Neurobiological Phenotypes Research Articles

Substance abuse in schizophrenia: Neurobiological correlates

Event Abstract Back to Event Substance abuse in schizophrenia: Neurobiological correlates Stephane Potvin1* 1 University of Montreal, Department of Psychiatry, Canada The lifetime prevalence of substance abuse among schizophrenia patients is close to 50%. The negative consequences of substance abuse in schizophrenia are well documented, but the aetiology of this comorbid condition remains unknown. According to the “affect regulation model”, schizophrenia patients abuse drugs in order to cope with their negative affects. Supporting the model, clinical studies have shown that dual diagnosis patients have less blunting of affect, but experience more negative affect. We hypothesized that patients with comorbid addiction would have increased cerebral activations in response to negative emotional stimuli, when compared to abstinent ones. Schizophrenia patients were divided into two groups: patients with (n= 12) (SCZ-ADD group) and without (n=11) (SCZ group) addiction (alcohol and/or cannabis). Using functional magnetic resonance imaging (fMRI), patients were scanned during passive viewing of emotionally negative pictures (International Affective Picture System) and of film excerpts eliciting sadness. Subjectively, the emotional experience induced by viewing the negative pictures and film excerpts was significantly higher in the SCZ-ADD group than in the SCZ group. Neurally, increased loci of activation were found in the medial prefrontal cortex (BA 10) in SCZ-ADD patients, relative to the SCZ group, and this was true for both emotional tasks. These results suggest that the functioning of the medial prefrontal cortex, thought to be impaired in patients with prominent negative symptoms, is more preserved in SCZ-ADD patients. Keywords: Addiction, Neuroimaging, Schizophrenia Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 16 – Neuroimaging in Paediatrics, Neurology and Psychiatry: from clinical phenomenology to neurobiological phenotypes; the Swiss Canadian Egyptian Neurodevelopemental Study (SCENS) Citation: Potvin S (2009). Substance abuse in schizophrenia: Neurobiological correlates. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.066 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: 20 Nov 2009; Published Online: 20 Nov 2009. * Correspondence: Stephane Potvin, University of Montreal, Department of Psychiatry, Montréal, Canada, stephane.potvin@usherbrooke.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 Stephane Potvin Google Stephane Potvin Google Scholar Stephane Potvin PubMed Stephane Potvin 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.

Functional and anatomical magnetic resonance imaging: From Paediatrics to Psychiatry

Event Abstract Back to Event Functional and anatomical magnetic resonance imaging: From Paediatrics to Psychiatry Cherine Fahim1* 1 Bâtiment Anthropole, Unil-Dorigny, Faculté des sciences sociales et politiques, Institut de psychologie et Faculté de Biologie et Médecine, Switzerland Two different studies will be presented: 1. The first study was conducted on a group of 23 children with a moderate score of depression- i.e. children who had sub-clinical symptoms of depression- using a DSM-IV based interactive interview for psychiatric and neurological symptoms were compared to 23 normal control children. All children were scanned using fMRI and DTI at the age of 8. The aim of the study was investigate if structural and functional differences related to depression could present at such an early age. We found abnormal function and structure in 6 out of 7 brain regions implicated in adult depression. 2. The second study investigated the effects of an antipsychotic (quetiapine) on the function and structure of the brain using fMRI and voxel based Morphometry after 5.5 months of treatment in a sub-group of schizophrenia patients (N=23) with blunted affect compared to schizophrenia patients without blunted affect. Clinically, patients receiving quetiapine showed a significant improvement in negative symptoms. Neurally, a significant increase in activity in brain region implicated in socio-emotional processing (orbitofrontal cortex, anterior cingulate cortex and fusiform gyrus) was detected following the treatment. In addition, grey matter densities in these same regions showed significant increase. The later two findings may explain the clinical improvement observed. Keywords: Depression, Neuroimaging, Schizophrenia Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 16 – Neuroimaging in Paediatrics, Neurology and Psychiatry: from clinical phenomenology to neurobiological phenotypes; the Swiss Canadian Egyptian Neurodevelopemental Study (SCENS) Citation: Fahim C (2009). Functional and anatomical magnetic resonance imaging: From Paediatrics to Psychiatry. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.062 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: 19 Nov 2009; Published Online: 19 Nov 2009. * Correspondence: Cherine Fahim, Bâtiment Anthropole, Unil-Dorigny, Faculté des sciences sociales et politiques, Institut de psychologie et Faculté de Biologie et Médecine, Lausanne 1015 Vaud, Switzerland, cherine.fahim@unil.ch 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 Cherine Fahim Google Cherine Fahim Google Scholar Cherine Fahim PubMed Cherine Fahim 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.

