Associate Professor of Psychiatry and Behavioral Sciences (General Psychiatry and Psychology)


  • DNA methylation in the TNF-alpha gene decreases along with aging among delirium inpatients. Neurobiology of aging Yamanashi, T., Saito, T., Yu, T., Alario, A., Comp, K., Crutchley, K. J., Sullivan, E. J., Anderson, Z. M., Marra, P. S., Chang, G., Wahba, N. E., Jellison, S. S., Meyer, A. A., Mathur, S., Pandharipande, P., Yoshino, A., Kaneko, K., Lee, S., Toda, H., Iwata, M., Shinozaki, G. 2021; 105: 310-317


    It has been suggested that aging and inflammation play key roles in the development of delirium. In the present study, we investigated the differences of the DNAm patterns in the TNF gene between patients with delirium and without. The data and samples derived from previous and ongoing cohort studies were analyzed. DNAm levels of the TNF gene were analyzed using the Illumina EPIC array genome-wide method and pyrosequencing method. Correlations between age and DNAm levels of each CpG were calculated. Several CpG in the TNF gene in blood showed negative correlation between their DNAm and age in delirium cases both with the EPIC array and by the pyrosequencing method. However, there was no CpG that had significant correlation between their DNAm and age regardless of delirium status among buccal samples. On the other hand, among peripheral blood mononuclear cells samples, it was found that several CpG showed negative correlation between their DNAm and age in delirium cases. The evidence of DNAm change in the TNF gene among delirious subjects was demonstrated.

    View details for DOI 10.1016/j.neurobiolaging.2021.05.005

    View details for PubMedID 34192631

  • New Cutoff Scores for Delirium Screening Tools to Predict Patient Mortality. Journal of the American Geriatrics Society Yamanashi, T., Iwata, M., Crutchley, K. J., Sullivan, E. J., Malicoat, J. R., Anderson, Z. M., Marra, P. S., Chang, G., Kaneko, K., Shinozaki, E., Lee, S., Shinozaki, G. 2021; 69 (1): 140-147


    Detecting delirium is important to identify patients with a high risk of poor outcomes. Although many different kinds of screening instruments for delirium exist, there is no solid consensus about which methods are the most effective. In addition, it is important to find the most useful tools in predicting outcomes such as mortality.Retrospective cohort study.University of Iowa Hospitals and Clinics.A total of 1,125 adult inpatients (mean age = 67.7; median age = 69).Post hoc analyses were performed based on existing data from the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), Delirium Rating Scale-Revised-98 (DRS), and the Delirium Observation Screening Scale (DOSS). Correlation among these scales and relationships between 365-day mortality and each scale were evaluated.A positive result on the CAM-ICU ("CAM-ICU positive") was associated with higher DRS and DOSS scores. A DRS score = 9/10 was the best cutoff to detect CAM-ICU positive, and DOSS = 2/3 was the best cutoff to detect CAM-ICU positive. CAM-ICU positive was associated with high 365-day mortality. DRS score = 9/10 and DOSS score = 0/1 were found to differentiate mortality risk the most significantly. Higher DRS and DOSS scores significantly coincided with a decrease in a patient's survival rate at 365 days.The best DRS and DOSS cutoff scores to differentiate 365-day mortality risk were lower than those commonly used to detect delirium in the literature. New cutoff scores for the DRS and DOSS might be useful in differentiating risk of mortality among hospital patients.

    View details for DOI 10.1111/jgs.16815

    View details for PubMedID 32905636

  • Bispectral EEG (BSEEG) quantifying neuro-inflammation in mice induced by systemic inflammation: A potential mouse model of delirium. Journal of psychiatric research Yamanashi, T., Malicoat, J. R., Steffen, K. T., Zarei, K., Li, R., Purnell, B. S., Najafi, A., Saito, K., Singh, U., Toth, B. A., Lee, S., Dailey, M. E., Cui, H., Kaneko, K., Cho, H. R., Iwata, M., Buchanan, G. F., Shinozaki, G. 2021; 133: 205-211


