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Item Opioid Use as a Predictor of Pain Outcomes in Iraq and Afghanistan Veterans with Chronic Pain: Analysis of a Randomized Controlled Trial(Oxford Academic, 2021) Bushey, Michael A.; Wu, Jingwei; Outcalt, Samantha D.; Krebs, Erin E.; Ang, Dennis; Kline, Matthew; Yu, Zhangsheng; Bair, Matthew J.; Psychiatry, School of MedicineOBJECTIVE: Our objectives were to: 1) assess the relationship between self-reported opioid use and baseline demographics, clinical characteristics and pain outcomes; and 2) examine whether baseline opioid use moderated the intervention effect on outcomes at 9 months. DESIGN: We conducted a secondary analysis of data from the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial, which found stepped-care to be effective for chronic pain in military veterans. SETTING: A post-deployment clinic and five general medicine clinics at a Veteran Affairs Medical Center. SUBJECTS: In total 241 veterans with chronic musculoskeletal pain; 220 with complete data at 9 months. METHODS: Examination of baseline relationships and multivariable linear regression to examine baseline opioid use as a moderator of pain-related outcomes including Roland Morris Disability Questionnaire (RMDQ), Brief Pain Inventory (BPI) Interference scale, and Graded Chronic Pain Scale (GCPS) at 9 months. RESULTS: Veterans reporting baseline opioid use (n = 80) had significantly worse RMDQ (16.0 ± 4.9 vs. 13.4 ± 4.2, P < .0001), GCPS (68.7 ± 12.0 vs. 65.0 ± 14.4, P = .049), BPI Interference (6.2 ± 2.2 vs. 5.0 ± 2.1, P < .0001), and depression (PHQ-9 12.5 ± 6.2 vs. 10.6 ± 5.7, P = .016) compared to veterans not reporting baseline opioid use. Using multivariable modeling we found that baseline opioid use moderated the intervention effect on pain-related disability (RMDQ) at 9 months (interaction Beta = -3.88, P = .0064) but not pain intensity or interference. CONCLUSIONS: In a stepped-care trial for pain, patients reporting baseline opioid use had greater improvement in pain disability at 9 months compared to patients not reporting opioid use.Item Human Brain Lipidomics: Utilities of Chloride Adducts in Flow Injection Analysis(MDPI, 2021-04-28) Wood, Paul L.; Hauther, Kathleen A.; Scarborough, Jon H.; Craney, Dustin J.; Dudzik, Beatrix; Cebak, John E.; Woltjer, Randall L.; Psychiatry, School of MedicineCeramides have been implicated in a number of disease processes. However, current means of evaluation with flow infusion analysis (FIA) have been limited primarily due to poor sensitivity within our high-resolution mass spectrometry lipidomics analytical platform. To circumvent this deficiency, we investigated the potential of chloride adducts as an alternative method to improve sensitivity with electrospray ionization. Chloride adducts of ceramides and ceramide subfamilies provided 2- to 50-fold increases in sensitivity both with analytical standards and biological samples. Chloride adducts of a number of other lipids with reactive hydroxy groups were also enhanced. For example, monogalactosyl diacylglycerols (MGDGs), extracted from frontal lobe cortical gray and subcortical white matter of cognitively intact subjects, were not detected as ammonium adducts but were readily detected as chloride adducts. Hydroxy lipids demonstrate a high level of specificity in that phosphoglycerols and phosphoinositols do not form chloride adducts. In the case of choline glycerophospholipids, the fatty acid substituents of these lipids could be monitored by MS2 of the chloride adducts. Monitoring the chloride adducts of a number of key lipids offers enhanced sensitivity and specificity with FIA. In the case of glycerophosphocholines, the chloride adducts also allow determination of fatty acid substituents. The chloride adducts of lipids possessing electrophilic hydrogens of hydroxyl groups provide significant increases in sensitivity. In the case of glycerophosphocholines, chloride attachment to the quaternary ammonium group generates a dominant anion, which provides the identities of the fatty acid substituents under MS2 conditions.Item The Independent Relationships of Metacognition, Mindfulness, and Cognitive Insight to Self-Compassion in Schizophrenia(Wolters Kluwer, 2020-01) Hochheiser, Jesse; Lundin, Nancy B.; Lysaker, Paul H.; Psychiatry, School of MedicineThe debilitating nature of psychosis may be exacerbated by societal stigma and feelings of social isolation over and above positive (e.g., hallucinations) and negative (e.g., flat affect) symptoms. Thus, recovery may be facilitated by increasing self-compassion, the ability to respond with a nonjudgmental attitude of kindness toward oneself as a result of connecting with one's own inadequacies and suffering. We conducted a stepwise regression in individuals with schizophrenia-spectrum disorders (n = 92) to determine the unique contributions of cognitive variables in predicting self-compassion, such as metacognition (the ability to form complex and integrated ideas about oneself and others), mindfulness, and cognitive insight. Results indicated that increased metacognitive awareness of others and mindfulness uniquely predicted greater self-compassion (i.e., self-kindness), whereas increased cognitive insight predicted greater lack of self-compassion (i.e., self-judgment). These findings suggest the potential for mindfulness and metacognitive interventions to increase positive self-compassion and promote recovery in psychosis.Item Piecing together fragments: Linguistic cohesion mediates