Publications by authors named "Fleur M Howells"

49 Publications

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals.

Mol Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Unit for Psychosomatics / CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
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http://dx.doi.org/10.1038/s41380-021-01098-xDOI Listing
April 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychiatry, University of Münster, Münster, Germany.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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http://dx.doi.org/10.1002/hbm.25249DOI Listing
October 2020

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

The prevalence and clinical correlates of substance use disorders in patients with psychotic disorders from an Upper-Middle-Income Country.

S Afr J Psychiatr 2020 28;26:1473. Epub 2020 Jul 28.

Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.

Background: Substance use disorders (SUDs) occur frequently in patients with psychotic disorders and have been associated with various demographic and clinical correlates. There is an absence of research on the prevalence and clinical correlates of SUDs in psychotic disorders in low-and-middle-income countries (LMICs).

Aim: We aimed to determine the prevalence and correlates of SUDs in psychotic disorders.

Setting: Patients attending a large secondary-level psychiatric hospital in Cape Town South Africa.

Methods: We used the Structured Clinical Interview for DSM-IV (SCID-I) to determine psychiatric and substance use diagnoses, depressive, anxiety, obsessive-compulsive and post-traumatic symptoms. We used logistic regression models to determine significant predictors of SUDs.

Results: In total sample ( = 248), 55.6% of participants had any SUD, 34.3% had cannabis use disorders, 30.6% alcohol use disorders, 27.4% methamphetamine use disorders, 10.4% methaqualone use disorders and 4.8% had other SUDs. There were significant associations with male sex for most SUDs, with younger age and Coloured ethnicity for methamphetamine use disorders, and with lower educational attainment for cannabis use disorders. Anxiety symptoms and suicide attempts were significantly associated with alcohol use disorders; a diagnosis of a substance induced psychosis with cannabis and methamphetamine use disorders. Across most SUDs legal problems and criminal involvement were significantly increased.

Conclusion: This study found a high prevalence and wide distribution of SUDs in patients with psychotic disorders, consistent with previous work from high income countries. Given clinical correlates, in individuals with psychotic disorders and SUDs it is important to assess anxiety symptoms, suicidality and criminal involvement.
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http://dx.doi.org/10.4102/sajpsychiatry.v26i0.1473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433243PMC
July 2020

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Jul 29. Epub 2020 Jul 29.

Division of Mental Health and Addicition, Oslo University Hospital, Oslo, Norway.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.
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http://dx.doi.org/10.1002/hbm.25098DOI Listing
July 2020

Differential effects of social isolation rearing on glutamate- and GABA-stimulated noradrenaline release in the rat prefrontal cortex and hippocampus.

Eur Neuropsychopharmacol 2020 07 15;36:111-120. Epub 2020 Jun 15.

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa; Neuroscience Institute, University of Cape Town, South Africa. Electronic address:

Social isolation rearing (SIR) provides an excellent model of early life adversity to investigate alterations in brain function. Few studies have investigated the effects of SIR on noradrenaline (NE) projections which arise from the locus coeruleus (LC), a system which regulates arousal and attentional processes, including the processing of novelty. In addition, there is a paucity of information on the effects of SIR in females. In this study we investigated the behavioural response to attentional processing of novelty and glutamate- and GABA-stimulated release of noradrenaline in the prefrontal cortex (PFC) and hippocampus (HC) of male and female rats. Sprague Dawley pups were reared in isolated or socialised housing conditions from weaning on postnatal day 21 (P21). At P78-83 animal behaviour was recorded from the three phases of the novel object recognition (NOR) task. Then at P90-94, NE release was measured in the PFC and HC after stimulating the tissue in vitro with either glutamate or GABA. Behaviourally SIR decreased novelty-related behaviour, male isolates showed effects of SIR during the NOR Test phase while female isolates showed effects of SIR during the Habituation phase. SIR PFC NE release was decreased when glutamate stimulation followed GABA stimulation and tended to increase when GABA stimulation followed glutamate stimulation, differences were predominantly due to male isolates. No SIR differences were found for HC. Early life adversity differentially affects the function of the LCNE system in males and females, evidenced by changes in attentional processing of novelty and stimulated noradrenaline release in the PFC.
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http://dx.doi.org/10.1016/j.euroneuro.2020.05.007DOI Listing
July 2020

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Mol Psychiatry 2020 May 18. Epub 2020 May 18.

Department of Psychiatry, University of Münster, Münster, Germany.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
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http://dx.doi.org/10.1038/s41380-020-0754-0DOI Listing
May 2020

The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium.

Am J Psychiatry 2020 06 26;177(6):537-547. Epub 2020 Mar 26.

School of Psychology, Centre for Neuroimaging and Cognitive Genomics, National Centre for Biomedical Engineering Science and Galway Neuroscience Centre, National University of Ireland Galway, Galway (Holleran, Cannon, McDonald, Morris, Mothersill, Donohoe); Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey (Kelly, Thompson, Jahanshad); Department of Psychiatry, University of Edinburgh, Edinburgh (Alloza, Lawrie); Department of Child and Adolescent Psychiatry, Instituto de Investigación Sanitaria Gregorio Marañón, IiSGM, Hospital General Universitario Gregorio Marañón, School of Medicine, CIBERSAM, Universidad Complutense, Madrid (Alloza, Arango, Janssen, Martinez); NORMENT, K.G. Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo (Agartz); Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo (Andreassen); Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome (Banaj, Piras, Spalletta); Mind Research Network and Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque (Calhoun); Neuroscience Research Australia and School of Psychiatry, University of New South Wales, Sydney (Carr); Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin (Corvin); Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital and Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Glahn); Department of Psychiatry, University of Pennsylvania, Philadelphia (Gur, Roalf, Satterthwaite); Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore (Hong, Kochunov, Rowland); National Institute of Mental Health, Klecany, Czech Republic (Hoschl, Spaniel); Department of Psychiatry and Mental Health (Howells, Stein, Uhlmann) and Neuroscience Institute (Howells, Stein), University of Cape Town, Cape Town, South Africa; Highfield Unit, Warneford Hospital, Oxford, U.K. (James); Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.Mex. (Liu); Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, Australia (Pantelis, Zalesky); Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine (Potkin); Priority Centre for Brain and Mental Health Research (Schall, Rasser) and Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Newcastle, Australia (Rasser); Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Spalletta); Kimel Family Translational Imaging-Genetics Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto (Voineskos); Department of Biomedical Engineering and Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia (Zalesky); Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, and Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine (van Erp); Department of Psychology, Georgia State University, Atlanta (Turner); and Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh (Deary).

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.

Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.

Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).

Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.
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http://dx.doi.org/10.1176/appi.ajp.2019.19030225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938666PMC
June 2020

The relationship between measurement of in vivo brain glutamate and markers of iron metabolism: A proton magnetic resonance spectroscopy study in healthy adults.

Eur J Neurosci 2020 02 29;51(4):984-990. Epub 2019 Oct 29.

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Fundamental human studies which address associations between glutamate and iron metabolism are needed. Basic research reports associations between glutamate and iron metabolism. Human studies report sex differences in iron metabolism and glutamate concentrations, which suggest that these relationships may differ by sex. We hypothesised associations would be apparent between in vivo glutamate and peripheral markers of iron metabolism, and these associations would differ by sex. To test this, we recruited 40 healthy adults (20 men, 20 women) and measured (a) standard clinical biomarker concentrations for iron metabolism and (b) an in vivo proxy for glutamate concentration, glutamate with glutamine in relation to total creatine containing metabolites using proton magnetic resonance spectroscopy studies with a two-dimensional chemical shift imaging slice, with voxels located in bilateral dorsolateral prefrontal cortices, anterior cingulate cortices and frontal white matter. Only the female group reported significant associations between peripheral markers of iron metabolism and Glx:tCr concentration: (a) right dorsolateral prefrontal cortex Glx:tCr associated positively with serum transferrin (r = .60, p = .006) and negatively with transferrin saturation (r = -.62, p = .004) and (b) right frontal white matter Glx:tCr associated negatively with iron concentration (r = -.59, p = .008) and transferrin saturation (r = -.65, p = .002). Our results support associations between iron metabolism and our proxy for in vivo glutamate concentration (Glx:tCr). These associations were limited to women, suggesting a stronger regulatory control between iron and glutamate metabolism. These associations support additional fundamental research into the molecular mechanisms of this regulatory control.
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http://dx.doi.org/10.1111/ejn.14583DOI Listing
February 2020

Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals.

