Browsing by Author "Breier, Alan"
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Item 39. Viruses and Schizophrenia: Implications for Pathophysiology and Treatment(Oxford University Press, 2018-04) Breier, Alan; Psychiatry, School of MedicineOverall 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.Item 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 ScienceAlthough 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.Item 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 MedicineBackground 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.Item 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 MedicineSchizophrenia 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.Item 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, AlanSchizophrenia 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.Item 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 MedicineAim 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.Item A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia(Office of the Vice Chancellor for Research, 2015-04-17) Walters, Kamilah; Mehdiyoun, Nicole; Francis, Michael; Breier, AlanSchizophrenia is a chronic and debilitating neuropsychiatric disease that occurs in approximately one percent of the population and is characterized by cognitive deficits, including difficulties with abstract thinking, discerning reality from fiction, and communication. Cognitive deficits are a prominent feature of the illness and contribute to significant occupational and social disabilities. Additionally, there are no clinically effective treatments for cognitive deficits in schizophrenia. Although the etiology of these symptoms is unknown, recent studies have shown an association between Herpes Simplex Virus 1 (HSV-1) exposure and the severity of cognitive deficits in the schizophrenic population. Valacyclovir is an oral antiviral medication approved by the United States Food and Drug Administration for treatment of herpes virus infections, including HSV-1. Results from a pilot study at the University of Pittsburgh show that treatment with adjunctive valacyclovir improved working and visual memory in comparison to placebo in a population of older adults with chronic phase schizophrenia. The primary goal of the main study is to determine the efficacy of adjunctive valacyclovir to improve cognition by studying visual and working memory in HSV-1 positive early phase schizophrenia patients in a multi-site clinical trial coordinated by the Indiana University Psychotic Disorders Program. The aim of this research is to present a comprehensive review of recent findings regarding the importance of HSV-1 exposure and inflammatory markers in schizophrenia, and to discuss the methods and expected outcomes of our ongoing study.Item Evaluating Acquisition Time of rfMRI in the Human Connectome Project for Early Psychosis. How Much Is Enough?(Springer, 2017-09) Bouix, Sylvain; Swago, Sophia; West, John D.; Pasternak, Ofer; Breier, Alan; Shenton, Martha E.; Radiology and Imaging Sciences, School of MedicineResting-state functional MRI (rfMRI) correlates activity across brain regions to identify functional connectivity networks. The Human Connectome Project (HCP) for Early Psychosis has adopted the protocol of the HCP Lifespan Project, which collects 20 min of rfMRI data. However, because it is difficult for psychotic patients to remain in the scanner for long durations, we investigate here the reliability of collecting less than 20 min of rfMRI data. Varying durations of data were taken from the full datasets of 11 subjects. Correlation matrices derived from varying amounts of data were compared using the Bhattacharyya distance, and the reliability of functional network ranks was assessed using the Friedman test. We found that correlation matrix reliability improves steeply with longer windows of data up to 11–12 min, and ≥14 min of data produces correlation matrices within the variability of those produced by 18 min of data. The reliability of network connectivity rank increases with increasing durations of data, and qualitatively similar connectivity ranks for ≥10 min of data indicates that 10 min of data can still capture robust information about network connectivities.Item Functional neuroanatomical correlates of episodic memory impairment in early phase psychosis(SpringerNature, 2016-03) Francis, Michael Matthew; Hummer, Tom A.; Vohs, Jenifer L.; Yung, Matthew G.; Liffick, Emily; Mehdiyoun, Nicole F.; Radnovich, Alexander J.; McDonald, Brenna C.; Saykin, Andrew J.; Breier, Alan; Department of Psychiatry, IU School of MedicineStudies have demonstrated that episodic memory (EM) is often preferentially disrupted in schizophrenia. The neural substrates that mediate EM impairment in this illness are not fully understood. Several functional magnetic resonance imaging (fMRI) studies have employed EM probe tasks to elucidate the neural underpinnings of impairment, though results have been inconsistent. The majority of EM imaging studies have been conducted in chronic forms of schizophrenia with relatively few studies in early phase patients. Early phase schizophrenia studies are important because they may provide information regarding when EM deficits occur and address potential confounds more frequently observed in chronic populations. In this study, we assessed brain activation during the performance of visual scene encoding and recognition fMRI tasks in patients with earlyphase psychosis (n = 35) and age, sex, and race matched healthy control subjects (n = 20). Patients demonstrated significantly lower activation than controls in the right hippocampus and left fusiform gyrus during scene encoding and lower activation in the posterior cingulate, precuneus, and left middle temporal cortex during recognition of target scenes. Symptom levels were not related to the imaging findings, though better cognitive performance in patients was associated with greater right hippocampal activation during encoding. These results provide evidence of altered function in neuroanatomical circuitry subserving EM early in the course of psychotic illness, which may have implications for pathophysiological models of this illness.Item Greater male than female variability in regional brain structure across the lifespan(Wiley, 2021) Wierenga, Lara M.; Doucet, Gaelle E.; Dima, Danai; Agartz, Ingrid; Aghajani, Moji; Akudjedu, Theophilus N.; Albajes‐Eizagirre, Anton; Alnæs, Dag; Alpert, Kathryn I.; Andreassen, Ole A.; Anticevic, Alan; Asherson, Philip; Banaschewski, Tobias; Bargallo, Nuria; Baumeister, Sarah; Baur‐Streubel, Ramona; Bertolino, Alessandro; Bonvino, Aurora; Boomsma, Dorret I.; Borgwardt, Stefan; Bourque, Josiane; Braber, Anouk; Brandeis, Daniel; Breier, Alan; Brodaty, Henry; Brouwer, Rachel M.; Buitelaar, Jan K.; Busatto, Geraldo F.; Calhoun, Vince D.; Canales‐Rodríguez, Erick J.; Cannon, Dara M.; Caseras, Xavier; Castellanos, Francisco X.; Chaim‐Avancini, Tiffany M.; Ching, Christopher R. K.; Clark, Vincent P.; Conrod, Patricia J.; Conzelmann, Annette; Crivello, Fabrice; Davey, Christopher G.; Dickie, Erin W.; Ehrlich, Stefan; Ent, Dennis; Fisher, Simon E.; Fouche, Jean‐Paul; Franke, Barbara; Fuentes‐Claramonte, Paola; Geus, Eco J. C.; Di Giorgio, Annabella; Glahn, David C.; Gotlib, Ian H.; Grabe, Hans J.; Gruber, Oliver; Gruner, Patricia; Gur, Raquel E.; Gur, Ruben C.; Gurholt, Tiril P.; Haan, Lieuwe; Haatveit, Beathe; Harrison, Ben J.; Hartman, Catharina A.; Hatton, Sean N.; Heslenfeld, Dirk J.; Heuvel, Odile A.; Hickie, Ian B.; Hoekstra, Pieter J.; Hohmann, Sarah; Holmes, Avram J.; Hoogman, Martine; Hosten, Norbert; Howells, Fleur M.; Hulshoff Pol, Hilleke E.; Huyser, Chaim; Jahanshad, Neda; James, Anthony C.; Jiang, Jiyang; Jönsson, Erik G.; Joska, John A.; Kalnin, Andrew J.; Karolinska Schizophrenia Project (KaSP) Consortium; Klein, Marieke; Koenders, Laura; Kolskår, Knut K.; Krämer, Bernd; Kuntsi, Jonna; Lagopoulos, Jim; Lazaro, Luisa; Lebedeva, Irina S.; Lee, Phil H.; Lochner, Christine; Machielsen, Marise W. J.; Maingault, Sophie; Martin, Nicholas G.; Martínez‐Zalacaín, Ignacio; Mataix‐Cols, David; Mazoyer, Bernard; McDonald, Brenna C.; McDonald, Colm; McIntosh, Andrew M.; McMahon, Katie L.; McPhilemy, Genevieve; Meer, Dennis; Menchón, José M.; Naaijen, Jilly; Nyberg, Lars; Oosterlaan, Jaap; Paloyelis, Yannis; Pauli, Paul; Pergola, Giulio; Pomarol‐Clotet, Edith; Portella, Maria J.; Radua, Joaquim; Reif, Andreas; Richard, Geneviève; Roffman, Joshua L.; Rosa, Pedro G. P.; Sacchet, Matthew D.; Sachdev, Perminder S.; Salvador, Raymond; Sarró, Salvador; Satterthwaite, Theodore D.; Saykin, Andrew J.; Serpa, Mauricio H.; Sim, Kang; Simmons, Andrew; Smoller, Jordan W.; Sommer, Iris E.; Soriano‐Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Szeszko, Philip R.; Temmingh, Henk S.; Thomopoulos, Sophia I.; Tomyshev, Alexander S.; Trollor, Julian N.; Uhlmann, Anne; Veer, Ilya M.; Veltman, Dick J.; Voineskos, Aristotle; Völzke, Henry; Walter, Henrik; Wang, Lei; Wang, Yang; Weber, Bernd; Wen, Wei; West, John D.; Westlye, Lars T.; Whalley, Heather C.; Williams, Steven C. R.; Wittfeld, Katharina; Wolf, Daniel H.; Wright, Margaret J.; Yoncheva, Yuliya N.; Zanetti, Marcus V.; Ziegler, Georg C.; Zubicaray, Greig I.; Thompson, Paul M.; Crone, Eveline A.; Frangou, Sophia; Tamnes, Christian K.; Psychiatry, School of MedicineFor many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.