Neurocognitive effects of an omega-3 fatty acid and vitamins E+C in schizophrenia: A randomised controlled trial.

There is need for more efficient treatment of neurocognitive deficits in schizophrenia. In this 16 weeks randomised, placebo-controlled trial, we examined neurocognitive effects of adding ethyl-eicosapentaenoate 2g/day and/or vitamins E 364mg/day + C 1000mg/day to antipsychotics in 53 patients aged 18-39 years with acute schizophrenia. For the sake of validating neurocognitive tests, healthy subjects, not taking trial drugs, were also included in the study. Ethyl-EPA given alone to patients with low baseline RBC polyunsaturated fatty acids (PUFA), and Vitamins E+C given alone to high PUFA patients, impaired sustained attention (Continuous Performance Test, CPT-IP d prime score), standardised effect sizes d = 0.78 and d = 0.69, respectively. These adverse effects were paralleled by excessive increases in long-chain PUFA and serum alpha-tocopherol, respectively. They were counteracted by combining ethyl-EPA and vitamins, d = 0.80 and d = 0.74 in low and high PUFA patients, respectively. No other neurocognitive tests yielded significant results. Plausible mechanisms of harmful effects are oxidative stress and lipid raft disruption.

Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.

BACKGROUND: The evidence base in cognitive rehabilitation in multiple sclerosis (MS) is still sparse. OBJECTIVE: The aim of the study was to investigate the effects of cognitive rehabilitation on cognitive and executive coping, psychological well-being and psychological aspects of health-related quality of life (HRQoL) in patients with MS. METHODS: One hundred and twenty patients with cognitive complaints, taking part in a 4-week multidisciplinary rehabilitation, were randomized to an intervention group (n = 60) and a control group (n = 60). Both groups underwent neuropsychological assessment with subsequent feedback and took part in general multidisciplinary MS rehabilitation. Additionally, the intervention group participated in cognitive group sessions as well as individual sessions. The main focus was to formulate Goal Attainment Scaling goals for coping with cognitive challenges. For 3 months past rehabilitation, the intervention group received biweekly telephone follow-up, focusing on goal attainment. RESULTS: Executive functioning improved significantly from baseline to four and 7 months in both groups. Improvements in psychological well-being and psychological aspects of HRQoL occurred only in the intervention group. CONCLUSION: Multicomponent cognitive rehabilitation administered within the context of multidisciplinary rehabilitation can improve psychological well-being and psychological aspects of HRQoL.

Reward responsiveness in patients with chronic pain.

BACKGROUND: It is proposed that changes in reward processing in the brain are involved in the pathophysiology of pain based on experimental studies. The first aim of the present study was to investigate if reward drive and/or reward responsiveness was altered in patients with chronic pain (PCP) compared to controls matched for education, age and sex. The second aim was to investigate the relationship between reward processing and nucleus accumbens volume in PCP and controls. Nucleus accumbens is central in reward processing and its structure has been shown to be affected by chronic pain conditions in previous studies. METHODS: Reward drive and responsiveness were assessed with the Behavioral Inhibition Scale/Behavioral Activation Scale, and nucleus accumbens volumes obtained from T1-weighted brain MRIs obtained at 3T in 19 PCP of heterogeneous aetiologies and 20 age-, sex- and education-matched healthy controls. Anhedonia was assessed with Beck's Depression Inventory II. RESULTS: The PCP group had significantly reduced scores on the reward responsiveness, but not reward drive. There was a trend towards smaller nucleus accumbens volume in the PCP compared to control group. There was a significant positive partial correlation between reward responsiveness and nucleus accumbens volume in the PCP group adjusted for anhedonia, which was significantly different from the same relationship in the control group. CONCLUSIONS: Reward responsiveness is reduced in chronic pain patients of heterogeneous aetiology, and this reduction was associated with nucleus accumbens volume. Reduced reward responsiveness could be a marker of chronic pain vulnerability, and may indicate reduced opioid function.

Serotonin transporter polymorphisms predict response inhibition in healthy volunteers.

Serotoninergic transmission is reliably implicated in inhibitory control processes. The aim of this study was to test the hypothesis if serotonin transporter polymorphisms mediate inhibitory control in healthy people. 141 healthy subjects, carefully screened for previous and current psychopathology, were genotyped for the 5-HTTLPR and rs25531 polymorphisms. Inhibitory control was ascertained with the Stop Signal Task (SST) from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The triallelic gene model, reclassified and presented in a biallelic functional model, revealed a dose-dependent gene effect on SST performance with Individuals carrying the low expressive allele had inferior inhibitory control compared to high expressive carriers. This directly implicates serotonin transporter polymorphisms (5-HTTLPR plus rs25531) in response inhibition in healthy subjects.