    Most of the animal studies using inflammation-induced cognitive change have relied on behavioral testing without objective and biologically solid methods to quantify the severity of cognitive disturbances. We have developed a bispectral EEG (BSEEG) method using a novel algorithm in clinical study. This method effectively differentiates between patients with and without delirium, and predict long-term mortality. In the present study, we aimed to apply our bispectral EEG (BSEEG) method, which can detect patients with delirium, to a mouse model of delirium with systemic inflammation induced by lipopolysaccharides (LPS) injection. We recorded EEG after LPS injection using wildtype early adulthood mice (2~3-month-old) and aged mice (18-19-month-old). Animal EEG recordings were converted for power spectral density to calculate BSEEG score using the similar BSEEG algorithm previously developed for our human study. The BSEEG score was relatively stable and slightly high during the day. Alternatively, the BSEEG score was erratic and low in average during the night. LPS injection increased the BSEEG score dose-dependently and diminished the diurnal changes. The mean BSEEG score increased much more in the aged mice group as dosage increased. Our results suggest that BSEEG method can objectively "quantify" level of neuro-Inflammation induced by systemic inflammation (LPS), and that this BSEEG method can be useful as a model of delirium in mice.

    View details for DOI 10.1016/j.jpsychires.2020.12.036

    View details for PubMedID 33360427

  • Topological data analysis (TDA) enhances bispectral EEG (BSEEG) algorithm for detection of delirium. Scientific reports Yamanashi, T., Kajitani, M., Iwata, M., Crutchley, K. J., Marra, P., Malicoat, J. R., Williams, J. C., Leyden, L. R., Long, H., Lo, D., Schacher, C. J., Hiraoka, K., Tsunoda, T., Kobayashi, K., Ikai, Y., Kaneko, K., Umeda, Y., Kadooka, Y., Shinozaki, G. 2021; 11 (1): 304


    Current methods for screening and detecting delirium are not practical in clinical settings. We previously showed that a simplified EEG with bispectral electroencephalography (BSEEG) algorithm can detect delirium in elderly inpatients. In this study, we performed a post-hoc BSEEG data analysis using larger sample size and performed topological data analysis to improve the BSEEG method. Data from 274 subjects included in the previous study were analyzed as a 1st cohort. Subjects were enrolled at the University of Iowa Hospitals and Clinics (UIHC) between January 30, 2016, and October 30, 2017. A second cohort with 265 subjects was recruited between January 16, 2019, and August 19, 2019. The BSEEG score was calculated as a power ratio between low frequency to high frequency using our newly developed algorithm. Additionally, Topological data analysis (TDA) score was calculated by applying TDA to our EEG data. The BSEEG score and TDA score were compared between those patients with delirium and without delirium. Among the 274 subjects from the first cohort, 102 were categorized as delirious. Among the 206 subjects from the second cohort, 42 were categorized as delirious. The areas under the curve (AUCs) based on BSEEG score were 0.72 (1st cohort, Fp1-A1), 0.76 (1st cohort, Fp2-A2), and 0.67 (2nd cohort). AUCs from TDA were much higher at 0.82 (1st cohort, Fp1-A1), 0.84 (1st cohort, Fp2-A2), and 0.78 (2nd cohort). When sensitivity was set to be 0.80, the TDA drastically improved specificity to 0.66 (1st cohort, Fp1-A1), 0.72 (1st cohort, Fp2-A2), and 0.62 (2nd cohort), compared to 0.48 (1st cohort, Fp1-A1), 0.54 (1st cohort, Fp2-A2), and 0.46 (2nd cohort) with BSEEG. BSEEG has the potential to detect delirium, and TDA is helpful to improve the performance.

