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Item Alcohol Affects the P3 Component of an Adaptive Stop Signal Task ERP(Elsevier, 2017) Plawecki, Martin H.; Windisch, Kyle A.; Wetherill, Leah; Kosubud, Ann E. K.; Dzemidzic, Mario; Kareken, David A.; O'Connor, Sean J.; Department of Psychiatry, School of MedicineBACKGROUND The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduces P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS One hundred and forty eight nondependent moderate to heavy social drinkers, age 21 to 27, participated in 2 single-blind, alcohol or placebo, counterbalanced sessions approximately one week apart. During each session, subjects performed an adaptive stop signal task (aSST) at (1) baseline, (2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and (3) approximately 135 minutes later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial based on the subject’s performance. RESULTS The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring “going” over “stopping,” and SLOW SSD favoring “stopping” over “going”. Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to SLOW SSD group. CONCLUSIONS The aSST is a robust and sensitive task for detecting alcohol induced changes in inhibition behavior as measured by the P3 component in a within subject design. Alcohol was associated with P3 component changes which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response related AUD risk.Item Alcohol enhances unprovoked 22-28 kHz USVs and suppresses USV mean frequency in High Alcohol Drinking (HAD-1) male rats(Elsevier, 2016-04-01) Thakore, Neha; Reno, James M.; Gonzales, Rueben A.; Schallert, Timothy; Bell, Richard L.; Maddox, W. Todd; Duvauchelle, Christine L.; Department of Psychiatry, School of MedicineHeightened emotional states increase impulsive behaviors such as excessive ethanol consumption in humans. Though positive and negative affective states in rodents can be monitored in real-time through ultrasonic vocalization (USV) emissions, few animal studies have focused on the role of emotional status as a stimulus for initial ethanol drinking. Our laboratory has recently developed reliable, high-speed analysis techniques to compile USV data during multiple-hour drinking sessions. Since High Alcohol Drinking (HAD-1) rats are selectively bred to voluntarily consume intoxicating levels of alcohol, we hypothesized that USVs emitted by HAD-1 rats would reveal unique emotional phenotypes predictive of alcohol intake and sensitive to alcohol experience. In this study, male HAD-1 rats had access to water, 15% and 30% EtOH or water only (i.e., Controls) during 8 weeks of daily 7-h drinking-in-the-dark (DID) sessions. USVs, associated with both positive (i.e., 50-55 kHz frequency-modulated or FM) and negative (i.e., 22-28 kHz) emotional states, emitted during these daily DID sessions were examined. Findings showed basal 22-28 kHz USVs were emitted by both EtOH-Naïve (Control) and EtOH-experienced rats, alcohol experience enhanced 22-28 kHz USV emissions, and USV acoustic parameters (i.e., mean frequency in kHz) of both positive and negative USVs were significantly suppressed by chronic alcohol experience. These data suggest that negative affective status initiates and maintains excessive alcohol intake in selectively bred HAD-1 rats and support the notion that unprovoked emissions of negative affect-associated USVs (i.e., 22-28 kHz) predict vulnerability to excessive alcohol intake in distinct rodent models.Item Concordance between DSM-IV and DSM-5 criteria for delirium diagnosis in a pooled database of 768 prospectively evaluated patients using the delirium rating scale-revised-98(BioMed Central, 2014-09-30) Meagher, David J.; Morandi, Alessandro; Inouye, Sharon K.; Ely, Wes; Adamis, Dimitrios; Maclullich, Alasdair J.; Rudolph, James L.; Neufeld, Karin; Leonard, Maeve; Bellelli, Giuseppe; Davis, Daniel; Teodorczuk, Andrew; Kreisel, Stefan; Thomas, Christine; Hasemann, Wolfgang; Timmons, Suzanne; O’Regan, Niamh; Grover, Sandeep; Jabbar, Faiza; Cullen, Walter; Dunne, Colum; Kamholz, Barbara; Van Munster, Barbara C.; De Rooij, Sophia E.; De Jonghe, Jos; Trzepacz, Paula T.; Department of Psychiatry, School of MedicineBackground The Diagnostic and Statistical Manual fifth edition (DSM-5) provides new criteria for delirium diagnosis. We examined delirium diagnosis using these new criteria compared with the Diagnostic and Statistical Manual fourth edition (DSM-IV) in a large dataset of patients assessed for delirium and related presentations. Methods Patient data (n = 768) from six prospectively collected cohorts, clinically assessed using DSM-IV and the Delirium Rating Scale-Revised-98 (DRS-R98), were pooled. Post hoc application of DRS-R98 item scores were used to rate DSM-5 criteria. ‘Strict’ and ‘relaxed’ DSM-5 criteria to ascertain delirium were compared to rates determined by DSM-IV. Results Using DSM-IV by clinical assessment, delirium was found in 510/768 