Neuropsychopharmacology 2019 12 21;44(13):2285-2293. Epub 2019 Aug 21.

Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R = 0.041, P < 0.001) and cingulum (right: R = 0.041, left: R = 0.040, P < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
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http://dx.doi.org/10.1038/s41386-019-0485-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898371PMC
December 2019

Food Cue Reactivity and the Brain-Heart Axis During Cognitive Stress Following Clinically Relevant Weight Loss.

Front Nutr 2018 4;5:135. Epub 2019 Jan 4.

Division of Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Successful weight loss maintainers are more vulnerable to stress induced eating. The aim of our study was to determine what effect an attention-demanding cognitive performance task had on brain-heart reactivity to visual food cues in women who maintained clinically relevant weight loss vs. women who had never weight cycled. A clinical weight loss group (CWL, = 17) and a BMI-matched control group (CTL, = 23) completed modified Stroop tasks that either included high calorie food pictures (Food Stroop) or excluded food cues (Office Stroop). ECG, breathing rate, and EEG were recorded. : The Eating Restraint scores (Three Factor Eating Questionnaire) of the CWL participants correlated negatively with their heart rates recorded during the Food Stroop task ( = 0.62, < 0.01). There was no such relationship in CTL participants. The P200 latencies in CWL participants evoked by the Stroop color-word cues at the C3 electrode were positively correlated to the log high frequency power in their cardiac spectrograms during the Food Stroop ( = 0.63, < 0.02). There were no such relationships in the Office Stroop task nor in CTL participants. s: Participants' heart rates were significantly lower ( < 0.05) and their RMSSD values and the log Total Power in their cardiac spectrograms were significantly greater during the Food Stroop vs. Office Stroop ( < 0.01, Bonferroni corrected). In conclusion Eating Restraint scores in CWL participants correlated with their Stroop heart rates, while the P200 latencies evoked by the Stroop cues correlated with the log high frequency power in their cardiac spectrograms (marker of cardiac vagal activation) during the Food Stroop task. This provides evidence that even 12 months after successful weight loss maintenance the cardiac ANS reactivity to food cues while completing a cognitive performance test was still different to that in individuals of normal weight who never weight cycled. Across all participants the cardiac ANS reactivity evoked by performing the Stroop task was lowered by food cues suggesting that the dampening effect of food cues on cardiac ANS reactivity may be one of the drivers of 'stress induced' eating.
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http://dx.doi.org/10.3389/fnut.2018.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328490PMC
January 2019

An introduction to psychedelic neuroscience.

Prog Brain Res 2018 15;242:1-23. Epub 2018 Nov 15.

Translational Neuroscience Group, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

This chapter is an introduction to the volume "Psychedelic Neuroscience" of Elsevier's Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. As the field is relatively new, there are discrepancies in the literature related to classification, composition and effects of the various psychedelics. Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuromodulatory systems. There is disparity in psychedelic brain imaging studies, delineating what is neural activity and hemodynamic needs further investigation for us to understand the brain "state" changes that are apparent. The psychedelic brain "state" is often compared to acute psychosis and we review the psychedelic animal models of psychosis and human brain imaging studies and contrast these to psychosis. The term "psychedelic" means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to "make conscious" that which was previously unconscious through changes in brain "state," but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research.
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http://dx.doi.org/10.1016/bs.pbr.2018.09.013DOI Listing
March 2019

Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.

Mol Psychiatry 2020 09 31;25(9):2130-2143. Epub 2018 Aug 31.

Department of Psychiatry, Yale University, New Haven, CT, USA.

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.
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http://dx.doi.org/10.1038/s41380-018-0228-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473838PMC
September 2020

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Biol Psychiatry 2018 11 14;84(9):644-654. Epub 2018 May 14.

Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.

Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.

Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2018.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177304PMC
November 2018

Electroencephalographic delta/alpha frequency activity differentiates psychotic disorders: a study of schizophrenia, bipolar disorder and methamphetamine-induced psychotic disorder.

Transl Psychiatry 2018 04 12;8(1):75. Epub 2018 Apr 12.

Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.

Electroencephalography (EEG) has been proposed as a neurophysiological biomarker to delineate psychotic disorders. It is known that increased delta and decreased alpha, which are apparent in psychosis, are indicative of inappropriate arousal state, which leads to reduced ability to attend to relevant information. On this premise, we investigated delta/alpha frequency activity, as this ratio of frequency activity may serve as an effective neurophysiological biomarker. The current study investigated differences in delta/alpha frequency activity, in schizophrenia (SCZ), bipolar I disorder with psychotic features and methamphetamine-induced psychosis. One hundred and nine participants, including individuals with SCZ (n = 28), bipolar I disorder with psychotic features (n = 28), methamphetamine-induced psychotic disorder (MPD) (n = 24) and healthy controls (CON, n = 29). Diagnosis was ascertained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition disorders and current medication was recorded. EEG was undertaken in three testing conditions: resting eyes open, resting eyes closed and during completion of a simple cognitive task (visual continuous performance task). EEG delta/alpha frequency activity was investigated across these conditions. First, delta/alpha frequency activity during resting eyes closed was higher in SCZ and MPD globally, when compared to CON, then lower for bipolar disorder (BPD) than MPD for right hemisphere. Second, delta/alpha frequency activity during resting eyes open was higher in SCZ, BPD and MPD for all electrodes, except left frontal, when compared to CON. Third, delta/alpha frequency activity during the cognitive task was higher in BPD and MPD for all electrodes, except left frontal, when compared to CON. Assessment of EEG delta/alpha frequency activity supports the delineation of underlying neurophysiological mechanisms present in psychotic disorders, which are likely related to dysfunctional thalamo-cortical connectivity. Delta/alpha frequency activity may provide a useful neurophysiological biomarker to delineate psychotic disorders.
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http://dx.doi.org/10.1038/s41398-018-0105-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895848PMC
April 2018

Progress in neuroscience in Africa: editorial.

Metab Brain Dis 2018 04;33(2):357-358

Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.

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http://dx.doi.org/10.1007/s11011-018-0213-7DOI Listing
April 2018

The impact of acute and short-term methamphetamine abstinence on brain metabolites: A proton magnetic resonance spectroscopy chemical shift imaging study.

Drug Alcohol Depend 2018 04 22;185:226-237. Epub 2018 Feb 22.

Department of Psychiatry and Mental Health, Groote Schuur Hospital, University of Cape Town, Anzio Rd., Observatory, 7925 Cape Town, South Africa; Neuroscience Institute, University of Cape Town, South Africa.

Background: Abuse of methamphetamine (MA) is a global health concern. Previous H-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites.

Methods: Adults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift H-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 ± 0.6 weeks, n = 31) and short-term MAA (5.1 ± 0.8 weeks, n = 22). The change in H-MRS metabolites over time (n = 19) was also investigated. Standard H-MRS metabolites are reported relative to Cr + PCr.

Results: Acute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM.

Conclusion: In acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first H-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.11.029DOI Listing
April 2018

Current and potential pharmacological and psychosocial interventions for anxiety symptoms and disorders in patients with schizophrenia: structured review.

Hum Psychopharmacol 2017 09 15;32(5). Epub 2017 Aug 15.

Department of Psychiatry, University of Cape Town, Cape Town, South Africa.

Objective: Between 30% and 62% of patients with schizophrenia present with co-morbid anxiety disorders that are associated with increased overall burden. Our aim was to summarize current and potential interventions for anxiety in schizophrenia.

Design: Structured review, summarizing pharmacological and psychosocial interventions used to reduce anxiety in schizophrenia and psychosis.

Results: Antipsychotics have been shown to reduce anxiety, increase anxiety, or have no effect. These may be augmented with another antipsychotic, anxiolytic, or antidepressant. Novel agents, such as L-theanine, pregabalin, and cycloserine, show promise in attenuating anxiety in schizophrenia. Psychosocial therapies have been developed to reduce the distress of schizophrenia. Cognitive behavioural therapy (CBT) has shown that benefit and refinements in the therapy have been successful, for example, for managing worry in schizophrenia. CBT usually involves more than 16 sessions, as short courses of CBT do not attenuate the presentation of anxiety in schizophrenia. To address time and cost, the development of manualized CBT to address anxiety in schizophrenia is being developed.

