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DeLisi, Lynn

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DeLisi

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Lynn

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DeLisi, Lynn
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    Pursuit of the “truth” about mental illness: the significance of findings in neuropsychiatric research, and lessons from the past
    (Les Laboratoires Servier, 2014) DeLisi, Lynn
    Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is “the pursuit of the truth” and not joining the latest “bandwagon fad” of “believers” is an important principle to adhere to when participating in the politics of science.
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    Weak dorsolateral prefrontal response to social criticism predicts worsened mood and symptoms following social conflict in people at familial risk for schizophrenia
    (Elsevier, 2018) Nook, Erik; Dodell-Feder, David; Germine, Laura; Hooley, Jill; DeLisi, Lynn; Hooker, Christine I.
    Understanding the specific mechanisms that explain why people who have relatives with schizophrenia (i.e., people at familial high risk; FHR) are more likely to develop the disorder is crucial for prevention. We investigated a diathesis-stress model of familial risk by testing whether FHR individuals under-recruit brain regions central to emotion regulation when exposed to social conflict, resulting in worse mood and symptoms following conflict. FHR and non-FHR participants listened to critical, neutral, and praising comments in an fMRI scanner before completing 4 weeks of daily-diary records. Compared to non-FHR individuals, FHR individuals under-recruited the bilateral dorsolateral prefrontal cortex (DLPFC)—a region strongly implicated in cognitive emotion regulation—following criticism. Furthermore, within FHR participants, weak DLPFC response to criticism in the laboratory task was associated with elevated negative mood and positive symptoms on days with distressing social conflicts in daily-diary assessments. Results extend diathesis-stress models of schizophrenia by clarifying neural and environmental pathways to dysregulation in FHR individuals.
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    Altered language network activity in young people at familial high-risk for schizophrenia
    (Elsevier BV, 2013) Thermenos, Heidi; Whitfield-Gabrieli, S.; Seidman, Larry Joel; Kuperberg, Gina; Juelich, R.J.; Divatia, S.; Riley, C.; Jabbar, G.A.; Shenton, Martha; Kubicki, Marek; Manschreck, Theo; Keshavan, Matcheri; DeLisi, Lynn
    Background—Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. Methods—Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. Results—There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. Conclusions—FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder.
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    Decreased axial diffusivity within language connections: A possible biomarker of schizophrenia risk
    (Elsevier BV, 2013) Kubicki, Marek; Shenton, Martha; Maciejewski, Paul; Pelavin, P.E.; Hawley, K.J.; Ballinger, T.; Swisher, T.; Jabbar, G.A.; Thermenos, Heidi; Keshavan, Matcheri; Seidman, Larry Joel; DeLisi, Lynn
    Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including Arcuate Fasciculus (AF), Uncinate Fasciculus (UF), and Inferior Occipitofrontal Fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion Tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia.
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    Alterations in brain structures underlying language function in young adults at high familial risk for schizophrenia
    (Elsevier BV, 2012) Francis, Alan N; Seidman, Larry Joel; Jabbar, Gul A.; Mesholam-Gately, Raquelle; Thermenos, Heidi; Juelich, Richard; Proal, Ashley; Shenton, Martha; Kubicki, Marek; Mathew, Ian; Keshavan, Matcheri; DeLisi, Lynn
    Introduction—Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia. Methods—T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N=46) and controls with no family history of illness (i.e. at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered. Results—No significant differences were observed between groups on any language measures. Controlling Intracranial volume, significantly smaller center Pars Triangularis (PT) (p<0.01) and right Pars Orbitalis (PO) (p < 0.01) volumes and reversal of the L > R Pars Orbitalis (p < 0.001) lateralization were observed in FHR subjects. In addition, the L Pars Triangularis and R Pars Orbitalis correlated with performance on tests of linguistic function in the FHR group. Conclusions—Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studied would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function.
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    Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders
    (2016) Morgan, Ling Z.; Rollins, Brandi; Sequeira, Adolfo; Byerley, William; DeLisi, Lynn; Schatzberg, Alan F.; Barchas, Jack D.; Myers, Richard M.; Watson, Stanley J.; Akil, Huda; Bunney, William E.; Vawter, Marquis P.
    Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.
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    Correlates to the variable effects of cannabis in young adults: a preliminary study
    (BioMed Central, 2012) Camera, Ariella; Tomaselli, Veronica; Fleming, Jerry; Jabbar, Gul A; Trachtenberg, Melissa; Galvez-Buccollini, Juan A; Proal, Ashley; Rosenthal, Richard N; DeLisi, Lynn
    Background: Cannabis use can frequently have adverse affects in those that use it and these can be amplified by various characteristics of an individual, from demographic and environmental variations to familial predisposition for mental illnesses. Methods: The current study of 100 individuals, who were cannabis users during their adolescence and may still be users, was a survey of the self perceived effects of cannabis and their correlates. A reliable family member was also interviewed for determination of family history of various major mental illnesses and substance use. Results: As many as 40% of cannabis users had paranoid feelings (suspiciousness) when using cannabis, although the most frequent effect was feeling relaxed (46%). Having a familial background for mental illnesses such as depression or schizophrenia did not determine the effects of cannabis nor its pattern of use, although the number of subjects with such a history was small. An age at which an individual began using cannabis did have an effect on how heavily it was used and the heavier the cannabis use, the more likely the individual was also to have had psychotic symptoms after use. There were no sex differences in effects of cannabis. These results are tempered by the reliance on self-report for many of the variables ascertained. Conclusion: Cannabis can frequently have negative effects in its users, which can be amplified by certain demographic and/or psychosocial factors. Thus, users with a specific profile may be at a higher risk of unpleasant effects from cannabis use and caution should be noted when cannabis is administered to young people for medicinal purposes.
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    Rare Mutations in N-methyl-D-aspartate Glutamate Receptors in Autism Spectrum Disorders and Schizophrenia
    (Nature Publishing Group, 2011) Tarabeux, J; Kebir, O; Hamdan, F F; Piton, A; Henrion, É; Millet, B; Fathalli, F; Joober, R; Rapoport, J L; Fombonne, É; Mottron, L; Forget-Dubois, N; Boivin, M; Michaud, J L; Drapeau, P; Lafrenière, R G; Rouleau, G A; Krebs, M-O; Gauthier, J.; DeLisi, Lynn; Xiong, L.; Spiegelman, D.
    Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.
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    A novel analytical framework for dissecting the genetic architecture of behavioral symptoms in neuropsychiatric disorders
    (Public Library of Science, 2010) Deo, Anthony J.; Costa, Ramiro; DeLisi, Lynn; DeSalle, Rob; Haghighi, Fatemeh
    Background: For diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms. Results and Methodology: We introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21. Conclusions: The findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression.