Browsing by Author "Breier, Alan"

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    39. Viruses and Schizophrenia: Implications for Pathophysiology and Treatment
    (Oxford University Press, 2018-04) Breier, Alan; Psychiatry, School of Medicine
    Overall Abstract: The viral hypothesis of schizophrenia posits that viral infections disrupts cortical circuits that give rise to schizophrenia psychopathology. Prenatal viral exposure during key neurodevelopmental periods, either through direct effects on fetal brain or exposure to excessive maternal cytokines and other chemokines, have been implicated. In addition, abnormal activation of dormant neuro-viruses have been linked to the pathophysiology of schizophrenia. Activation of dormant viruses has potentially important treatment implication for therapies, such as valacyclovir, that suppress viral activity. Among the viruses that have been mostly frequently associated with schizophrenia include herpes simplex virus type 1 (HSV1) and Epstein-Barr virus (EBV). The purpose of this symposium is to focus on the role of viruses in the pathophysiology of schizophrenia and results of antiviral treatment trials in this illness.
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    A preliminary choroid plexus volumetric study in individuals with psychosis
    (Wiley, 2023) Senay, Olcay; Seethaler, Magdalena; Makris, Nikos; Yeterian, Edward; Rushmore, Jarrett; Cho, Kang Ik K.; Rizzoni, Elizabeth; Heller, Carina; Pasternak, Ofer; Szczepankiewicz, Filip; Westin, Carl-Frederik; Losak, Jan; Ustohal, Libor; Tomandl, Josef; Vojtisek, Lubomir; Kudlicka, Peter; Kikinis, Zora; Holt, Daphne; Lewandowski, Kathryn E.; Lizano, Paulo; Keshavan, Matcheri S.; Öngür, Dost; Kasparek, Tomas; Breier, Alan; Shenton, Martha E.; Seitz-Holland, Johanna; Kubicki, Marek; Psychiatry, School of Medicine
    The choroid plexus (ChP) is part of the blood‐cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging‐based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.
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    Affective Systems Induce Formal Thought Disorder in Early-Stage Psychosis
    (APA, 2016-05) Minor, Kyle S.; Marggraf, Matthew P.; Davis, Beshaun J.; Mehdiyoun, Nicole F.; Breier, Alan; Department of Psychology, School of Science
    Although formal thought disorder (FTD) has been described since early conceptualizations of psychosis, its underlying mechanisms are unclear. Evidence suggests FTD may be influenced by affective and cognitive systems; however, few have examined these relationships—with none focusing on early-stage psychosis (EP). In this study, positive FTD and speech production were measured in sex- and race-matched EP (n = 19) and healthy control (n = 19) groups by assessing “reactivity”—a change in experimental compared with baseline conditions—across baseline, affective, and cognitive conditions. Relationships with functioning were also examined within each group. Three key findings emerged: (a) the EP group displayed large differences in positive FTD and speech production, (b) those with EP exhibited affective reactivity for positive FTD, and (c) positive FTD and affective reactivity were linked with poor real-world functioning in EP and these relationships did not considerably change when controlling for positive symptom (e.g., delusions, hallucinations) severity. Our findings provide preliminary evidence that affective, but not cognitive, systems play a critical role in positive FTD. Affective reactivity, in particular, may aid in predicting those with EP who go on to develop serious social impairments. Future work should focus on whether affective systems differentially influence those at separate points on the psychosis-spectrum in an effort to establish evidence-based treatments for FTD.
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    Antipsychotic Efficacy of KarXT (Xanomeline−Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study
    (Physicians Postgraduate Press, 2022-05-11) Weiden, Peter J.; Breier, Alan; Kavanagh, Sarah; Miller, Andrew C.; Brannan, Stephen K.; Paul, Steven M.; Psychiatry, School of Medicine
    Objective: To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination oral agent KarXT (xanomeline-trospium) in the treatment of schizophrenia. Methods: Post hoc analysis was conducted for EMERGENT-1 (NCT03697252), a 5-week, inpatient, placebo-controlled, phase 2 study of acute psychosis in patients who met DSM-5 criteria for schizophrenia. The EMERGENT-1 study was conducted between September 2018 and August 2019. Categorical thresholds of response used were PANSS total score reductions of ≥ 20%, ≥ 30%, ≥ 40%, and ≥ 50% between baseline and study end. Number needed to treat (NNT) for each categorical threshold was calculated. The proportion of KarXT- and placebo-treated patients achieving each response threshold at weeks 2, 4, and 5 was assessed. Marder 5-factor analysis of PANSS assessed response with KarXT across symptom domains. Results: A total of 83 patients in the KarXT group and 87 patients in the placebo group were included in the modified intent-to-treat analysis. Response rates with KarXT ranged from 59.0% for a ≥ 20% threshold to 15.7% for a ≥ 50% threshold. All response rates with KarXT were significantly higher than in the placebo arm (P < .05), with NNTs ranging from 3 (≥ 20% improvement) to 11 (≥ 50% improvement). KarXT was associated with a significantly higher response rate relative to placebo as early as 2 weeks for ≥ 20% (P = .0001) and ≥ 30% (P = .0022) thresholds and at 4 weeks for the ≥ 40% (P = .0049) and ≥ 50% (P = .0041) thresholds. Each of the Marder 5 factors showed significant differences favoring KarXT over placebo (P < .05) by 2 weeks and continuing through week 5 (endpoint Cohen d effect sizes, 0.48-0.66). Conclusions: KarXT provided clinically meaningful responder rates on PANSS total score compared with placebo at each response threshold, providing further support of the successful primary and secondary endpoints. Response was demonstrated as early as 2 weeks relative to placebo. KarXT demonstrated improvements vs placebo in all 5 factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression). Trial Registration: ClinicalTrials.gov identifier: NCT03697252.
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    Are Selective Estrogen Receptor Beta Agonists Potential Therapeutics for Schizophrenia?
    (Oxford University Press, 2020-05-18) Breier, Alan; Liffick, Emily; Hummer, Tom; Vohs, Jennifer; Mehdiyoun, Nicole; Yang, Ziyi; Saykin, Andrew J.; McDonald, Brenna; Francis, Michael; Medicine, School of Medicine
    Background Estrogen therapies, such as estradiol, have shown promise as therapeutics for schizophrenia; however, safety and tolerability concerns, including feminization effects in men and cancer and stroke risk in pre-menopausal women, may limit their broader use. Estradiol binds to both the estrogen alpha (ERA) and beta (ERB) receptors. ERB receptors appear not to mediate many of the concerning side effects of estrogen therapies. In addition, beta receptors have unique localization in cortical regions (i.e., hippocampus), and improve social behaviors and cognition in some animal models, which has led to interests in these compounds for testing in schizophrenia. To our knowledge, there have been no previous clinical trials of selective ERB agonists in schizophrenia. LY500307 is a highly selective agent for beta receptors without effects on estrogen alpha receptors when doses are constrained. Doses that are too high may engage alpha receptors but the alpha engaging threshold dose has not been fully determined in patient groups. The purpose of this dose-response study was to determine: ERB selectivity doses of LY500307 (i.e., without engaging alpha receptors); safety and tolerability; brain target engagement; and effects on cognition and symptoms. Methods A two-staged, double-blind, 8-week, adjunctive to APDs, adaptive phase 1b/2a trial design was conducted in men with schizophrenia (women were not included because of the lack of toxicology, safety, phase 1 and clinical data supporting use in this population). Three LY500307 doses and placebo were evaluated: 25 mg/day, 75 mg/day, and 150 mg/day. The primary markers for estrogen beta receptor selectivity was lack of effects on total testosterone levels (TT) and no feminization signs. Target engagement was assessed with an N-back working memory fMRI task and the electrophysiology measure mismatch negativity (MMN). Cognitive effects were assessed by the MCCB Composite score. Negative and total symptoms were assessed by the NSA-16 and PANSS, respectively. The primary analyses included all subjects and compared the slope from the three LY500307 dosing arms to the placebo slope in order to evaluate the dose responses. The linear mixed model with random intercept was employed and secondary analyses assessed differences between mean changes of the two higher dose arms combined (75 mg and 150 mg) versus placebo. Results Ninety-four patients were randomized across the placebo and three LY500307 dosing arms. There were no effects on plasma TT levels and no evidence of feminization, suggesting all doses were selective for the beta receptor. No significant adverse events were observed. There were no significant differences between the slopes of the three drug doses versus placebo on the brain target engagement variables (fMRI/N-back: F=0.24, p=0.868; MMN (Duration): F=1.08, p=0.358; MMN (Frequency): F=0.89, p=0.446) or on the cognitive/symptom measures (MCCB composite: F=0.87, p=0.458; NSA-16: F=1.79, p=0.148; and PANSS Total: F=0.69, p=0.558.) Secondary analyses also failed to show any significant effects of LY500307 versus placebo on any of the study variables. Discussion Conclusions: This study indicates that the ERB agonist LY500307 was selective, safe, and well tolerated in patients with schizophrenia. This selective ERB agonist, however, failed to demonstrate any significant effects on brain targets, cognition, negative and total symptoms. Potential issues related to dosing and characteristics of the patient population will be discussed. These data suggest that estrogen alpha receptor activation may be necessary to yield positive results in this patient population. Future studies are needed to confirm these findings.
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    Auditory feature perception and auditory hallucinatory experiences in schizophrenia spectrum disorder
    (Springer, 2017-09-21) Schnakenberg Martin, Ashley M.; Bartolomeo, Lisa; Howell, Josselyn; Hetrick, William P.; Bolbecker, Amanda R.; Breier, Alan; Kidd, Gary; O’Donnell, Brian F.; Psychiatry, School of Medicine
    Schizophrenia spectrum disorder (SZ) is associated with deficits in auditory perception as well as auditory verbal hallucinations (AVH). However, the relationship between auditory feature perception and auditory verbal hallucinations (AVH), one of the most commonly occurring symptoms in psychosis, has not been well characterized. This study evaluated perception of a broad range of auditory features in SZ and to determine whether current AVHs relate to auditory feature perception. Auditory perception, including frequency, intensity, duration, pulse-train and temporal order discrimination, as well as an embedded tone task, was assessed in both AVH (n = 20) and non-AVH (n = 24) SZ individuals and in healthy controls (n = 29) with the Test of Basic Auditory Capabilities (TBAC). The Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) was used to assess the experience of auditory hallucinations in patients with SZ. Findings suggest that compared to controls, the SZ group had greater deficits on an array of auditory features, with non-AVH SZ individuals showing the most severe degree of abnormality. IQ and measures of cognitive processing were positively associated with performance on the TBAC for all SZ individuals, but not with the HPSVQ scores. These findings indicate that persons with SZ demonstrate impaired auditory perception for a broad range of features. It does not appear that impaired auditory perception is associated with recent auditory verbal hallucinations, but instead associated with the degree of intellectual impairment in SZ.
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    Brain Activation Patterns during Visual Scene Encoding and Recognition fMRI Tasks in Early Phase Psychosis
    (Office of the Vice Chancellor for Research, 2015-04-17) Ayoubi, Nawead Z.; Mehdiyoun, Nicole F.; Yung, Matthew G.; Hummer, Tom; Francis, Michael M.; Breier, Alan
    Schizophrenia is a chronic and disabling illness that is associated with significant impairments in areas such as independent living, social functioning, and vocational functioning. Cognitive dysfunction is a core facet of schizophrenia with deficits occurring in areas of abstraction, attention, language, and memory. Episodic memory (EM) is a cognitive domain that has been shown to be impaired in schizophrenia. EM combines event-specific autobiographical experiences and information regarding the context in which events took place. Patients with schizophrenia may exhibit broad impairments in EM, with deficits occurring during encoding and retrieval with both visual and verbal tasks. There are a number of inconsistencies in the EM fMRI literature and indicating a need for first episode psychosis (FEP) versus chronic phase schizophrenia research. FEP have fewer and less severe medical comorbidities, shorter durations of antipsychotic treatment exposure, and lower severity of illness, all of which can impact data interpretation. In this study, brain activation patterns were assessed during performance of visual scene encoding and recognition fMRI tasks in FEP patients and healthy control subjects. It is hypothesized that FEP patients would demonstrate decreased activation during encoding and recognition in the main areas that mediate EM function, namely the hippocampus, prefrontal, and parietal cortices. Within the FEP group correlations can be determined by comparing brain activation patterns with cognition (Brief Assessment of Cognition in Schizophrenia [BACS]) and symptom (Positive and Negative Syndrome Scale [PANSS]) outcome measures. Results indicate that during the encoding task FEP exhibited significantly lower activation in the hippocampus and fusiform gyrus when compared to controls. During the recognition task FEP showed a significantly weaker cortical response in the posterior cingulate cortex, the precuneus, and the left middle temporal cortex when compared to controls. These results demonstrate a pattern of alteration in hippocampal, parietal, and temporal activity during EM processes in FEP. Altered hippocampal response in FEP may reflect dysfunctional binding mechanisms and less efficient encoding.
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    Brain-age prediction: Systematic evaluation of site effects, and sample age range and size
    (Wiley, 2024) Yu, Yuetong; Cui, Hao-Qi; Haas, Shalaila S.; New, Faye; Sanford, Nicole; Yu, Kevin; Zhan, Denghuang; Yang, Guoyuan; Gao, Jia-Hong; Wei, Dongtao; Qiu, Jiang; Banaj, Nerisa; Boomsma, Dorret I.; Breier, Alan; Brodaty, Henry; Buckner, Randy L.; Buitelaar, Jan K.; Cannon, Dara M.; Caseras, Xavier; Clark, Vincent P.; Conrod, Patricia J.; Crivello, Fabrice; Crone, Eveline A.; Dannlowski, Udo; Davey, Christopher G.; de Haan, Lieuwe; de Zubicaray, Greig I.; Di Giorgio, Annabella; Fisch, Lukas; Fisher, Simon E.; Franke, Barbara; Glahn, David C.; Grotegerd, Dominik; Gruber, Oliver; Gur, Raquel E.; Gur, Ruben C.; Hahn, Tim; Harrison, Ben J.; Hatton, Sean; Hickie, Ian B.; Hulshoff Pol, Hilleke E.; Jamieson, Alec J.; Jernigan, Terry L.; Jiang, Jiyang; Kalnin, Andrew J.; Kang, Sim; Kochan, Nicole A.; Kraus, Anna; Lagopoulos, Jim; Lazaro, Luisa; McDonald, Brenna C.; McDonald, Colm; McMahon, Katie L.; Mwangi, Benson; Piras, Fabrizio; Rodriguez-Cruces, Raul; Royer, Jessica; Sachdev, Perminder S.; Satterthwaite, Theodore D.; Saykin, Andrew J.; Schumann, Gunter; Sevaggi, Pierluigi; Smoller, Jordan W.; Soares, Jair C.; Spalletta, Gianfranco; Tamnes, Christian K.; Trollor, Julian N.; Van't Ent, Dennis; Vecchio, Daniela; Walter, Henrik; Wang, Yang; Weber, Bernd; Wen, Wei; Wierenga, Lara M.; Williams, Steven C. R.; Wu, Mon-Ju; Zunta-Soares, Giovana B.; Bernhardt, Boris; Thompson, Paul; Frangou, Sophia; Ge, Ruiyang; ENIGMA-Lifespan Working Group; Psychiatry, School of Medicine
    Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.
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    Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia
    (Springer Nature, 2022) Di Biase, Maria A.; Geaghan, Michael P.; Reay, William R.; Seidlitz, Jakob; Weickert, Cynthia Shannon; Pébay, Alice; Green, Melissa J.; Quidé, Yann; Atkins, Joshua R.; Coleman, Michael J.; Bouix, Sylvain; Knyazhanskaya, Evdokiya E.; Lyall, Amanda E.; Pasternak, Ofer; Kubicki, Marek; Rathi, Yogesh; Visco, Andrew; Gaunnac, Megan; Lv, Jinglei; Mesholam-Gately, Raquelle I.; Lewandowski, Kathryn E.; Holt, Daphne J.; Keshavan, Matcheri S.; Pantelis, Christos; Öngür, Dost; Breier, Alan; Cairns, Murray J.; Shenton, Martha E.; Zalesky, Andrew; Psychiatry, School of Medicine
    Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
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    Characterization of white matter abnormalities in early-stage schizophrenia
    (Wiley, 2016) Hummer, Tom A.; Francis, Michael M.; Vohs, Jenifer L.; Liffick, Emily; Mehdiyoun, Nicole F.; Breier, Alan; Department of Psychiatry, IU School of Medicine
    Aim White matter abnormalities have been reported in schizophrenia and may indicate altered cortical network integrity and structural connectivity, which have been hypothesized as key pathophysiological components of this illness. In this study, we aimed to further characterize the nature and progression of white matter alterations during the early stages of the disorder. Methods We employed diffusion tensor imaging (DTI) approaches to investigate fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) in 40 patients with schizophrenia and related psychotic disorders (aged 18–30 years) who were within 5 years of illness, along with an age-, sex- and race-matched sample of 21 healthy controls. Relationships with illness duration, lifetime antipsychotic medication exposure and symptom levels were examined. Results Patients had lower FA and higher RD than controls in numerous white matter tracts, including the corpus callosum (CC) and the superior longitudinal fasciculus. Illness duration was associated with lower FA and higher RD, most prominently in the CC. No group differences or relationships to illness duration were detected with AD, and no relationships between any DTI measurements and lifetime antipsychotic medication use were found. Conclusions This investigation provides evidence of widespread disruptions to structural connectivity in the early stages of schizophrenia. The relationship to illness duration, coupled with an absence of relationships to AD or antipsychotic drug exposure, provides evidence of a progressive disease process, although prospective assessments with repeated DTI measurements are needed to fully characterize the trajectory of white matter abnormalities in this illness.