Normal feeding and body weight in Fischer 344 rats lacking the cholecystokinin-1 receptor gene

A large body of evidence has demonstrated that one mechanism by which cholecystokinin (CCK) inhibits food intake through activation of CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. OLETF rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic, obese, and predisposed to type 2 diabetes. Recently, by introgressing the OLETF-derived, CCK1R-null gene onto a Fischer 344 genetic background, we have been able to generate a CCK1R-deficient, congenic rat strain, F344.Cck1r −/−, that in contrast to OLETF rats, possesses a lean and normoglycemic phenotype. In the present study, the behavioral and neurobiological phenotype of this rat strain was characterized more fully. As expected, intraperitoneal injections of CCK-8 inhibited intake of chow and Ensure Plus and induced Fos responses in the area postrema and the gelatinosus, commissural and medial subdivisions of the nucleus tractus solitarius of wild-type F344.Cck1r +/+ rats, whereas CCK-8 was without effect on food intake or Fos induction in the F344.Cck1r −/− rats. F344.Cck1r −/− and F344.Cck1r +/+ rats did not differ in body weight and showed comparable weight gain when maintained on Ensure Plus for 2 weeks. Also, no difference was found in 24-h food intake, and dark-phase meal frequency or meal size between F344.Cck1r +/+ and F344.Cck1r −/− rats. As expected, blockade of endogenous CCK action at CCK1R increased food intake and blocked the effects of peripheral CCK-8 in wild-type F344.Cck1r +/+ rats. These results confirm that in rats with a F344 background, CCK-1R mediates CCK-8-induced inhibition of food intake and Fos activation in the hindbrain and demonstrate that selective genetic ablation of CCK1R is not associated with altered meal patterns, hyperphagia, or excessive weight gain on a palatable diet.

From genes to psychoses and back: the role of the 5HT2α-receptor and prepulse inhibition in schizophrenia

Decomposition of schizophrenia into neurobiological vulnerability traits is necessary to understand the complex genetic underpinnings of this phenomenologically defined disorder. This issue is discussed with a focus on prepulse inhibition (PPI) as a neurobiological phenotype and the 5HT2a-receptor as a candidate gene. A series of recent studies illuminates that PPI and 5HT2a-receptors present as vulnerability markers for schizophrenia; a functional sequence variant in the 5HT2a-gene is contributing to this relationship and might consequently contribute to the genetic predisposition to schizophrenia with a very small risk increase.

Polymorphisms in the catechol‐O‐methyltransferase (COMT) gene influence plasma total homocysteine levels

Elevated plasma total homocysteine (tHcy) is a risk factor for various disorders. We investigated whether functional polymorphisms in catechol-O-methyltransferase (COMT) influence tHcy, since COMT activity produces S-adenosylhomocysteine (SAH), a homocysteine precursor. We hypothesized that high activity COMT variants would be associated with high tHcy, since they presumably result in increased formation of SAH. We genotyped 780 community-dwelling elderly individuals for functional COMT (Val(158)Met and A(-287)G) and methylenetetrahydrofolate reductase (MTHFR; C(677)T) polymorphisms, and measured plasma tHcy. As predicted, COMT Val(158) carriers had significantly higher tHcy than Met(158) homozygotes. The effect was limited to individuals homozygous for the MTHFR T(677) allele. In addition, individuals homozygous for the COMT G(-287) allele tended to have lower tHcy levels. High activity variants of COMT interact with the low activity variant of MTHFR to increase tHcy levels. The effect on tHcy may contribute to the reported associations of COMT genotype with psychiatric and neurobiological phenotypes. The results also indicate that COMT activity may influence a broader range of biochemical pathways than hitherto appreciated.

Behavioral and physiological effects of an infant-neglect manipulation in a bi-parental, twinning primate: Impact is dependent on familial factors

Experimental animal studies and epidemiological and clinical human studies demonstrate that atypical infant-caregiving can exert short- and long-term effects on offspring phenotype, including increased long-term risk of affective disorders. Whilst the early environment is therefore a major determinant of behavioral, physiological and neurobiological phenotypes, the effects of early adversity exhibit individual variation, presumably due to differences in environment-genotype interactions. Twin studies provide a powerful model with which to study such interactions. However, human twin studies rarely include analysis of genotype-environment interactions or of individuals exposed to extreme environments, and rat studies have rarely attempted to utilize littermates (i.e. dizygotic twins) to investigate environment-genotype interactions. Here, we report on the effects of repeated deprivation of caregiving in the common marmoset, a primate that exhibits dizygotic twinning and bi-parental care. Breeding pairs each contributed early deprived (ED) twins and control (CON) twins, thereby allowing for the study of effects of ED, parentage and ED-parentage interaction. Significant ED x parentage interaction effects were obtained for basal urinary, plasma and cerebrospinal-fluid cortisol titers (infancy-adolescence), and basal levels of social and maintenance behaviors (juveniles); basal urinary cortisol titers during a 2-week period of repeated psychosocial challenge (juveniles), and social and exploratory behavior during psychosocial challenge (juveniles). Significant main effects of ED were obtained for: basal levels of time spent in contact with parents (ED>CON; juveniles) and in locomotor activity (ED<CON; adolescents); basal and psychosocial-stress-related systolic blood pressure (ED>CON; juveniles); time spent in locomotor activity (ED<CON), contact calling (ED<CON) and exploring novelty (ED>CON) during psychosocial challenge (juveniles). This study provides evidence for long-term effects of early environment on bio-behavioral traits and states in marmosets specifically, and the importance of including parental factors in developmental studies in mammals generally.