A single dose of antidepressant alters eye-gaze patterns across face stimuli in healthy women.

BACKGROUND: Early neurocognitive changes in emotional processing are seen following SSRI administration, which may be involved in mechanisms of action. However, the perceptual processes underpinning these effects have not been specified. METHODS: In a double-blind, placebo-controlled eye-tracking study, we assessed the effect of single dose of citalopram (20 mg) in 25 healthy females. Face stimuli with direct and averted gaze were presented while visual scan patterns and pupil sizes were monitored. Subjective state was monitored using visual analogue scales. RESULTS: There were no significant effects of citalopram on subjective state. However, the citalopram group displayed increased saccade numbers and shorter fixation duration during face viewing compared to the placebo group. Volunteers receiving citalopram also showed reduced monitoring of the eye region irrespective of the direct or averted eye position of the stimuli. The citalopram group also showed significantly larger pupil sizes than the control group. CONCLUSIONS: These results suggest that the SSRI administration affects the perceptual processing of face stimuli. The current pattern of findings is consistent with anxiogenic-like mechanisms early on in SSRI treatment. Eye-tracking provides a novel method to characterise and detect these effects.

Serotonin transporter polymorphisms (5-HTTLPR) in emotion processing: implications from current neurobiology.

The candidate gene approach directly tests the effects of genetic variation within a potentially contributing gene in an association study. However, the candidate gene approach is limited by how much is known about the biology of the disease being investigated. The serotonin transporter gene SLC6A4 has been studied more than any other single candidate gene in the field of neurobiology. Transcription of the serotonin transporter gene is modulated by a polymorphic region, 5-HTTLPR, near the promoter. 5-HTTLPR genotype has been associated with individual variation in emotion processing, brain structure, and brain function. We present an updated review of the biological literature on the serotonin transporter polymorphism. Recent imaging and behavioral studies of the role of 5-HTTLPR genotype in emotion processing are discussed in light of new biological findings related to 5-HTTLPR variation. We also examine the clinical implications of discoveries about the role of serotonin and 5-HTTLPR genotype in neural plasticity and behavioral malleability.

Predictors of executive complaints and executive deficits in multiple sclerosis.

OBJECTIVES: To investigate executive complaints and objective executive deficits and their relations to both depression and neurological function in multiple sclerosis (MS). MATERIALS AND METHODS: One hundred and twenty MS patients participating in multidisciplinary rehabilitation underwent assessment with the Expanded Disability Status Scale (EDSS), neuropsychological tests of executive function, self-report measures of executive function (BRIEF-A), and depression (BDI-II). RESULTS: Multivariate regression analysis showed that moderate depression and above (BDI-II > 20) significantly predicted a high degree of subjective executive complaints. Multivariate regression analysis showed that EDSS scores above 4.3 significantly predicted executive cognitive deficit, measured by neuropsychological tests. CONCLUSION: Among the study variables, depression was the strongest predictor of executive complaints. A high degree of neurological disability was the strongest predictor for executive deficit, measured by neuropsychological tests.

The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on behaviour in 5-year-old children: a prospective cohort study on 1628 children.

OBJECTIVE: To examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on behaviour in children at the age of 5 years. DESIGN: Prospective cohort study. SETTING: Neuropsychological testing in four Danish cities, 2003-2008. POPULATION: A total of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol drinking patterns during early pregnancy. When the children were 5 years of age the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ) were completed by the mothers and a preschool teacher, respectively. The full statistical model included the following potential confounding factors: maternal binge drinking or low to moderate alcohol consumption, respectively; parental education; maternal IQ; prenatal maternal smoking; the child's age at testing; the child's gender; maternal age; parity; maternal marital status; family home environment; postnatal parental smoking; prepregnancy maternal body mass index (BMI); and the child's health status. MAIN OUTCOME MEASURE: Behaviour among children assessed by the SDQ parent and teacher forms. RESULTS: Adjusted for all potential confounding factors, no statistically significant associations were observed between maternal low to moderate average weekly alcohol consumption and SDQ behavioural scores (OR 1.1, 95% CI 0.5-2.3; OR 1.1, 95% CI 0.6-2.1 for the total difficulties scores) or between binge drinking and SDQ behavioural scores (OR 1.2, 95% CI 0.8-1.7; OR 0.8, 95% CI 0.6-1.2). CONCLUSION: This study observed no consistent effects of low to moderate alcohol consumption or binge drinking in early pregnancy on offspring behaviour at the age of 5 years.

The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on selective and sustained attention in 5-year-old children.

OBJECTIVE: The aim was to examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on children's attention at 5 years of age. DESIGN: Prospective follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. POPULATION: A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol consumption during pregnancy. At 5 years of age, the children were tested with the recently developed Test of Everyday Attention for Children at Five (TEACh-5). Parental education, maternal IQ, maternal smoking in pregnancy, the child's age at testing, gender, and tester were considered core confounding factors, whereas the full model also controlled the following potential confounding factors: maternal binge drinking or low to moderate alcohol consumption, age, body mass index (BMI), parity, home environment, postnatal smoking in the home, child's health status, and indicators for hearing and vision impairments. MAIN OUTCOME MEASURES: TEACh-5 attention scores. RESULTS: There were no significant effects on test performance in children of mothers drinking up to 8 drinks per week compared with children of mothers who abstained, but there was a significant association between maternal consumption of 9 or more drinks per week and risk of a low overall attention score (OR 3.50, 95% CI 1.15-10.68). No consistent or significant associations were observed between binge drinking and attention test scores. CONCLUSIONS: The findings suggest an effect of maternal consumption of 9 or more drinks per week on attention functions in children, but the study detected no effects of lower levels of maternal consumption and no consistent effects of maternal binge drinking.

The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on executive function in 5-year-old children.

OBJECTIVE: To examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on children's executive functions at the age of 5 years. DESIGN: Follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. Population A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol drinking patterns during early pregnancy. When the children were 5 years old, the parent and teacher forms of the Behaviour Rating Inventory of Executive Function (BRIEF) were completed by the mothers and a preschool teacher. Parental education, maternal IQ, prenatal maternal smoking, the child's age at testing, and the child's gender were considered core confounding factors. The full model also included maternal binge drinking or low to moderate alcohol consumption, maternal age, parity, maternal marital status, family home environment, postnatal parental smoking, pre-pregnancy maternal body mass index (BMI), and the health status of the child. MAIN OUTCOME MEASURES: The BRIEF parent and teacher forms. RESULTS: Adjusted for all potential confounding factors, no statistically significant associations between maternal low to moderate average weekly consumption and BRIEF index scores were observed.In adjusted analyses, binge drinking in gestational week 9 or later was significantly associated with elevated Behavioural Regulation Index parent Scores (2.04, 95% CI 0.33­3.76), and with the risk of high scores on the Metacognitive Index assessed by the teacher (OR 2.06, 95% CI 1.01­4.23) [corrected]. CONCLUSIONS: This study did not observe significant effects of low to moderate alcohol consumption during pregnancy on executive functioning at the age of 5 years. Furthermore, only weak and no consistent associations between maternal binge drinking and executive functions were observed.

Verbal memory functions in unipolar major depression with and without co-morbid anxiety.

The aim of this study was to examine both executive control of verbal working memory and verbal learning as well as long-term storage function in outpatients with major depressive disorder (n = 61) compared to healthy controls (n = 92). A total of 37 patients had no co-morbid anxiety disorder, whereas 24 had a co-morbid anxiety disorder. Both patient groups showed impaired working memory test performance compared to healthy controls. Patients with co-morbid depression and anxiety disorder performed significantly below the depression group. Only patients with depression and co-morbid anxiety displayed deficient long-term memory function compared to healthy controls. The present results show impairments in various memory functions in patients presenting depression and depression with co-morbid anxiety disorder.

Executive functions are impaired in adolescents engaging in non-suicidal self-injury.

BACKGROUND: The aim of this study was to investigate three main aspects of executive functions (EFs), i.e. shifting, updating and inhibition, in adolescents engaging in non-suicidal self-injury (NSSI) as compared with healthy controls. METHOD: EFs were assessed using the Intra/Extradimensional Set Shift, the Spatial Working Memory (SWM) Test and the Stop Signal Test (SST) from the Cambridge Neuropsychological Test Automated Battery (CANTAB), in a high-severity NSSI group (n=33), a low-severity NSSI group (n=29) and a healthy control group (n=35). Diagnostic characteristics were examined using the Kiddie-Sads-Present and Lifetime Version. RESULTS: There were group differences on the SWM Test. A trend towards an interaction effect of sex revealed that males in the high-severity NSSI group made significantly more errors than males and females in the control group. Both males and females in the high-severity NSSI group made poor use of an efficient strategy in completing the test. The low-severity NSSI group performed poorly on the SST, making more errors than the control group and showing an impaired ability to inhibit initiated responses, as compared with the high-severity NSSI group. There were group differences in frequencies of current and previous major depressive disorder. However, no effects of these diagnoses were found on any of the EF tests. CONCLUSIONS: This study demonstrates that NSSI subgroups have distinct deficits in EFs. The high-severity NSSI group has working memory deficits, while the low-severity NSSI group has impaired inhibitory control. This supports the emotion regulation hypothesis.

Attentional functions in major depressive disorders with and without comorbid anxiety.

The aim of this study was to explore if the divergent results regarding attentional functions in patients with mood disorders are due to selective impairments in higher level or more basic and distinctive attentional subcomponents. We compared outpatients with current major depressive disorders (MDD; n = 37) and MDD with comorbid anxiety disorder (MDDA; n = 24) with healthy controls (n = 92) on Stroop and Attentional Network Test (ANT). The current data indicate that significant impairment in attentional functions corresponds to the presence of MDD and MDDA. MDDA displayed significantly lower performance on the Stroop variables, and MDD were significantly impaired in the alerting function in ANT. These results show impairments on different levels of attention in mood disorders. MDDA show impairments on higher level executive attention functions, whereas MDD display deficits at the basic attentional level. These findings suggest that including comorbid anxiety disorder in MDD is important for future research.

Cognitive impairment after three decades of multiple sclerosis.

BACKGROUND: Population-based studies of cognitive impairment in patients with multiple sclerosis (MS) with long disease duration are limited. The aim of this study was to evaluate long-term outcome and the predictors of cognitive impairment in a cohort of patients with MS. METHODS: Patients living in Oslo, Norway, with definite MS and onset in 1940-1980 alive on 1 May 2006 were included. Disability was assessed by Expanded Disability Status Scale (EDSS). Cognitive functioning was assessed in terms of psychomotor speed, attention, learning/memory and executive functions. RESULTS: A total of 123 patients was included. EDSS was < or =3.0 in 26% and > or =6.0 in 60% after mean disease duration of 34.5 years. Cognitive impairment was found in 48% of the patients eligible for neuropsychological evaluation (n = 84). Typical pattern was moderate impairment within areas of information processing, attention and memory. In the univariate analysis, younger onset age was significantly associated with cognitive impairment (P = 0.014). Younger onset age (P = 0.017) and disease course (secondary progressive vs. relapsing-remitting MS, P = 0.049) were significantly associated with cognitive impairment in the multivariate analysis. CONCLUSIONS: After three decades of disease, half of the MS patients experienced reduced cognitive functioning; however, nearly one-third of the patients were only mildly disabled based on the EDSS. Younger onset age was associated with higher prevalence of cognitive impairment. A thorough evaluation of cognitive function in addition to EDSS is essential for evaluating long-term impairment in patients with MS.

Patients with problematic opioid use can be weaned from codeine without pain escalation.

BACKGROUND: Brief treatments for chronic non-malignant pain patients with problematic opioid use are warranted. The aims of the present study were to investigate (1) whether it is possible to withdraw codeine use in such patients with a brief cognitive-behavioural therapy (CBT), (2) whether this could be done without pain escalation and reduction in quality of life and (3) to explore the effects of codeine reduction on neurocognitive functioning. METHODS: Eleven patients using codeine daily corresponding to 40-100 mg morphine were included. Two specifically trained physicians treated the patients with six CBT sessions, tapering codeine gradually within 8 weeks. Codeine use, pain intensity, quality of life and neuropsychological functioning were assessed at pre-treatment to the 3-month follow-up. RESULTS: Codeine use was significantly reduced from mean 237 mg [standard deviation (SD) 65] pre-treatment to 45 mg (SD 66) post-treatment and to 48 mg (SD 65) at follow-up without significant pain escalation or reductions in quality of life. Moreover, neuropsychological functioning improved significantly on some tests, while others remained unchanged. CONCLUSION: The promising findings of codeine reduction in this weaning therapy programme for pain patients with problematic opioid use should be further evaluated in a larger randomized control trial comparing this brief CBT with both another brief treatment and attention placebo condition.

Selective deficit in executive functioning among patients with borderline personality disorder.

BACKGROUND: The aim of this study was to investigate the functioning of patients with borderline personality disorder (BPD) compared to healthy controls on five neuropsychological domains, with regard to the possible effect of differences in IQ.MethodOut-patients and in-patients with BPD (n=35) and healthy comparison subjects (n=35) were tested with an extensive neuropsychological battery, where most cognitive domains were covered by several tests. RESULTS: When controlling for the effect of IQ, patients were found to have reduced executive functioning as compared to healthy controls. With regard to the other neuropsychological domains (working memory, attention, long-term verbal memory, and long-term non-verbal memory), no differences were found between the two groups. Within-subject analyses also identified executive functioning as a selective deficit among patients whereas long-term verbal memory was identified as a relative strength. An association was identified between the covariate general intellectual functioning and every neuropsychological domain. No statistically significant differences were found between the subgroups of patients with and without co-morbid post-traumatic stress disorder (PTSD) or between those with and without co-morbid major depression, or between the medicated and unmedicated subgroups on any of the neuropsychological domains. CONCLUSIONS: Patients with BPD demonstrate a selective deficit in executive functioning. This corroborates studies that have identified frontal regions as potential neurobiological substrates of the BPD syndrome. The relative strength of the verbal long-term memory function raises pertinent questions regarding the presumed importance of hippocampal structures.

Pathological dissociation and neuropsychological functioning in borderline personality disorder.

OBJECTIVE: Transient, stress-related severe dissociative symptoms or paranoid ideation is one of the criteria defining the borderline personality disorder (BPD). Examinations of the neuropsychological correlates of BPD reveal various findings. The purpose of this study was to investigate the association between dissociation and neuropsychological functioning in patients with BPD. METHOD: The performance on an extensive neuropsychological battery of patients with BPD with (n=10) and without (n=20) pathological dissociation was compared with that of healthy controls (n=30). RESULTS: Patients with pathological dissociation were found to have reduced functioning on every neuropsychological domain when compared with healthy controls. Patients without pathological dissociation were found to have reduced executive functioning, but no other differences were found. CONCLUSION: Pathological dissociation is a clinical variable that differentiates patients with BPD with regard to cognitive functioning.

Reduced insight in bipolar I disorder: neurofunctional and neurostructural correlates: a preliminary study.

BACKGROUND: To correlate measures of insight for own psychopathology to structural and functional brain imaging findings in 21 patients with DSM-IV bipolar I disorder. METHODS: Insight was assessed using the Scale to Assess Unawareness of Mental Disorder (SUMD). Resting single photon emission computed tomography (SPECT) and computed tomography (CT) was conducted in patients and 21 normal comparison subjects matched for age, gender and handedness. RESULTS: Reduced general insight and symptom awareness, but not symptom attribution, were significantly related to cortical and subcortical atrophy, respectively. No correlations between SPECT and insight measures were identified. LIMITATIONS: Limited sample size and the use of resting state SPECT. CONCLUSIONS: General and symptom awareness were related to measures of brain atrophy but not to neurofunctioning as measured by SPECT. Future research should consider the structure and function of specific cortical regions, including the frontal and parietal cortices.

Proton magnetic resonance spectroscopy and cognition in patients with spastin mutations.

The hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. Axonal loss in the long corticospinal tracts has been shown. Supraspinal symptoms and findings in the most common dominant HSP type, SPG4, support the theory that the disease also causes cerebral neuronal damage in specific parts of the brain. To investigate whether SPG4-HSP is associated with neuronal biochemical changes detectable on MR spectroscopy (MRS), single-voxel proton MRS of the brain was performed in eight subjects from four families with genetically confirmed SPG4-type HSP and eight healthy age-matched controls. Volumes of interest (VOI) were located in the frontal white matter and motor cortex. N-acetyl-aspartate-to-creatine ratio (NAA/Cr), N-acetyl-aspartate-to-choline (NAA/Cho), cholin to creatin (Cho/Cr) and myo-inositol-to-creatine (Ins/Cr) ratios were calculated for both locations. Neuropsychological tests were performed to support the neuroradiological findings. The Cho/Cr ratio in motor cortex (MC) of SPG4-HSP subjects was significantly lower than in controls. This reduction of the Cho/Cr ratio in SPG4 subjects was significantly associated with age-related verbal learning- and memory (CVLT) reduction. Our findings support involvement of motor cortex in SPG4-HSP. Proton MRS could be a useful tool for detecting metabolite abnormalities in areas of brain that appear normal on MRI. Cho/Cr ratio may be a marker of neurodegenerative process in SPG4-HSP.

Relationship of cognitive impairment to psychiatric symptoms in multiple sclerosis.

Psychiatric and cognitive changes are common in patients with multiple sclerosis (MS), but their relationship has not received much attention. We studied the relationship between psychiatric symptoms and verbal memory, working memory, and mental speed in 78 patients with MS and 40 healthy control subjects using linear regression analyses. The MS group exhibited impaired performance on all cognitive tests. Apathy was associated with intrusions and depression with impaired memory and mental speed. The association between apathy and intrusions supports the hypothesis that lesions in frontal areas or frontal connections contribute to a specific neuropsychiatric syndrome in patients with MS.