patients (66%). Strict DSM-5 criteria categorized 158 as delirious including 155 (30%) with DSM-IV delirium, whereas relaxed DSM-5 criteria identified 466 as delirious, including 455 (89%) diagnosed by DSM-IV (P <0.001). The concordance between the different diagnostic methods was: 53% (ĸ = 0.22) between DSM-IV and the strict DSM-5, 91% (ĸ = 0.82) between the DSM-IV and relaxed DSM-5 criteria and 60% (ĸ = 0.29) between the strict versus relaxed DSM-5 criteria. Only 155 cases were identified as delirium by all three approaches. The 55 (11%) patients with DSM-IV delirium who were not rated as delirious by relaxed criteria had lower mean DRS-R98 total scores than those rated as delirious (13.7 ± 3.9 versus 23.7 ± 6.0; P <0.001). Conversely, mean DRS-R98 score (21.1 ± 6.4) for the 70% not rated as delirious by strict DSM-5 criteria was consistent with suggested cutoff scores for full syndromal delirium. Only 11 cases met DSM-5 criteria that were not deemed to have DSM-IV delirium. Conclusions The concordance between DSM-IV and the new DSM-5 delirium criteria varies considerably depending on the interpretation of criteria. Overly-strict adherence for some new text details in DSM-5 criteria would reduce the number of delirium cases diagnosed; however, a more ‘relaxed’ approach renders DSM-5 criteria comparable to DSM-IV with minimal impact on their actual application and is thus recommended.Item Contrasting Metacognitive, Social Cognitive and Alexithymia Profiles in Adults with Borderline Personality Disorder, Schizophrenia and Substance Use Disorder(Elsevier, 2017-11) Lysaker, Paul H.; George, Sunita; Chaudoin-Patzoldt, Kelly A.; Pec, Ondrej; Bob, Petr; Leonhardt, Bethany L.; Vohs, Jenifer L.; James, Alison V.; Wickett, Amanda; Buck, Kelly D.; Dimaggio, Giancarlo; Department of Psychiatry, School of MedicineDeficits in the ability to recognize and think about mental states are broadly understood to be a root cause of dysfunction in Borderline Personality Disorder (PD). This study compared the magnitude of those deficits relative to other forms of serious mental illness or psychiatric conditions. Assessments were performed using the metacognition assessment scale-abbreviated (MAS-A), emotion recognition using the Bell Lysaker Emotion Recognition Test and alexithymia using the Toronto Alexithymia Scale among adults with schizophrenia (n = 65), Borderline PD (n = 34) and Substance Use disorder without psychosis or significant Borderline traits (n = 32). ANCOVA controlling for age revealed the Borderline PD group had significantly greater levels of metacognitive capacity on the MAS-A than the schizophrenia group and significantly lower levels of metacognitive capacity than the Substance Use group. Multiple comparisons revealed the Borderline PD group had significantly higher self-reflectivity and awareness of the other's mind than the schizophrenia group but lesser mastery and decentration on the MAS-A than substance use group, after controlling for self-report of psychopathology and overall number of PD traits. The Borderline PD and Schizophrenia group had significantly higher levels of alexithymia than the substance use group. No differences were found for emotion recognition. Results suggest metacognitive functioning is differentially affected in different mental disorders.Item Cue-Dependent Inhibition in Posttraumatic Stress Disorder and Attention- Deficit/Hyperactivity Disorder(Elsevier, 2017-10) Adams, Zachary W.; Meinzer, Michael; Mandel, Howard; Voltin, Joshua; Caughron, Blaine; Sallee, Floyd R.; Hmner, Mark; Wang, Zhewu; Department of Psychiatry, School of MedicineObjective Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are common among military veterans, but the comorbidity of these two psychiatric disorders remains largely unstudied. Evaluating response inhibition and cue-dependent learning as behavioral and neurocognitive mechanisms underlying ADHD/PTSD can inform etiological models and development of tailored interventions. Method A cued go/no-go task evaluated response inhibition in 160 adult males. Participants were recruited from the community and a Veterans Administration medical center. Four diagnostic groups were identified: ADHD-only, PTSD-only, ADHD + PTSD, controls. Results Group differences were observed across most indices of inhibitory functioning, reaction time, and reaction time variability, whereby PTSD-only and ADHD + PTSD participants demonstrated deficits relative to controls. No cue dependency effects were observed. Conclusion Finding complement prior work on neurocognitive mechanisms underlying ADHD, PTSD, and ADHD + PTSD. Lack of expected group differences for the ADHD-only group may be due to limited power. Additional work is needed to better characterize distinctions among clinical groups, as well as to test effects among women and youth.Item Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania(Mary Ann Liebert, 2016-04) Altinay, Murat I.; Hulvershorn, Leslie