Conclusions: The presence of coexisting anxiety symptoms and co-morbid anxiety disorders should be ascertained when assessing patients with schizophrenia or other psychoses as a range of pharmacological and psychosocial treatments are available.
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http://dx.doi.org/10.1002/hup.2628DOI Listing
September 2017

First-Rank Symptoms in Methamphetamine Psychosis and Schizophrenia.

Psychopathology 2016 8;49(6):429-435. Epub 2016 Dec 8.

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Background: Methamphetamine psychosis (MAP) symptomatology has been described as indistinguishable from that of schizophrenia (SZ), yet research comparing these two disorders on specific psychotic symptoms such as schneiderian first-rank symptoms (FRS) is lacking. We aimed to determine and compare the occurrence and associations of FRS in patients diagnosed with MAP and with SZ.

Sampling And Method: Data from SCID-I interviews performed on patients with either a diagnosis of SZ or MAP were compared. We calculated the prevalence of different FRS between MAP and SZ patients and used logistic regression to assess the association between FRS and diagnosis.

Results: 102 patients were included in the study (MAP = 33, SZ = 69). Thought broadcasting occurred significantly more often in SZ (42%) than in MAP (24.2%) patients (adjusted OR = 3.02; 95% CI: 1.12-8.15; p = 0.028), while auditory hallucinations (voices conversing) were significantly higher in MAP (48.5%) than in SZ (20.3%) patients (adjusted OR = 0.27; 95% CI: 0.10-0.66; p = 0.004). However, there was no significant difference in the occurrence of one or more FRS in MAP and SZ, with most FRS showing overlap.

Conclusions: We found that first-rank auditory hallucinations were more prevalent in MAP, whereas first-rank delusions of thought broadcasting were more prevalent in SZ. However, there was a substantial overlap in MAP and SZ for most FRS. This is consistent with the finding that FRS may have limited diagnostic specificity and that there is significant overlap in the symptoms of MAP and SZ. Future research into the neurobiology of delusions and hallucinations needs to take FRS into account.
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http://dx.doi.org/10.1159/000452476DOI Listing
March 2017

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex.

Brain Imaging Behav 2017 Oct;11(5):1497-1514

Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.
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http://dx.doi.org/10.1007/s11682-016-9629-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540813PMC
October 2017

Progress in neuroscience in Africa: editorial.

Metab Brain Dis 2016 Feb;31(1):1-2

Department of Human Biology, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.1007/s11011-016-9790-5DOI Listing
February 2016

Interhemispheric Functional Brain Connectivity in Neonates with Prenatal Alcohol Exposure: Preliminary Findings.

Alcohol Clin Exp Res 2016 Jan;40(1):113-21

Department of Psychiatry and Mental Health (JCI, FMH, J-PF, NK, DJS), University of Cape Town, Cape Town, South Africa.

Background: Children exposed to alcohol in utero demonstrate reduced white matter microstructural integrity. While early evidence suggests altered functional brain connectivity in the lateralization of motor networks in school-age children with prenatal alcohol exposure (PAE), the specific effects of alcohol exposure on the establishment of intrinsic connectivity in early infancy have not been explored.

Methods: Sixty subjects received functional imaging at 2 to 4 weeks of age for 6 to 8 minutes during quiet natural sleep. Thirteen alcohol-exposed (PAE) and 14 age-matched control (CTRL) participants with usable data were included in a multivariate model of connectivity between sensorimotor intrinsic functional connectivity networks. Seed-based analyses of group differences in interhemispheric connectivity of intrinsic motor networks were also conducted. The Dubowitz neurological assessment was performed at the imaging visit.

Results: Alcohol exposure was associated with significant increases in connectivity between somatosensory, motor networks, brainstem/thalamic, and striatal intrinsic networks. Reductions in interhemispheric connectivity of motor and somatosensory networks did not reach significance.

