conscious perception, and to a lesser extent visual processing speed. Secondary analyses revealed no significant correlations between TVA parameter estimates and severity of ADHD symptomatology. At follow-up, significant improvements were found specifically for visual processing speed; this improvement had a large effect size, and remained when controlling for re-test effects, IQ, and dyslexia screen performance. There were no significant correlations between changes in visual processing speed and changes in ADHD symptomatology. CONCLUSIONS: ADHD in adults may be associated with deficits in three distinct aspects of visual attention. Improvements after 6 weeks of medication are seen specifically in visual processing speed, which could represent an improvement in alertness. Clinical symptoms and visual attentional deficits may represent separate aspects of ADHD in adults.

Accuracy of diagnostic classification algorithms using cognitive-, electrophysiological-, and neuroanatomical data in antipsychotic-naïve schizophrenia patients.

BACKGROUND: A wealth of clinical studies have identified objective biomarkers, which separate schizophrenia patients from healthy controls on a group level, but current diagnostic systems solely include clinical symptoms. In this study, we investigate if machine learning algorithms on multimodal data can serve as a framework for clinical translation. METHODS: Forty-six antipsychotic-naïve, first-episode schizophrenia patients and 58 controls underwent neurocognitive tests, electrophysiology, and magnetic resonance imaging (MRI). Patients underwent clinical assessments before and after 6 weeks of antipsychotic monotherapy with amisulpride. Nine configurations of different supervised machine learning algorithms were applied to first estimate the unimodal diagnostic accuracy, and next to estimate the multimodal diagnostic accuracy. Finally, we explored the predictability of symptom remission. RESULTS: Cognitive data significantly classified patients from controls (accuracies = 60-69%; p values = 0.0001-0.009). Accuracies of electrophysiology, structural MRI, and diffusion tensor imaging did not exceed chance level. Multimodal analyses with cognition plus any combination of one or more of the remaining three modalities did not outperform cognition alone. None of the modalities predicted symptom remission. CONCLUSIONS: In this multivariate and multimodal study in antipsychotic-naïve patients, only cognition significantly discriminated patients from controls, and no modality appeared to predict short-term symptom remission. Overall, these findings add to the increasing call for cognition to be included in the definition of schizophrenia. To bring about the full potential of machine learning algorithms in first-episode, antipsychotic-naïve schizophrenia patients, careful a priori variable selection based on independent data as well as inclusion of other modalities may be required.

Investigation of sleep spindle activity and morphology as predictors of neurocognitive functioning in medicated patients with schizophrenia.

Neurocognitive impairment is a trait marker of schizophrenia, but no effective treatment has yet been identified. Sleep spindle deficits have been associated with diminished sleep-dependent memory learning. We examined whether this link could be extended into various cognitive domains by investigating the association of a neurocognitive test battery (the Brief Assessment of Cognition in Schizophrenia) with sleep spindle activity and morphology. We examined 37 outpatients diagnosed with schizophrenia and medicated with both antipsychotics and benzodiazepines. Participants underwent 1 night polysomnography and test of neurocognitive functioning. We identified and analysed sleep spindles in all non-rapid eye movement sleep and in non-rapid eye movement sleep stage 2 in a central electroencephalography channel using an automatic sleep spindle detector previously validated. Slow sleep spindle density was computed from a frontal electroencephalography channel as well. We found no association between cognitive functioning and sleep spindle density or sleep spindle morphology for spindles in non-rapid eye movement sleep when controlling for gender, age, symptom severity, and daily dose of antipsychotics and benzodiazepines. For spindles in non-rapid eye movement sleep stage 2, we found that motor speed was associated with frontal slow sleep spindle density. We conclude that frontal slow spindle density might predict motor speed in medicated patients with schizophrenia, but that no other sleep spindle activity or sleep spindle morphology measures were predictors of neurocognitive functioning.

Sleep efficiency and neurophysiological patterns in middle-aged men are associated with cognitive change over their adult life course.

Disrupted sleep is a contributing factor to cognitive ageing, while also being associated with neurodegenerative disorders. Little is known, however, about the relation of sleep and the gradual cognitive changes over the adult life course. Sleep electroencephalogram (EEG) patterns are potential markers of the cognitive progress. To test this hypothesis, we assessed sleep architecture and EEG of 167 men born in the Copenhagen Metropolitan Area in 1953, who, based on individual cognitive testing from early (~18 years) to late adulthood (~58 years), were divided into 85 subjects with negative and 82 with positive cognitive change over their adult life. Participants underwent standard polysomnography, including manual sleep scoring at age ~58 years. Features of sleep macrostructure were combined with a number of EEG features to distinguish between the two groups. EEG rhythmicity was assessed by spectral power analysis in frontal, central and occipital sites. Functional connectivity was measured by inter-hemispheric EEG coherence. Group differences were assessed by analysis of covariance (p < 0.05), including education and severity of depression as potential covariates. Subjects with cognitive decline exhibited lower sleep efficiency, reduced inter-hemispheric connectivity during rapid eye movement (REM) sleep, and slower EEG rhythms during stage 2 non-REM sleep. Individually, none of these tendencies remained significant after multiple test correction; however, by combining them in a machine learning approach, the groups were separated with 72% accuracy (75% sensitivity, 67% specificity). Ongoing medical screenings are required to confirm the potential of sleep efficiency and sleep EEG patterns as signs of individual cognitive progress.