Prefrontal Cortex Volume Research Articles

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

Herpes Simplex Virus 1 Exposure May Affect the Course of Schizophrenia

Core deficits involving executive functioning in schizophrenia can greatly diminish quality of life and function and are highly variable among patients for little-understood reasons. In cross-sectional studies, herpes simplex virus type 1 (HSV-1) exposure has been associated with cognitive impairments and with low prefrontal cortex volume in schizophrenia patients. In this prospective, 1-year study …

Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer's disease and behavioral variant frontotemporal dementia

Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer's disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed.

REGIONAL BRAIN CORTICAL THINNING AND SYSTEMIC INFLAMMATION IN OLDER PERSONS WITHOUT DEMENTIA

To the editor: Regional cortical thinning occurs in aging1, in Alzheimer’s disease (AD)2 and its prodromal stages2–3, but little is known about its biological basis. This thinning may reflect the presence of neuroinflammation associated with deposition of AD pathology and neurodegeneration. Aging is associated with upregulation of inflammation-associated genes in the brain as well as microglial activation4. Post-mortem examination of older persons without dementia has shown that up to 40% have evidence of AD pathology5 and inflammatory mechanisms are upregulated in regions of the aged brain known to be vulnerable to deposition of AD pathology6. Brain characteristics of older persons have been linked to level of circulating inflammatory markers: circulating interleukin-6 (IL-6) has been associated with hippocampal, medial prefrontal cortex and cerebellum volumes in middle-aged adults7, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNFα) have been associated with white-matter hyperintensities8 and total brain atrophy in community-based samples of older persons without dementia or stroke9 , and it has been shown that neuroinflammation is triggered easily by systemic inflammatory stimuli10. Using imaging methodology that measures regional atrophy across the entire cortical mantle1–3 and data from the Rush Memory and Aging Project, a prospective epidemiological, community-based cohort study of aging5, we tested the hypothesis that regional cortical thinning is associated with level of systemic inflammation in aging. Twenty-nine older persons without dementia or other neurological and psychiatric conditions and not taking anti-inflammatory medications (age M = 81.2, SD = 4.9; M education = 14.6, SD = 2.5; 76% female) were characterized as having high or low levels of systemic inflammation based on the upper and lower quartiles of a composite measure of circulating CRP and TNFα, prototypical biomarkers of inflammation that have been utilized in many studies of aging. Age and education did not differ significantly between groups and there were no significant correlations between level of inflammation with age, education or sex (all ps > .05). High-resolution T1-weighted anatomical data were obtained on a 1.5 Tesla GE MRI scanner using an MPRAGE sequence. Thickness across the cortical mantle was estimated using Freesurfer software (http://surfer.nmr.mgh.harvard.edu) and an exploratory statistical map was generated using a 2-class general linear model based on computing the effect of inflammation level on cortical thickness at every voxel of each hemisphere with a conservative threshold of p < 0.012. Regional clusters in which cortical thickness differed by the level of inflammation were identified and examined independently. The high inflammation group had significant cortical thinning, compared to the low inflammation group in four left-hemisphere and six right-hemisphere regions (Table 1). Two-tailed t-tests indicated that, for each individual region, group differences in thickness were highly significant. All differences survived a Bonferroni-corrected probability level of .00007 except left hemisphere post-central. There was no significant group difference in cortical thickness in a control region chosen a-priori (BA 17, cuneus, left and right hemisphere ps = .93 & .24). Table 1 Thinning by region for high (HI) and low (LI) inflammation groups We found a pattern of regional cortical thinning that was associated with level of systemic inflammation in older persons without dementia. The pattern was similar to that previously reported for nondemented elders1 and, notably, included regions of primary motor (pre-central), somatosensory (post-central), auditory (transverse temporal) and visual (pericalcarine, lingual) cortex. The findings suggest that regions of cortex are, indeed, differentially vulnerable to thinning in older persons, that this vulnerability is associated with level of systemic inflammation, and that it occurs not only in expected association areas, but also in regions of primary sensory and motor cortices. The association between cortical thinning and systemic inflammation in the current study was also evident in some of the same regions (superior frontal, superior parietal and precuneus) reported in persons with, or at risk for, clinical AD2,3. The findings suggest that these association areas may be particularly vulnerable to presence of inflammatory mechanisms and that the associated cortical thinning can be seen in older persons who do not have dementia. Although the participants in this study were sampled from a clinical-pathological study in which a comprehensive clinical evaluation allowed for the relevant exclusions, the sample size was relatively small and the results are preliminary. However, the effect sizes that were obtained were large and the pattern of regional cortical thinning that emerged was consistent with other studies of aging and AD that have used the same methods. Although preliminary, the results of this study are important because they suggest the presence of regional cortical thinning in older persons who do not have dementia and link it to a potential risk factor for neurodegeneration in aging, systemic inflammation.

Orbital prefrontal cortex volume correlates with social cognitive competence

Intentionality, or Theory of Mind, is the ability to explain and predict the behaviour of others by attributing to them intentions and mental states and is hypothesised to be one of several social cognitive mechanisms which have impacted upon brain size evolution. Though the brain activity associated with processing this type of information has been studied extensively, the neuroanatomical correlates of these abilities, e.g. whether subjects who perform better have greater volume of associated brain regions, remain to be investigated. Because social abilities of this type appear to have evolved relatively recently, and because the prefrontal cortex (PFC) was the last brain region to develop both phylogenetically and ontogenetically, we hypothesised a relationship between PFC volume and intentional competence. To test this, we estimated the volume of four regional prefrontal subfields in each cerebral hemisphere, in 40 healthy adult humans by applying stereological methods on T1-weighted magnetic resonance images. Our results reveal a significant linear relationship between intentionality score and volume of orbital PFC (p=0.01). Since this region is known to be involved in the processing of social information our findings support the hypothesis that brain size evolution is, at least in part, the result of social cognitive mechanisms supporting social cohesion.

Reduced Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment

Childhood emotional maltreatment (CEM) has been associated with a profound and enduring negative impact on behavioral and emotional functioning. Animal models have shown that adverse rearing conditions, such as maternal separation, can induce a cascade of long-term structural alterations in the brain, particularly in the hippocampus, amygdala, and prefrontal cortex. However, in humans, the neurobiological correlates of CEM are unknown. Using high-resolution T1-weighted 3T magnetic resonance imaging, anatomical scans and a whole-brain optimized voxel-based morphometry approach, we examined whether healthy control subjects and unmedicated patients with depression and/or anxiety disorders reporting CEM before age 16 (n = 84; age: mean = 38.7) displayed structural brain changes compared with control subjects and patients who reported no childhood abuse (n = 97; age: mean = 36.6). We found that self-reported CEM is associated with a significant reduction in predominantly left dorsal medial prefrontal cortex volume, even in the absence of physical or sexual abuse during childhood. In addition, reduced medial prefrontal cortex in individuals reporting CEM is present in males and females, independent of concomitant psychopathology. In this study, we show that CEM is associated with profound reductions of medial prefrontal cortex volume, suggesting that sustained inhibition of growth or structural damage can occur after exposure to CEM. Given the important role of the medial prefrontal cortex in the regulation of emotional behavior, our finding might provide an important link in understanding the increased emotional sensitivity in individuals reporting CEM.

P.1.e.011 Fronto-limbic interaction of working memory and emotion in the medial prefrontal cortex

Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants.Right-handed subjects (21–50 years), meeting DSM-IV criteria for MDD, either with (n = 19) or without (n = 20) childhood sexual or physical abuse. Healthy controls (n = 34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm × 1.0 mm × 1.0 mm were acquired with a Siemens Sonata 1.5T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate.MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex. Limitations: This study was cross sectional and the sample size was limited for subgroup and correlational analyses.Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD.

Neuroanatomical Characteristics and Speech Perception in Noise in Older Adults

Previous research has attributed older adults' difficulty with perceiving speech in noise to peripheral hearing loss. However, recent studies have suggested a more complex picture and implicate the central nervous system in sensation and sensory deficits. This study examines the relationship between the neuroanatomical structure of cognitive brain regions and the ability to perceive speech in noise in older adults. In particular, the neuroanatomical characteristics of the left ventral and dorsal prefrontal cortex (PFC) are considered relative to standard measures of hearing in noise. The participants were 15 older and 14 younger right-handed native speakers of American English who had no neurologic deficits and scored better than normal on standardized cognitive tests. We measured the participants' peripheral hearing ability and their ability to perceive speech in noise using established tests. Anatomical magnetic resonance images were taken and analyzed to extract regional volumes and thicknesses of several key neuroanatomical structures. Younger adults had better hearing sensitivity and better speech perception in noise ability than older adults. For the older adults only, the volume of the left pars triangularis and the cortical thickness of the left superior frontal gyrus were significant predictors of performance on the speech in noise test. These findings suggest that, in addition to peripheral structures, the central nervous system also contributes to the ability to perceive speech in noise. In older adults, a decline in the relative volume and cortical thickness of the PFC during aging can therefore be a factor in a declining ability to perceive speech in a naturalistic environment. These findings are consistent with the decline-compensation hypothesis, which states that a decline in sensory processing caused by cognitive aging can be accompanied by an increase in the recruitment of more general cognitive areas as a means of compensation. We found that a larger PFC volume may compensate for declining peripheral hearing. Clinically, recognizing the contribution of the cerebral cortex expands treatment possibilities for hearing loss in older adults beyond peripheral hearing aids to include strategies for improving cognitive function. We conclude by considering several mechanisms by which the PFC may facilitate speech perception in noise, including inhibitory control, attention, cross-modal compensation, word prediction and phonological working memory, although no definitive conclusion can be drawn.

Decreased Prefrontal Cortical Volume Associated with Increased Bedtime Cortisol in Traumatized Youth

The purpose of this study was to investigate prefrontal cortex (PFC) volumes in youth with posttraumatic stress symptoms (PTSS) and explore the relationship between cortisol secretion and PFC volumes. Total brain tissue volumes, segmented areas of the PFC, and diurnal cortisol secretion were examined in a sample of 33 youth aged 10 to 16 years. Cerebral volumes were available for 45 subjects (30 PTSS and 15 control subjects). Youth with PTSS had significantly decreased total brain tissue and total cerebral gray volumes in comparison with healthy control subjects. While controlling for total cerebral gray volume, the PTSS group demonstrated decreased left ventral and left inferior prefrontal gray volumes. A significant negative association was found between prebedtime cortisol levels and left ventral PFC gray volumes for the full sample. Findings suggest associations between posttraumatic stress and PFC neurodevelopment. Findings also suggest a link between PFC development and cortisol secretion.

Relationship of parental bonding styles with gray matter volume of dorsolateral prefrontal cortex in young adults

Previous epidemiologic studies using the parental bonding instrument (PBI), a self-report scale to rate attitudes of parents during the first 16 years, have suggested that a lower parental care score or higher parental overprotection score could lead to an increased risk of several psychiatric disorders, including schizophrenia and mood disorder. However, neuroimaging studies of an association between PBI scores and brain developmental abnormalities are still limited. In this region-of-interest analysis study using a cross-sectional design, we examined 50 normal young adults, in terms of relationships of parental bonding styles during the first 16 years measured by PBI with regional gray matter (GM) volume in the dorsolateral prefrontal cortex (DLPFC). Our study showed that paternal care score positively correlated with the GM volume in the left DLPFC, and paternal and maternal overprotection score negatively correlated with the GM volume in the left DLPFC. In conclusion, our results suggest that in normal young adults, lower paternal care and higher parental overprotection scores correlated with the GM volume reduction in the DLPFC

Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression

Early emotional stress is associated with a life-long burden of risk for later depression and stressful life events contribute to the development of depressive episodes. In this study we investigated whether childhood stress is associated with structural brain alterations in patients with major depression (MD). Forty-three patients with MD and 44 age as well as gender matched healthy control subjects were investigated using high-resolution magnetic resonance imaging (MRI). Region of interest analysis of the hippocampus, whole brain voxel-based morphometry (VBM) and assessment of childhood stress was carried out. Significantly smaller hippocampal white matter and prefrontal gray matter volume was observed in patients with MD compared to healthy controls. In particular left hippocampal white matter was smaller in patients, who had emotional childhood neglect, compared to those without neglect. For male patients this effect was seen in the left and right hippocampus. Moreover, physical neglect during childhood affected prefrontal gray matter volume in healthy subjects. Both emotional neglect and brain structural abnormalities predicted cumulative illness duration and there was a significant interaction between emotional neglect and prefrontal volumes as well as hippocampal white matter on the illness course. Childhood neglect resulted in hippocampal white matter changes in patients with major depression, pronounced at the left side and in males. Most interestingly, childhood stress and brain structure volumes independently predicted cumulative illness course. Subjects with both, structural brain changes and childhood emotional neglect seem to be at a very high risk to develop a more severe illness course.

Dorsolateral Prefrontal Cortex Magnetic Resonance Imaging Measurements and Cognitive Performance in Autism

This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.

Subregional parcellation and segmentation of the prefrontal cortex in children &amp;ndash; Protocol calibration

Event Abstract Back to Event Subregional parcellation and segmentation of the prefrontal cortex in children – Protocol calibration M. A. Garcia-Barrera1*, J. Hatter1, N. Trujillo-Orrego2, K. Gicas1, J. Wilson1 and G. W. Hynd3 1 CORTEX, University of Victoria, Department of Psychology, Canada 2 University of Antioquia, Neuroscience Group, Colombia 3 College of Charleston, United States Due to its functional association to executive functioning, the study of the morphological configuration of prefrontal cortex (PFC) in neurodevelopmental disorders is of great relevance in neuropsychology. One robust example comes from the neuroimaging literature in Attention Deficit/Hyperactivity Disorder (ADHD). Our study aimed to examine the sensitivity of a PFC parcellation protocol to detect cortical differences, after a refined calibration and when applied to a preliminary pediatric sample of children with ADHD (n=5) and matched controls. Our protocol included parcellation and manual tracing following a semi-automated extraction of each Region of Interest (namely ventromedial, orbitolateral, dorsomedial and dorsolateral) and subsequent gray/white matter segmentation using Analyze 9.0 (Mayo Clinic, 2009) on a series of structural MRIs. Results demonstrated the sensitivity of our protocol to detect small scale differences in gray and white matter thickness, characterized by a significant (p< 0.05) smaller bilateral dorsomedial gray cortical PFC volume in the ADHD group while a trend towards a thicker white matter volume in left dorsolateral areas was also found in ADHD and after controlling for total brain volumes. These differences were not captured by a total PFC volume analysis. Intra and inter-rater tracing reliabilities were above criterion (> .90) for all areas. Conference: The 20th Annual Rotman Research Institute Conference, The frontal lobes, Toronto, Canada, 22 Mar - 26 Mar, 2010. Presentation Type: Poster Presentation Topic: Frontal Lobe Development Citation: Garcia-Barrera MA, Hatter J, Trujillo-Orrego N, Gicas K, Wilson J and Hynd GW (2010). Subregional parcellation and segmentation of the prefrontal cortex in children – Protocol calibration. Conference Abstract: The 20th Annual Rotman Research Institute Conference, The frontal lobes. doi: 10.3389/conf.fnins.2010.14.00061 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Jun 2010; Published Online: 28 Jun 2010. * Correspondence: M. A Garcia-Barrera, CORTEX, University of Victoria, Department of Psychology, Victoria, Canada, mgarcia@uvic.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers M. A Garcia-Barrera J. Hatter N. Trujillo-Orrego K. Gicas J. Wilson G. W Hynd Google M. A Garcia-Barrera J. Hatter N. Trujillo-Orrego K. Gicas J. Wilson G. W Hynd Google Scholar M. A Garcia-Barrera J. Hatter N. Trujillo-Orrego K. Gicas J. Wilson G. W Hynd PubMed M. A Garcia-Barrera J. Hatter N. Trujillo-Orrego K. Gicas J. Wilson G. W Hynd Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Individual Differences in Right Dorsolateral Prefrontal Cortex Volumes, Whole Brain Activity and Memory Performance in Healthy Young and Older Adults

Event Abstract Back to Event Individual Differences in Right Dorsolateral Prefrontal Cortex Volumes, Whole Brain Activity and Memory Performance in Healthy Young and Older Adults Y. Czechowska1, C L Grady1, 2, R. Languay1, J C Pruessner1, M N Rajah1* and L. Valiquette1 1 McGill University, Douglas Mental Health University Institute, Canada 2 University of Toronto, Rotman Research Institute at Baycrest, Canada We conducted an fMRI study on 25 young and 26 older healthy adults and reported deficits in right dorsolateral PFC (DLPFC) activity that were linked to context memory reductions deficits in older adults (Rajah et al 2010). To extend this result we conducted semi-automatic volume segmentation of left and right DLFPC in this cohort and found a near significant (p = .055) group-by-hemispheric difference in DLPFC volume, due to older adults exhibiting smaller right versus left DLPFC volumes compared to young adults. To determine if this age-difference in right DLPFC volume was linked with changes in right DLPFC structure-function associations, we conducted a multivariate partial least squares (ST-PLS) seed analysis, using right DLPFC volumes and accuracy scores. One significant effect (p<.001) was indentified, which reflected group differences in the network of brain regions activated in association with correct context retrieval and larger right DLPFC volumes. In young adults improved retrieval accuracy and larger right DLPFC volumes was associated with increased bilateral DLPFC activity and right hippocampal activity. In contrast, in older adults retrieval accuracy and larger right DLPFC volumes was associated with increased activity in left, but not right, DLPFC, bilateral ventrolateral PFC and caudate. This supports the argument that age-related deficits in context memory retrieval may be due to changes in right DLPFC structure, function and its structure-function associations with the retrieval network, including right hippocampus. Conference: The 20th Annual Rotman Research Institute Conference, The frontal lobes, Toronto, Canada, 22 Mar - 26 Mar, 2010. Presentation Type: Poster Presentation Topic: Cognitive Neuroscience Citation: Czechowska Y, Grady C, Languay R, Pruessner J, Rajah M and Valiquette L (2010). Individual Differences in Right Dorsolateral Prefrontal Cortex Volumes, Whole Brain Activity and Memory Performance in Healthy Young and Older Adults. Conference Abstract: The 20th Annual Rotman Research Institute Conference, The frontal lobes. doi: 10.3389/conf.fnins.2010.14.00116 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Jun 2010; Published Online: 30 Jun 2010. * Correspondence: M N Rajah, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada, maria.rajah@mcgill.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Y. Czechowska C L Grady R. Languay J C Pruessner M N Rajah L. Valiquette Google Y. Czechowska C L Grady R. Languay J C Pruessner M N Rajah L. Valiquette Google Scholar Y. Czechowska C L Grady R. Languay J C Pruessner M N Rajah L. Valiquette PubMed Y. Czechowska C L Grady R. Languay J C Pruessner M N Rajah L. Valiquette Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Cortical-Striatal Integration of Cocaine History and Prefrontal Dysfunction in Animal Modeling of Dual Diagnosis

High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability. We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHLs)-a neurodevelopmental model of schizophrenia (vs. SHAM-operated control animals)--and a behaviorally sensitizing cocaine history (15 mg/kg/day x 5 days vs. saline injections) on acute cocaine-induced neural activation signaled by c-Fos expression. Stereological assessment of activation densities spanned six ventral to dorsal cortical-striatal compartments. Cortically, NVHLs showed hypoactivation and decreased volume of the ventral medial prefrontal cortex. In contrast, cocaine history was only expressed subcortically and as a hyperactivating effect in the dorsal striatum where significant NVHL-induced hyperactivation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypoactivation and cocaine history-related increases in striatal activation. These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis.

IMAGING STUDY: Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ-using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16-18. Extensive exclusionary criteria included co-morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high-resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group-by-gender interactions were observed (P < 0.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same-gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.

Neuroanatomic Alterations and Social and Communication Deficits in Monozygotic Twins Discordant for Autism Disorder

Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic. These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research involving twins who are concordant and discordant for autism is essential to disentangle the genetic and environmental contributions to autism.

Increased Left Subgenual Prefrontal Cortex and Right Infralimbic Cortex Volumes in Post-Traumatic Stress Disorder

Increased Left Subgenual Prefrontal Cortex and Right Infralimbic Cortex Volumes in Post-Traumatic Stress Disorder

The relation of worry to prefrontal cortex volume in older adults with and without generalized anxiety disorder

Despite the widespread prevalence of generalized anxiety disorder (GAD) in later life, almost nothing is known about the neural aspects of worry in adults over the age of 60. Given the ongoing rapid increase in the older adult population, the relatively poor response rates to current interventions for late life GAD, and the effects of age-related changes to the brain, additional research on worry neurobiology is needed. The study group comprised 15 older GAD patients and 15 matched controls who were compared on clinical measures and brain volumes. It was expected that prefrontal cortex (PFC) volumes [medial orbital cortex (mOFC), dorsolateral cortex (DLPFC)] would show positive relations to worry scores, and weaker relations to more general measures of anxiety and depression. Negative relations were expected between amygdala volumes and worry scores. As expected, mOFC volumes were positively related to worry scores; however, DLPFC and amygdala volumes were not. The mOFC is involved in emotional decision-making under uncertain conditions and has the ability to suppress the amygdala, both of which are hypothesized functions of worry. Results are partly consistent with GAD theory and suggest that worry may involve neural areas that are also involved in the successful control of anxiety.

A Longitudinal Study of the Effects of Lithium Treatment on Prefrontal and Subgenual Prefrontal Gray Matter Volume in Treatment-Responsive Bipolar Disorder Patients

Article AbstractObjective: Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder. Method: The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich.Results: Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786). Conclusion: The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimer's disease.