A.; Karne, Harish; Beall, Erik B.; Anand, Amit; Department of Psychiatry, School of MedicineBipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related.Item Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study(Elsevier, 2017) Brikell, Isabell; Ghirardi, Laura; D'Onofrio, Brian M.; Dunn, David W.; Almqvist, Catarina; Dalsgaard, Søren; Kuja-Halkola, Ralf; Larsson, Henrik; Department of Psychiatry, School of MedicineBackground Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. Methods We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors. Results Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33–3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75–1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54–1.74), full siblings (OR = 1.56, 95% CI = 1.46–1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14–1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96–1.25), and cousins (OR = 1.15, 95% CI = 1.10–1.20). The genetic correlation was 0.21 (95% CI = 0.02–0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23–0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = −0.16–0.79). Conclusions This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.Item Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)(Future Medicine Ltd., 2012-12) Lahiri, Debomoy K.; Maloney, Bryan; Department of Psychiatry, School of MedicineThe goal of genome-wide association studies is to identify SNPs unique to disease. It usually involves a single sampling from subjects' lifetimes. While primary DNA sequence variation influences gene-expression levels, expression is also influenced by epigenetics, including the ‘somatic epitype’ (GSE), an epigenotype acquired postnatally. While genes are inherited, and novel polymorphisms do not routinely appear, GSE is fluid. Furthermore, GSE could respond to environmental factors (such as heavy metals) and to differences in exercise, maternal care and dietary supplements – all of which postnatally modify oxidation or methylation of DNA, leading to altered gene expression. Change in epigenetic status may be critical for the development of many diseases. We propose a ‘longitudinal epigenome-wide association study’, wherein GSE are measured at multiple time points along with subjects' histories. This Longitudinal epigenome-wide association study, based on the ‘dynamic’ somatic epitype over the ‘static’ genotype, merits further investigation.Item Metacognitive profiles in schizophrenia and bipolar disorder: Comparisons with healthy controls and correlations with negative symptoms(Elsevier, 2017-11) Popolo, Raffaele; Smith, Elizabeth; Lysaker, Paul H.; Lestingi, Krizia; Cavallo, Francesca; Melchiorre, Luisa; Santone, Cristina; Dimaggio, Giancarlo; Department of Psychiatry, School of MedicineWhile deficits in metacognition, or the ability to notice and reflect upon mental states has been observed in schizophrenia and linked with poorer concurrent and future function, it is unknown whether these deficits are unique to schizophrenia. Accordingly, this study assessed metacognition using the Metacognitive Assessment Scale–Abbreviated (MAS-A) and the Metacognitions Questionnaire– 30 (MCQ-30) among 26 adults with schizophrenia, 23 with bipolar disorder and 23 healthy controls. Symptom levels of the psychiatric groups were assessed with the Brief Psychiatric Rating Scale. ANCOVA controlling for age and education revealed that the schizophrenia group had lower scores on the MAS-A total and its subscales compared to the bipolar group and healthy controls. The bipolar disorder group also had lower MAS-A scores than the healthy control group. No group differences were found for the MCQ-30. Examination of symptom correlates revealed MAS-A scores were most commonly related to negative symptoms in both clinical groups. The total score and need for control subscale of MCQ-30 was related to total symptomatology and positive symptoms in patients with bipolar disorder. Correlations between the two measures of metacognition revealed that higher MAS-A scores were significantly related to lower scores on the Need to Control Thoughts MCQ-30 subscale.Item Opioid Doses and Acute Care Utilization Outcomes for Adults with Sickle Cell Disease: Emergency Department versus Acute Care Unit(Elsevier, 2017) Molokie, Robert E.; Montminy, Chariz; Dionisio, Corissa; Farooqui, Muhammad Ahmen; Gowhari, Michel; Yao, Yingwei; Suarez, Marie L.; Ezenwa, Miriam O.; Schlaeger, Judith M.; Wang, Zaijie J.; Wilkie, Diana J.; Department of Psychiatry, School of MedicineBackground Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. Methods In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. Findings Pain on admission to the ED averaged 8.7 ± 1.5 and to the ACU averaged 8.0 ± 1.6. The average pain on discharge from the ED was 6.4 ± 3.0 and for the ACU was 4.5 ± 2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. Conclusions Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions.