Browsing by Author "Hummer, Tom"
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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 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 Digital Media and Developing Brains: Concerns and Opportunities(Springer, 2024) Hutton, John S.; Piotrowski, Jessica Taylor; Bagot, Kara; Blumberg, Fran; Canli, Turhan; Chein, Jason; Christakis, Dimitri A.; Grafman, Jordan; Griffin, James A.; Hummer, Tom; Kuss, Daria J.; Lerner, Matthew; Marcovitch, Stuart; Paulus, Martin P.; Perlman, Greg; Romeo, Rachel; Thomason, Moriah E.; Turel, Ofir; Weinstein, Aviv; West, Gregory; Hurst‑Della Pietra, Pamela; Potenza, Marc N.; Psychiatry, School of MedicinePurpose of review: The incorporation of digital technologies and their use in youth's everyday lives has been increasing rapidly over the past several decades with possible impacts on youth development and mental health. This narrative review aimed to consider how the use of digital technologies may be influencing brain development underlying adaptive and maladaptive screen-related behaviors. Recent findings: To explore and provide direction for further scientific inquiry, an international group of experts considered what is known, important gaps in knowledge, and how a research agenda might be pursued regarding relationships between screen media activity and neurodevelopment from infancy through childhood and adolescence. While an understanding of brain-behavior relationships involving screen media activity has been emerging, significant gaps exist that have important implications for the health of developing youth. Summary: Specific considerations regarding brain-behavior relationships involving screen media activity exist for infancy, toddlerhood, and early childhood; middle childhood; and adolescence. Transdiagnostic frameworks may provide a foundation for guiding future research efforts. Translating knowledge gained into better interventions and policy to promote healthy development is important in a rapidly changing digital technology environment.Item Functional connectivity in frontostriatal networks differentiate offspring of parents with substance use disorders from other high-risk youth(Elsevier, 2021) Kwon, Elizabeth; Hummer, Tom; Andrews, Katharine D.; Finn, Peter; Aalsma, Matthew; Bailey, Allen; Hanquier, Jocelyne; Wang, Ting; Hulvershorn, Leslie; Psychiatry, School of MedicineBackground: Family history (FH) of substance use disorders (SUDs) is known to elevate SUD risk in offspring. However, the influence of FH SUDs has been confounded by the effect of externalizing psychopathologies in the addiction risk neuroimaging literature. Thus, the current study aimed to assess the association between parental SUDs and offspring functional connectivity in samples matched for psychopathology and demographics. Methods: Ninety 11-12-year-old participants with externalizing disorders were included in the study (48 FH+, 42 FH-). We conducted independent component analyses (ICA) and seed-based analyses (orbitofrontal cortex; OFC, nucleus accumbens (NAcc), dorsolateral prefrontal cortex) with resting state data. Results: FH+ adolescents showed stronger functional connectivity between the right lateral OFC seed and anterior cingulate cortex compared to FH- adolescents (p < 0.05, corrected). Compared to FH-, FH+ adolescents showed stronger negative functional connectivity between the left lateral OFC seed and right postcentral gyrus and between the left NAcc seed and right middle occipital gyrus (p < 0.05, corrected). Poorer emotion regulation was associated with more negative connectivity between right occipital/left NAcc among FH+ adolescents based on the seed-based analysis. FH- adolescents had stronger negative functional connectivity between ventral attention/salience networks and dorsal attention/visuospatial networks in the ICA. Conclusions: Both analytic methods found group differences in functional connectivity between brain regions associated with executive functioning and regions associated with sensory input (e.g., postcentral gyrus, occipital regions). We speculate that families densely loaded for SUD may confer risk by altered neurocircuitry that is associated with emotion regulation and valuation of external stimuli beyond what would be explained by externalizing psychopathology alone.Item Global white matter microstructural abnormalities associated with addiction liability score in drug naïve youth(Springer Nature, 2018-02) Hulvershorn, Leslie; Hummer, Tom; Wu, Yu-Chien; Tarter, Ralph; Rea, Parker; Anand, Amit; Andrew Chambers, R.; Finn, Peter; Psychiatry, School of MedicineAbnormalities in brain white matter (WM) structure have been reported in youths having a family history of substance use disorders (SUDs). It was hypothesized that these abnormalities constitute features of the liability for SUDs transmitted across generations. The association between severity of intergenerational risk for SUD, measured by the Transmissible Liability Index (TLI), and white matter microstructure was examined. Diffusion tensor imaging (DTI) measured WM microstructure in forty-four drug-naïve 10-14 year-olds (N = 19 with parental SUD). Metrics of WM microstructure (i.e., fractional anisotropy, radial diffusivity, mean diffusivity and axial diffusivity) were quantified across the whole brain and in four tracts of interest: anterior corona radiata, superior and inferior longitudinal fasciculi and superior fronto-occipital fasciculi. The TLI was completed by the youths, their parents and, when available, their teachers. The relationship between WM structure and TLI score across the entire group was evaluated using linear multiple regression and between group comparisons were also examined. Fractional anisotropy and radial diffusivity in multiple tracts across the brain were significantly associated with TLI scores. Confirming and extending prior research, the findings indicate that global atypicality in WM tracts was linearly related to liability for eventual SUD development in drug naïve youths.Item O12.3.Effects of Fingolimod, A Potent Anti-Inflammatory Agent, On Brain Structure, Function, And Symptoms in Schizophrenia(Oxford University Press, 2019-04) Breier, Alan; Hummer, Tom; Vohs, Jennifer; Mehdyoun, Nicole; Liffick, Emily; Francis, Michael; Medicine, School of MedicineBackground New medications with novel targets are needed for schizophrenia. Several lines of evidence indicate that inflammatory processes including aberrant lymphocytic activity may be related to the pathophysiology of this illness. These data suggest that agents with anti-inflammatory actions, including modulation of lymphocytes and their inflammatory substrates, may prove to be efficacious for schizophrenia. Fingolimod is a powerful anti-inflammatory agent that is used in the treatment of relapsing multiple sclerosis. It is a sphingosine-1-phosphate (S1P) receptor modulator that decreases circulating lymphocytes through sequestration in lymph tissues. In addition, evidence suggest that it stimulates oligodendrocytes and may enhance white matter integrity. The purpose of this study was to assess the effects of fingolimod in schizophrenia. Methods Subjects with schizophrenia (N=40) were recruited through the Indiana University Psychotic Disorders Programs and randomized 1:1 in a double-blind, eight-week clinical trial of fingolimod 0.5 mg/day and placebo. Circulating total lymphocytes were determined and effects were assessed on symptoms (PANSS), cognition (BACS), plasma cytokines, white matter integrity (DTI) and cortical connectivity (resting fMRI). Results Results revealed a significant decrease in lymphocytes in subjects taking fingolimod versus placebo (treatment x time; F = 61.2, p < 0.001). Fingolimod treated subjects had a mean maximal drop in lymphocytes from baseline of 79.2% with all fingolimod treated subjects experiencing decrements greater than 60%. There was a trend toward higher mean skeletal fractional anisotropy (FA) post-treatment in the fingolimod group. Within the fingolmiod group, there were significant or trend-level correlations between FA increase and decrease in lymphocytes in the genu and body of the corpus collosum and the right superior longitudinal fasciculus. There were also significant group-by-visit interactions in connectivity of left prefrontal cortical (PFC) seeds with clusters in the cerebellum, driven by higher PFC-cerebellum connectivity following fingolimod treatment. There were no improvements (treatment x time) in PANSS total (F = 0.66, p= 0.52), any of the PANSS subscales, or BACS composite score (F = 0.54, p = 0.44). Serious side effects were not observed, and a full safety report will be provided. Discussion Fingolimod produced a strong anti-inflammatory response with substantial reductions in circulating lymphocytes in all treated subjects. Brain effects were observed. However, this response was not accompanied by improvements in symptoms or cognition. These data suggest that fingolimod’s target of S1P modulation and robust anti-inflammatory warrant further investigation in schizophrenia.Item Virtual Reality to Assess and Treat Childhood Aggression(2022) Mineart, Riley; Wood, Zebulun M.; Hummer, TomThe lack of advancement within the existing forms of assessment and treatment for youth aggression result in inaccurate data. The potential of advancement needs to be addressed, as accurate assessments of aggressive behavior lead to affective treatment. The integration of virtual reality will help fill the gap between clinical treatment and the real environments in which aggressive behaviors occur. I have developed a paradigm with the long-term goal of improving the efficiency and accuracy of assessments and treatments. The capabilities of virtual reality are limitless, and will provide positive long-term affects on youth aggression. The long-term goals will build on this to address the existing problems.