Publications

The manuscripts published by our T32 Fellows provides a glimpse into the breadth of work done in our T32 program. Listed below is a portion of the 100+ manuscripts our T32 Fellows have published in the last 10 years.  Recent are highlighted in the top 3 sections.

Local versus long-range connectivity patterns of auditory disturbance in schizophrenia

                  Schizophrenia Research

                       Volume 228, February 2021, Pages 262-270

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Stephanie M.Hare, Bhim M. Adhikari, Xiaoming Du, Laura Garci, Heather Bruce, Peter Kochunov, Jonathan Z. Simon, L. Elliot Hong

 

     Auditory hallucinations are a debilitating symptom of schizophrenia. Effective treatment is limited because the underlying neural mechanisms remain unknown. Our study investigates how local and long-range functional connectivity is associated with auditory perceptual disturbances (APD) in schizophrenia. APD was assessed using the Auditory Perceptual Trait and State Scale. Resting state fMRI data were collected for N=99 patients with schizophrenia. Local functional connectivity was estimated using regional homogeneity (ReHo) analysis; long-range connectivity was estimated using resting state functional connectivity (rsFC) analysis. Mediation analyses tested whether local (ReHo) connectivity significantly mediated associations between long-distance rsFC and APD. Severity of APD was significantly associated with reduced ReHo in left and right putamen, left temporoparietal junction (TPJ), and right hippocampus-pallidum. Higher APD was also associated with reduced rsFC between the right putamen and the contralateral putamen and auditory cortex. Local and long-distance connectivity measures together explained 40.3% of variance in APD (P < 0.001), with the strongest predictor being the left TPJ ReHo (P < 0.001). Additionally, TPJ ReHo significantly mediated the relationship between right putamen – left putamen rsFC and APD (Sobel test, P = 0.001). Our findings suggest that both local and long-range functional connectivity deficits contribute to APD, emphasizing the role of striatum and auditory cortex. Considering the translational impact of these circuit-based findings within the context of prior clinical trials to treat auditory hallucinations, we propose a model in which correction of both local and long-distance functional connectivity deficits may be necessary to treat auditory hallucinations.

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Adam J. Culbreth, Qiong Wu, Shuo Chen, Bhim M. Adhikari, L. Elliot Hong, James M. Gold, James A. Waltz 

     

     A growing body of research has suggested that people with schizophrenia (SZ) exhibit altered patterns of functional and anatomical brain connectivity. For example, many previous resting state functional connectivity (rsFC) studies have shown that, compared to healthy controls (HC), people with SZ demonstrate hyperconnectivity between subregions of the thalamus and sensory cortices, as well as hypoconnectivity between subregions of the thalamus and prefrontal cortex. In addition to thalamic findings, hypoconnectivity between cingulo-opercular brain regions thought to be involved in salience detection has also been commonly reported in people with SZ. However, previous studies have largely relied on seed-based analyses. Seed-based approaches require researchers to define a single a priori brain region, which is then used to create a rsFC map across the entire brain. While useful for testing specific hypotheses, these analyses are limited in that only a subset of connections across the brain are explored. In the current manuscript, we leverage novel network statistical techniques in order to detect latent functional connectivity networks with organized topology that successfully differentiate people with SZ from HCs. Importantly, these techniques do not require a priori seed selection and allow for whole brain investigation, representing a comprehensive, data-driven approach to determining differential connectivity between diagnostic groups. Across two samples, (Sample 1: 35 SZ, 44 HC; Sample 2: 65 SZ, 79 HC), we found evidence for differential rsFC within a network including temporal and thalamic regions. Connectivity in this network was greater for people with SZ compared to HCs. In the second sample, we also found evidence for hypoconnectivity within a cingulo-opercular network of brain regions in people with SZ compared to HCs. In summary, our results replicate and extend previous studies suggesting hyperconnectivity between the thalamus and sensory cortices and hypoconnectivity between cingulo-opercular regions in people with SZ using data-driven statistical and graph theoretical techniques. 

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

                                             Human Brain Mapping 

                                                                          Volume 41, 2020, pgs 767–778

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Bhim M AdhikariJuergen DukartJoerg F HippAnna ForsythRebecca McMillanSuresh D MuthukumaraswamyMeghann C RyanL Elliot HongSimon B EickhoffNeda JahandshadPaul M ThompsonLaura M RowlandPeter Kochunov

     

     Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

 Publications from our T32 Fellows during the last 5 years.

  (T32 Fellows in bold; 50+ publications; over 50% first authored) 

  • Hare SM, Adhikari BM, Du X, Garcia L, Bruce H, Kochunov P, Simon JZ, Hong LE (2021), Local versus long-range connectivity patterns of auditory disturbance in schizophrenia. Schizophr Res 228:262-270.

  • Culbreth AJ, Wu Q, Chen S, Adhikari BM, Hong LE, Gold JM, Waltz JA (2021), Temporal-thalamic and cingulo-opercular connectivity in people with schizophrenia. Neuroimage Clin 29:102531.

  • Culbreth AJ, Waltz JA, Frank MJ, Gold JM (2021), Retention of Value Representations Across Time in People With Schizophrenia and Healthy Control Subjects. Biol Psychiatry Cogn Neurosci Neuroimaging 6:420-428.

  • Kochunov P, Ryan MC, Yang Q, Hatch KS, Zhu A, Thomopoulos SI, Jahanshad N, Schmaal L, ,… Adhikari, BM… Hare, S... et al. et al. (2021), Comparison of regional brain deficit patterns in common psychiatric and neurological disorders as revealed by big data. Neuroimage Clin 29:102574.

  • Wijtenburg SA, West J, Korenic SA, Kuhney F, Gaston FE, Chen H, Rowland LM (2021), Multimodal Neuroimaging Study of Visual Plasticity in Schizophrenia. Front Psychiatry 12:644271.

  • Wisner KM, Chiappelli J, Savransky A, Fisseha F, Rowland LM, Kochunov P, Hong LE (2020), Cingulum and abnormal psychological stress response in schizophrenia. Brain Imaging Behav 14:548-561.

  • Thompson PM, Jahanshad N, Ching CRK, Salminen LE, Thomopoulos SI, Bright J, Baune BT, Bertolin S,...Adhikari, BM... et al. (2020), ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Transl Psychiatry 10:100.

  • Hare SM, Chiappelli J, Savransky A, Adhikari BM, Wisner K, Kvarta M, Goldwaser E, Du X, et al. (2020), The Role of Hippocampal Functional Connectivity on Multisystem Subclinical Abnormalities in Schizophrenia. Psychosom Med 82:623-630.

  • Adhikari BM, Dukart J, Hipp JF, Forsyth A, McMillan R, Muthukumaraswamy SD, Ryan MC, Hong LE, et al. (2020), Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia. Hum Brain Mapp 41:767-778.

  • Korenic SA, Klingaman EA, Wickwire EM, Gaston FE, Chen H, Wijtenburg SA, Rowland LM (2020), Sleep quality is related to brain glutamate and symptom severity in schizophrenia. J Psychiatr Res 120:14-20.

  • Chen MH, Korenic SA, Wickwire EM, Wijtenburg SA, Hong LE, Rowland LM (2020), Sex Differences in Subjective Sleep Quality Patterns in Schizophrenia. Behav Sleep Med 18:668-679.

  • Wijtenburg SA, Kapogiannis D, Korenic SA, Mullins RJ, Tran J, Gaston FE, Chen S, Mustapic M, et al. (2019), Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia. Schizophr Res 208:324-330.

  • Shukla DK, Wijtenburg SA, Chen H, Chiappelli JJ, Kochunov P, Hong LE, Rowland LM (2019), Anterior Cingulate Glutamate and GABA Associations on Functional Connectivity in Schizophrenia. Schizophr Bull 45:647-658.

  • Shukla DK, Chiappelli JJ, Sampath H, Kochunov P, Hare SM, Wisner K, Rowland LM, Hong LE (2019), Aberrant Frontostriatal Connectivity in Negative Symptoms of Schizophrenia. Schizophr Bull 45:1051-1059.

  • Gaudiot C, Du X, Summerfelt A, Hare SM, Bustillo JR, Rowland LM, Hong LE (2019), A working memory related mechanism of auditory hallucinations. J Abnorm Psychol 128:423-430.

  • Elmer GI, Palacorolla H, Mayo CL, Brown PL, Jhou TC, Brady D, Shepard PD (2019), The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior. Behav Brain Res 359:950-957.

  • Du X, Choa FS, Chiappelli J, Wisner KM, Wittenberg G, Adhikari B, Bruce H, Rowland LM, et al. (2019), Aberrant Middle Prefrontal-Motor Cortex Connectivity Mediates Motor Inhibitory Biomarker in Schizophrenia. Biol Psychiatry 85:49-59.

  • Adhikari BM, Jahanshad N, Shukla D, Turner J, Grotegerd D, Dannlowski U, Kugel H, Engelen J, et al. (2019), A resting state fMRI analysis pipeline for pooling inference across diverse cohorts: an ENIGMA rs-fMRI protocol. Brain Imaging Behav 13:1453-1467.

  • Adhikari BM, Hong LE, Sampath H, Chiappelli J, Jahanshad N, Thompson PM, Rowland LM, Calhoun VD, et al. (2019), Functional network connectivity impairments and core cognitive deficits in schizophrenia. Hum Brain Mapp 40:4593-4605.

  • Savransky A, Chiappelli J, Fisseha F, Wisner KM, Xiaoming D, Mirmomen SM, Jones AD, Adhikari BM, et al. (2018), Elevated allostatic load early in the course of schizophrenia. Transl Psychiatry 8:246.

  • Chiappelli J, Shi Q, Wijtenburg SA, Quiton R, Wisner K, Gaston F, Kodi P, Gaudiot C, et al. (2018), Glutamatergic Response to Heat Pain Stress in Schizophrenia. Schizophr Bull 44:886-895.

  • Chiappelli J, Rowland LM, Notarangelo FM, Wijtenburg SA, Thomas MAR, Pocivavsek A, Jones A, Wisner K, et al. (2018), Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology 43:1706-1711.

  • Brown PL, Zanos P, Wang L, Elmer GI, Gould TD, Shepard PD (2018), Isoflurane but Not Halothane Prevents and Reverses Helpless Behavior: A Role for EEG Burst Suppression? Int J Neuropsychopharmacol 21:777-785.

  • Adhikari BM, Jahanshad N, Shukla D, Glahn DC, Blangero J, Reynolds RC, Cox RW, Fieremans E, et al. (2018), Heritability estimates on resting state fMRI data using ENIGMA analysis pipeline. Pac Symp Biocomput 23:307-318.

  • Adhikari BM, Jahanshad N, Shukla D, Glahn DC, Blangero J, Fox PT, Reynolds RC, Cox RW, et al. (2018), Comparison of heritability estimates on resting state fMRI connectivity phenotypes using the ENIGMA analysis pipeline. Hum Brain Mapp 39:4893-4902.

  • Lee J, Yoon YB, Wijtenburg SA, Rowland LM, Chen H, Gaston FE, Song IC, Cho KIK, et al. (2018), Lower glutamate level in temporo-parietal junction may predict a better response to tDCS in schizophrenia. Schizophr Res 201:422-423.

  • Rowland LM, Demyanovich HK, Wijtenburg SA, Eaton WW, Rodriguez K, Gaston F, Cihakova D, Talor MV, et al. (2017), Antigliadin Antibodies (AGA IgG) Are Related to Neurochemistry in Schizophrenia. Front Psychiatry 8:104.

  • Demro C, Rowland L, Wijtenburg SA, Waltz J, Gold J, Kline E, Thompson E, Reeves G, et al. (2017), Glutamatergic metabolites among adolescents at risk for psychosis. Psychiatry Res 257:179-185.

  • Wijtenburg SA, Wright SN, Korenic SA, Gaston FE, Ndubuizu N, Chiappelli J, McMahon RP, Chen H, et al. (2017), Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A (1)H-MRS and pCASL study. Neuropsychopharmacology 42:562-571.

  • Savransky A, Chiappelli J, Rowland LM, Wisner K, Shukla DK, Kochunov P, Hong LE (2017), Fornix Structural Connectivity and Allostatic Load: Empirical Evidence From Schizophrenia Patients and Healthy Controls. Psychosom Med 79:770-776.

  • Erickson MA, Albrecht MA, Robinson B, Luck SJ, Gold JM (2017), Impaired suppression of delay-period alpha and beta is associated with impaired working memory in schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging 2:272-279.

  • Erickson MA, Albrecht M, Ruffle A, Fleming L, Corlett P, Gold J (2017), No association between symptom severity and MMN impairment in schizophrenia: A meta-analytic approach. Schizophr Res Cogn 9:13-17.

  • Chiappelli J, Kochunov P, Savransky A, Fisseha F, Wisner K, Du X, Rowland LM, Hong LE (2017), Allostatic load and reduced cortical thickness in schizophrenia. Psychoneuroendocrinology 77:105-111.

  • Brown PL, Palacorolla H, Brady D, Riegger K, Elmer GI, Shepard PD (2017), Habenula-Induced Inhibition of Midbrain Dopamine Neurons Is Diminished by Lesions of the Rostromedial Tegmental Nucleus. J Neurosci 37:217-225.

  • Rowland LM, Krause BW, Wijtenburg SA, McMahon RP, Chiappelli J, Nugent KL, Nisonger SJ, Korenic SA, et al. (2016), Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. Mol Psychiatry 21:198-204.

  • Lamichhane B, Adhikari BM, Dhamala M (2016), Salience Network Activity in Perceptual Decisions. Brain Connect 6:558-571.

  • Erickson MA, Ruffle A, Gold JM (2016), A Meta-Analysis of Mismatch Negativity in Schizophrenia: From Clinical Risk to Disease Specificity and Progression. Biol Psychiatry 79:980-987.

  • Elmer GI, Brown PL, Shepard PD (2016), Engaging Research Domain Criteria (RDoC): Neurocircuitry in Search of Meaning. Schizophr Bull 42:1090-1095.

  • Brown PL, Shepard PD (2016), Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat. J Neurophysiol 116:1161-1174.

  • Rowland LM, Summerfelt A, Wijtenburg SA, Du X, Chiappelli JJ, Krishna N, West J, Muellerklein F, et al. (2016), Frontal Glutamate and gamma-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia. JAMA Psychiatry 73:166-174.

  • Rowland LM, Pradhan S, Korenic S, Wijtenburg SA, Hong LE, Edden RA, Barker PB (2016), Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study. Transl Psychiatry 6:e967.

  • Korenic SA, Nisonger SJ, Krause BW, Wijtenburg SA, Hong LE, Rowland LM (2016), Effectiveness of fast mapping to promote learning in schizophrenia. Schizophr Res Cogn 4:24-31.

  • Bustillo JR, Rediske N, Jones T, Rowland LM, Abbott C, Wijtenburg SA (2016), Reproducibility of phase rotation stimulated echo acquisition mode at 3T in schizophrenia: Emphasis on glutamine. Magn Reson Med 75:498-502.

  • Wijtenburg SA, Yang S, Fischer BA, Rowland LM (2015), In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: application to schizophrenia. Neurosci Biobehav Rev 51:276-295.

  • Wright SN, Hong LE, Winkler AM, Chiappelli J, Nugent K, Muellerklein F, Du X, Rowland LM, et al. (2015), Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia. Hum Brain Mapp 36:3793-3804.

  • Wang L, Lu H, Brown PL, Rea W, Vaupel B, Yang Y, Stein E, Shepard PD (2015), Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway. PLoS One 10:e0127773.

  • Rao J, Chiappelli J, Kochunov P, Regenold WT, Rapoport SI, Hong LE (2015), Is schizophrenia a neurodegenerative disease? Evidence from age-related decline of brain-derived neurotrophic factor in the brains of schizophrenia patients and matched nonpsychiatric controls. Neurodegener Dis 15:38-44.

  • Nugent KL, Chiappelli J, Sampath H, Rowland LM, Thangavelu K, Davis B, Du X, Muellerklein F, et al. (2015), Cortisol Reactivity to Stress and Its Association With White Matter Integrity in Adults With Schizophrenia. Psychosom Med 77:733-742.

  • Nugent KL, Chiappelli J, Rowland LM, Hong LE (2015), Cumulative stress pathophysiology in schizophrenia as indexed by allostatic load. Psychoneuroendocrinology 60:120-129.

  • Erickson MA, Hahn B, Leonard CJ, Robinson B, Gray B, Luck SJ, Gold J (2015), Impaired working memory capacity is not caused by failures of selective attention in schizophrenia. Schizophr Bull 41:366-373.

  • Chiappelli J, Rowland LM, Wijtenburg SA, Muellerklein F, Tagamets M, McMahon RP, Gaston F, Kochunov P, et al. (2015), Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia. Neuropsychopharmacology 40:2157-2164.

  • Chiappelli J, Hong LE, Wijtenburg SA, Du X, Gaston F, Kochunov P, Rowland LM (2015), Alterations in frontal white matter neurochemistry and microstructure in schizophrenia: implications for neuroinflammation. Transl Psychiatry 5:e548.