Conclusions: Although results are preliminary, findings suggest PAE may disrupt the temporal coherence in blood oxygenation utilization in intrinsic networks underlying motor performance in newborn infants. Studies that employ longitudinal designs to investigate the effects of in utero alcohol exposure on the evolving resting-state networks will be key in establishing the distribution and timing of connectivity disturbances already described in older children.
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http://dx.doi.org/10.1111/acer.12930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556616PMC
January 2016

Alcohol exposure in utero is associated with decreased gray matter volume in neonates.

Metab Brain Dis 2016 Feb 29;31(1):81-91. Epub 2015 Nov 29.

Department of Psychiatry and Mental Health and MRC Unit on Anxiety & Stress Disorders, University of Cape Town, Cape Town, South Africa.

Neuroimaging studies have indicated that prenatal alcohol exposure is associated with alterations in the structure of specific brain regions. However, the temporal specificity of such changes and their behavioral consequences are less known. Here we explore the brain structure of infants with in utero exposure to alcohol shortly after birth. T2 structural MRI images were acquired from 28 alcohol-exposed infants and 45 demographically matched healthy controls at 2-4 weeks of age on a 3T Siemens Allegra system as part of large birth cohort study, the Drakenstein Child Health Study (DCHS). Neonatal neurobehavior was assessed at this visit; early developmental outcome assessed on the Bayley Scales of Infant Development III at 6 months of age. Volumes of gray matter regions were estimated based on the segmentations of the University of North Carolina neonatal atlas. Significantly decreased total gray matter volume was demonstrated for the alcohol-exposed cohort compared to healthy control infants (p < 0.001). Subcortical gray matter regions that were significantly different between groups after correcting for overall gray matter volume included left hippocampus, bilateral amygdala and left thalamus (p < 0.01). These findings persisted even when correcting for infant age, gender, ethnicity and maternal smoking status. Both early neurobehavioral and developmental adverse outcomes at 6 months across multiple domains were significantly associated with regional volumes primarily in the temporal and frontal lobes in infants with prenatal alcohol exposure. Alcohol exposure during the prenatal period has potentially enduring neurobiological consequences for exposed children. These findings suggest the effects of prenatal alcohol exposure on brain growth is present very early in the first year of life, a period during which the most rapid growth and maturation occurs.
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http://dx.doi.org/10.1007/s11011-015-9771-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556617PMC
February 2016

Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model.

Brain Res 2016 Jun 23;1641(Pt B):291-305. Epub 2015 Nov 23.

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa. Electronic address:

While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System.
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http://dx.doi.org/10.1016/j.brainres.2015.11.019DOI Listing
June 2016

Genetic predisposition and early life experience interact to determine glutamate transporter (GLT1) and solute carrier family 12 member 5 (KCC2) levels in rat hippocampus.

Metab Brain Dis 2016 Feb;31(1):169-82

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders. While it is typically treated with medications that target dopamine and norepinephrine transmission, there is increasing evidence that other neurotransmitter systems, such as glutamate and GABA, may be involved. The aetiology of ADHD is unknown; however, there is evidence that early life stress may contribute to the development of the disorder. In the present study we used proteomic analysis (iTRAQ) followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis to investigate hippocampal protein profiles of three rat strains: an animal model of ADHD, spontaneously hypertensive rats (SHR), their control Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD). We additionally investigated how these protein profiles are affected by maternal separation, a model of early life stress. Our findings show that solute carrier family 12 member 5 (KCC2) is increased in SHR hippocampus. The glutamate transporter GLT1 splice variant, GLT1b, was increased (proteomic analysis) while total GLT1 (comprised mostly of GLT1a splice variant) was reduced (Western blot analysis) in SHR hippocampus, compared to WKY and SD--a pattern that is consistent with elevated extracellular glutamate levels. Maternal separation increased total GLT1 in hippocampi of SHR, WKY, and SD, and reduced GLT1b in SHR hippocampus. Together these findings provide evidence for disturbed glutamatergic and GABAergic transmission in SHR hippocampus, maternal separation effects on glutamate uptake in hippocampi of all three strains, as well a unique effect of maternal separation on GLT1b levels in SHR hippocampus. These data suggest significant involvement of glutamatergic and GABAergic transmission in the neuropathophysiology of ADHD, and implicates changes in glutamatergic transmission as a result of early life stress.
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http://dx.doi.org/10.1007/s11011-015-9742-5DOI Listing
February 2016
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