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      Does the Brain Matter? Cortical Alterations in Pediatric Bipolar Disorder: A Critical Review of Structural and Functional Magnetic Resonance Studies

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          Abstract

          Pediatric bipolar disorder (PBD) is associated with significant psychosocial impairment, high use of mental health services and a high number of relapses and hospitalization. Neuroimaging techniques provide the opportunity to study the neurodevelopmental processes underlying PBD, helping to identify the endophenotypic markers of illness and early biological markers of PBD. The aim of the study is to review available studies assessing structural and functional brain correlates associated with PBD. PubMed, ISI Web of Knowledge and PsychINFO databases have been searched. Studies were included if they enrolled patients aged 0-18 years with a main diagnosis of PBD according to ICD or DSM made by a mental health professional, adopted structural and/or functional magnetic resonance as the main neuroimaging method, were written in English and included a comparison with healthy subjects. Of the 400 identified articles, 46 papers were included. Patients with PBD present functional and anatomic alterations in structures normally affecting regulations and cognition. Structural neuroimaging revealed a significant reduction in gray matter, with cortical thinning in bilateral frontal, parietal and occipital cortices. Functional neuroimaging studies reported a reduced engagement of the frontolimbic and hyperactivation of the frontostriatal circuitry. Available studies on brain connectivity in PBD patients potentially indicate less efficient connections between regions involved in cognitive and emotional functions. A greater functional definition of alteration in brain functioning of PBD patients will be useful to set up a developmentally sensitive targeted pharmacological and non-pharmacological intervention.

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          Are the dorsal and ventral hippocampus functionally distinct structures?

          One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus).
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            Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder.

            Youths with bipolar disorder are ideal for studying illness pathophysiology given their early presentation, lack of extended treatment, and high genetic loading. Adult bipolar disorder MRI studies have focused increasingly on limbic structures and the thalamus because of their role in mood and cognition. On the basis of adult studies, the authors hypothesized a priori that youths with bipolar disorder would have amygdalar, hippocampal, and thalamic volume abnormalities. Forty-three youths 6-16 years of age with DSM-IV bipolar disorder (23 male, 20 female) and 20 healthy comparison subjects (12 male, eight female) similar in age and sex underwent structured and clinical interviews, neurological examination, and cognitive testing. Differences in limbic and thalamic brain volumes, on the logarithmic scale, were tested using a two-way (diagnosis and sex) univariate analysis of variance, with total cerebral volume and age controlled. The subjects with bipolar disorder had smaller hippocampal volumes. Further analysis revealed that this effect was driven predominantly by the female bipolar disorder subjects. In addition, both male and female youths with bipolar disorder had significantly smaller cerebral volumes. No significant hemispheric effects were seen. These findings support the hypothesis that the limbic system, in particular the hippocampus, may be involved in the pathophysiology of pediatric bipolar disorder. While this report may represent the largest MRI study of pediatric bipolar disorder to date, more work is needed to confirm these findings and to determine if they are unique to pediatric bipolar disorder.
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              Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

              Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                CN
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                12 May 2023
                12 May 2023
                : 21
                : 6
                : 1302-1318
                Affiliations
                [1 ]deptDepartment of Psychiatry , University of Campania “L. Vanvitelli” , Naples, , Italy
                Author notes
                [* ]Address correspondence to this author at the Department of Psychiatry, University of Campania “L. Vanvitelli”, Naples, Italy; Tel: 0039 0815666514; E-mail: mario.luciano@ 123456unicampania.it
                Article
                CN-21-1302
                10.2174/1570159X20666220927114417
                10324338
                36173069
                f4228c5b-d3be-44fb-9d17-459c537ec2a6
                © 2023 Bentham Science Publishers

                This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode)

                History
                : 28 April 2022
                : 24 June 2022
                : 28 July 2022
                Categories
                Medicine, Neurology, Pharmacology, Neuroscience

                Pharmacology & Pharmaceutical medicine
                pediatric bipolar disorder,functional magnetic resonance,structural magnetic resonance,brain,functional connectivity,mri

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