Alterations in regional brain metabolism in genetic and pharmacological models of reduced NMDA receptor function

A mouse line has been developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor [Cell 98 (1999) 427]. These NR1 hypomorphic mice represent an experimental model of reduced NMDA receptor function that may be relevant to the pathophysiology of schizophrenia. To further characterize the neurobiological phenotype resulting from developmental NMDA receptor hypofunction, regional brain metabolic activity was assessed by autoradiographic analysis of 14C-2-deoxyglucose (2-DG) uptake. In addition, ligand binding to NMDA, AMPA, and kainate receptors was measured by quantitative autoradiography. MK-801 binding to NMDA receptors was reduced markedly throughout the brain of the NR1 hypomorphic mice. However, no alteration in 3H-AMPA or 3H-kainate binding was apparent in any region examined. Neuroanatomically specific alterations in regional 2-DG uptake were observed in the NR1 hypomorphic animals. Reduced relative 2-DG uptake was observed in the medial prefrontal and anterior cingulate cortices. Altered patterns of 2-DG uptake were also found in neocortical regions, with selective reductions of uptake in layer 6 in frontal regions of somatosensory and motor cortices. These data indicate alterations in cortical circuitry in the NR1 hypomorphic animals and are consistent with functional imaging studies in chronic schizophrenia patients which typically show reduced frontal cortical metabolic activity. Reduced relative 2-DG uptake was also found in the caudate, accumbens, hippocampus, and select thalamic regions in the NR1-deficient mice. However, in many other brain regions no alteration in 2-DG uptake was observed. The alterations in 2-DG uptake in the NR1 hypomorphic mice were distinctly different compared to those observed after acute challenge with the selective NMDA antagonist MK-801 in wild-type mice. The altered patterns of brain 2-DG uptake in the NR1 hypomorphic mice found in the present work, together with the altered behavioral phenotypes previously described, suggest that the mice may provide a valuable model to study novel therapeutic strategies to counteract the neurobiological consequences of chronic developmental NMDA receptor hypofunction.

MRI analysis of an inherited speech and language disorder: structural brain abnormalities.

Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.

Senescence-accelerated mouse (SAM): a biogerontological resource in aging research

The senescence-accelerated mouse (SAM), consisting of 14 senescence-prone inbred strains (SAMP) and 4 senescence-resistant inbred strains (SAMR) has been under development since 1970 through the selective inbreeding of AKR/J strain mice donated by the Jackson laboratory in 1968, based on the data of the grading score of senescence, life span, and pathologic phenotypes. The characteristic feature of aging common to all SAMP and SAMR mice is accelerated senescence and normal aging, respectively. Furthermore, SAMP and SAMR strains manifest various pathobiological phenotypes which include such neurobiological phenotypes as deficits in learning and memory, emotional disorders, abnormal circadian rhythms, brain atrophy, hearing impairment, etc., and are often characteristic enough to differentiate the strains. Various efforts are currently being made using the SAM model to clarify the underlying mechanisms in accelerated senescence as well as the etiopathogenic mechanisms in age-associated pathobiologies. Genetic background and significance of SAM development are discussed.

Analysing hippocampal function in transgenic mice: an ethological perspective

Advances in molecular genetics and transgenic technology have led to the dawn of a new era for neuroscience: manipulation of single genes now makes it possible to dissect the complexities of neurobiological phenotypes and to understand many of the intricacies of brain and behaviour, even in mammals. The phenotypical analysis of these mutant animals is complicated because the potential outcome of gene manipulation is difficult to predict. While behavioural analysis should form an integral part of any multidisciplinary research programme investigating the phenotypical effects of single genes on hippocampal function, it is crucial that the behavioural tests are designed and conducted appropriately. Approaches that take species-specific behavioural characteristics into account and use ethological methods could be the most useful for interpreting these behavioural findings and understanding the biological mechanisms of brain function.

Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype

Background: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent “intermediate phenotypes” that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. Methods: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. Results: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined “low hippocampal NAA/CRE phenotypes” yielded relative risk estimates (λ S) of between 3.8 and 8.8, suggesting this characteristic is heritable. Conclusions: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.