    View details for DOI 10.1038/s41598-020-79391-y

    View details for PubMedID 33431928

    View details for PubMedCentralID PMC7801387

  • Mortality prediction by bispectral electroencephalography among 502 patients: its role in dementia. Brain communications Saito, T., Malicoat, J. R., Leyden, L. R., Williams, J. C., Jellison, S. S., Long, H., Hellman, M. M., Crutchley, K. J., Anderson, Z. E., Lo, D., Modukuri, M. V., Schacher, C. J., Yoshino, A., Toda, H., Shinozaki, E., Cho, H. R., Lee, S., Shinozaki, G. 2021; 3 (2): fcab037


    Complications of delirium and dementia increase mortality; however, it is difficult to diagnose delirium accurately, especially among dementia patients. The bispectral electroencephalography score can detect delirium and predict mortality in elderly patients. We aimed to develop an efficient and reliable bispectral electroencephalography device for high-throughput screening. We also hypothesized that bispectral electroencephalography score can predict mortality among dementia patients. A prospective cohort study was conducted between January 2016 and December 2018 to measure bispectral electroencephalography from elderly patients and correlate with outcomes. A total of 502 elderly (55 years old or older) patients with and without dementia were enrolled. For a replication of the utility of bispectral electroencephalography, mortalities between bispectral electroencephalography-positive and bispectral electroencephalography-negative group were compared. In addition, patients with and without dementia status were added to examine the utility of bispectral electroencephalography among dementia patients. The mortality within 180 days in the bispectral electroencephalography-positive group was higher than that of the bispectral electroencephalography-negative group in both the replication and the total cohorts. Mortality of those in the bispectral electroencephalography-positive group showed a dose-dependent increase in both cohorts. When the dementia patients showed bispectral electroencephalography positive, their mortality was significantly higher than those with dementia but who were bispectral electroencephalography-negative. Mortality within 30 days in the bispectral electroencephalography-positive group was significantly higher than that of the bispectral electroencephalography-negative group. The utility of the bispectral electroencephalography to predict mortality among large sample of 502 elderly patients was shown. The bispectral electroencephalography score can predict mortality among elderly patients in general, and even among dementia patients, as soon as 30 days.

    View details for DOI 10.1093/braincomms/fcab037

    View details for PubMedID 34136808

    View details for PubMedCentralID PMC8204260

  • The relationship between DNA methylation in neurotrophic genes and age as evidenced from three independent cohorts: differences by delirium status. Neurobiology of aging Saito, T., Braun, P. R., Daniel, S., Jellison, S. S., Hellman, M., Shinozaki, E., Lee, S., Cho, H. R., Yoshino, A., Toda, H., Shinozaki, G. 2020; 94: 227-235


    We previously reported the association between DNA methylation (DNAm) of pro-inflammatory cytokine genes and age. In addition, neurotrophic factors are known to be associated with age and neurocognitive disorders. Therefore, we hypothesized that DNAm of neurotrophic genes change with age, especially in delirium patients. DNAm was analyzed using the Illumina HumanMethylation450 or HumanMethylationEPIC BeadChip Kit in 3 independent cohorts: blood from 383 Grady Trauma Project subjects, brain from 21 neurosurgery patients, and blood from 87 inpatients with and without delirium. Both blood and brain samples showed that most of the DNAm of neurotrophic genes were positively correlated with age. Furthermore, DNAm of neurotrophic genes was more positively correlated with age in delirium cases than in non-delirium controls. These findings support our hypothesis that the neurotrophic genes may be epigenetically modulated with age, and this process may be contributing to the pathophysiology of delirium.

    View details for DOI 10.1016/j.neurobiolaging.2020.06.003

    View details for PubMedID 32650186

    View details for PubMedCentralID PMC7444651

  • Bispectral EEG (BSEEG) to assess arousal after electro-convulsive therapy (ECT). Psychiatry research Zarei, K., Sparr, N. A., Trapp, N. T., Neuhaus, E. D., Cromwell, J. W., Boes, A. D., Shinozaki, G. 2020; 285: 112811


    Postictal confusion is encountered among most patients following electro-convulsive therapy (ECT). This study aimed to test the capabilities of a point-of-care electroencephalography (EEG) method to quantitatively measure and monitor postictal confusion immediately following ECT. We evaluated whether a two-channel frontal EEG device may provide a purely quantitative measure of the postictal state that could aid in the continuous, clinical monitoring of patients following ECT.50 patients receiving ECT at the University of Iowa Hospitals and Clinics were recruited for this study. Subsequently, we obtained 5 min of frontal bispectral EEG (BSEEG) recording from a hand-held EEG device at baseline and 10-20 min following ECT. We performed power spectral density analysis to yield a "BSEEG" score and to capture the difference between patients at baseline and after ECT.The BSEEG score was demonstrated to be a significant indicator of postictal confusion compared to baseline. For 5 patients, we also obtained continuous EEG recordings following ECT to determine the time course required for a patient's BSEEG score to return to baseline. In this subset of patients, it took between 2 and 3 h in duration for the BSEEG score to return to the baseline range.In this pilot study, we showed that BSEEG score was able to distinguish between baseline condition and postictal confusion in patients treated with ECT, and assess the duration for recovery from postictal confusion following ECT. BSEEG may provide a more sensitive measure of arousal in patients following ECT compared to traditional survey-based methods.

    View details for DOI 10.1016/j.psychres.2020.112811

    View details for PubMedID 32032823

    View details for PubMedCentralID PMC7605101

  • Epigenetics of neuroinflammation: Immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients. Journal of psychiatric research Saito, T., Toda, H., Duncan, G. N., Jellison, S. S., Yu, T., Klisares, M. J., Daniel, S., Andreasen, A. J., Leyden, L. R., Hellman, M. M., Shinozaki, E., Lee, S., Yoshino, A., Cho, H. R., Shinozaki, G. 2020; 129: 61-65


    Previously our study has shown that the DNA methylation (DNAm) levels at CpG sites in the pro-inflammatory cytokine gene, TNF-alpha, decrease along with aging, suggesting the potential role of DNAm in aging and heightened inflammatory process leading to increased risk for delirium. However, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, we examined genome-wide DNAm differences in blood between patients with delirium and controls to identify useful epigenetic biomarkers for delirium. Data from a total of 87 subjects (43 delirium cases) were analyzed by a genome-wide DNAm case-control association study. A genome-wide significant CpG site near the gene of LDLRAD4 was identified (p = 5.07E-8). In addition, over-representation analysis showed several significant pathways with a false discovery rate adjusted p-value < 0.05. The top pathway with a Gene Ontology term was immune response, and the second top pathway with a Kyoto Encyclopedia of Genes and Genomes term was cholinergic synapse. Significant DNAm differences related to immune/inflammatory response were shown both at gene and pathway levels between patients with delirium and non-delirium controls. This finding indicates that DNAm status in blood has the potential to be used as epigenetic biomarkers for delirium.

    View details for DOI 10.1016/j.jpsychires.2020.06.005

    View details for PubMedID 32590150

    View details for PubMedCentralID PMC7486988

  • Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples. Psychiatry and clinical neurosciences Braun, P. R., Tanaka-Sahker, M., Chan, A. C., Jellison, S. S., Klisares, M. J., Hing, B. W., Shabbir, Y., Gaul, L. N., Nagahama, Y., Robles, J., Heinzman, J. T., Sabbagh, S., Cramer, E. M., Duncan, G. N., Yuki, K., Close, L. N., Dlouhy, B. J., Howard, M. A., Kawasaki, H., Stein, K. M., Potash, J. B., Shinozaki, G. 2019; 73 (6): 323-330


    Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed.Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array.Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways.High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

    View details for DOI 10.1111/pcn.12835

    View details for PubMedID 30821055

    View details for PubMedCentralID PMC6561812

  • Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Translational psychiatry Braun, P. R., Han, S., Hing, B., Nagahama, Y., Gaul, L. N., Heinzman, J. T., Grossbach, A. J., Close, L., Dlouhy, B. J., Howard, M. A., Kawasaki, H., Potash, J. B., Shinozaki, G. 2019; 9 (1): 47


    Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5-61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.86) and buccal-brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.

    View details for DOI 10.1038/s41398-019-0376-y

    View details for PubMedID 30705257

    View details for PubMedCentralID PMC6355837