the relationship between executive function and metacognition in schizophrenia(Elsevier, 2020-01) Lundin, Nancy B.; Hochheiser, Jesse; Minor, Kyle S.; Hetrick, William P.; Lysaker, Paul H.; Psychiatry, School of MedicineSpeech disturbances are prevalent in psychosis. These may arise in part from executive function impairment, as research suggests that inhibition and monitoring are associated with production of cohesive discourse. However, it is not yet understood how linguistic and executive function impairments in psychosis interact with disrupted metacognition, or deficits in the ability to integrate information to form a complex sense of oneself and others and use that synthesis to respond to psychosocial challenges. Whereas discourse studies have historically employed manual hand-coding techniques, automated computational tools can characterize deep semantic structures that may be closely linked with metacognition. In the present study, we examined whether higher executive functioning promotes metacognition by way of altering linguistic cohesion. Ninety-four individuals with schizophrenia-spectrum disorders provided illness narratives and completed an executive function task battery (Delis-Kaplan Executive Function System). We assessed the narratives for linguistic cohesion (Coh-Metrix 3.0) and metacognitive capacity (Metacognition Assessment Scale – Abbreviated). Selected linguistic indices measured the frequency of connections between causal and intentional content (deep cohesion), word and theme overlap (referential cohesion), and unique word usage (lexical diversity). In path analyses using bootstrapped confidence intervals, we found that deep cohesion and lexical diversity independently mediated the relationship between executive functioning and metacognitive capacity. Findings suggest that executive control abilities support integration of mental experiences by way of increasing causal, goal-driven speech and word expression in individuals with schizophrenia. Metacognitive-based therapeutic interventions for psychosis may promote insight and recovery in part by scaffolding use of language that links ideas together.Item Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms(Mary Ann Liebert, Inc., 2021-04-15) Zeiler, Frederick A.; McFadyen, Charles; Newcombe, Virginia F.J.; Synnot, Anneliese; Donoghue, Emma L.; Ripatti, Samuli; Steyerberg, Ewout W.; Gruen, Russel L.; McAllister, Thomas W.; Rosand, Jonathan; Palotie, Aarno; Maas, Andrew I.R.; Menon, David K.; Psychiatry, School of MedicineThere is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.Item Depression Comorbid With Stroke, Traumatic Brain Injury, Parkinson’s Disease, and Multiple Sclerosis: Diagnosis and Treatment(American Psychiatric Association, 2020-04) Conroy, Susan K.; Brownlowe, Katherine B.; McAllister, Thomas W.; Psychiatry, School of MedicineDepression is common among patients with neurologic disorders, and it has long been considered more difficult to treat than depression in the general population. In this review, the authors consider challenges in the diagnosis and treatment of depression among patients with stroke, traumatic brain injury, Parkinson’s disease, and multiple sclerosis. For each disorder, the authors discuss the epidemiology and time course of depression as well as review the physiologic and psychological etiologies of depression. In addition, for each disorder, they review screening tools and diagnostic considerations, including differential diagnosis; discuss etiological factors, both neurobiological and psychological; and assess evidence for various depression treatments, including pharmacologic, psychosocial, and neuromodulatory therapies. The evidence suggests that depression is common among patients with neurologic disorders and that it is crucial for general psychiatrists to provide treatment for this population.Item How do delirium motor subtypes differ in phenomenology and contributory aetiology? a cross-sectional, multisite study of liaison psychiatry and palliative care patients(BMJ, 2021-04-14) Glynn, Kevin; McKenna, Frank; Lally, Kevin; O’Donnell, Muireann; Grover, Sandeep; Chakrabarti, Subho; Avasthi, Ajit; Mattoo, Surendra K.; Sharma, Akhilesh; Ghosh, Abhishek; Shah, Ruchita; Hickey, David; Fitzgerald, James; Davis, Brid; O'Regan, Niamh; Adamis, Dimitrious; Williams, Olugbenja; Awan, Fahad; Dunne, C.; Cullen, Walter; McInerney, Shane; McFarland, John; Jabbar, Faiza; O'Connell, Henry; Trzepacz, Paula T.; Leonard, Maeve; Meagher, David; Psychiatry, School of MedicineObjectives: To investigate whether delirium motor subtypes differ in terms of phenomenology and contributory aetiology. Design: Cross-sectional study. Setting: International study incorporating data from Ireland and India across palliative care, old age liaison psychiatry and general adult liaison psychiatry settings. Participants: 1757 patients diagnosed with delirium using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM IV). Primary and secondary outcome measures: Hyperactive, mixed and hypoactive delirium subtypes were identified using the abbreviated version of the Delirium Motor Subtype Scale. Phenomenology was assessed using the Delirium Rating Scale Revised. Contributory aetiologies were assessed using the Delirium Aetiology Checklist (DEC), with a score >2 indicating that the aetiology was likely or definitely contributory. Results: Hypoactive delirium was associated with dementia, cerebrovascular and systemic infection aetiologies (p<0.001) and had a lower overall burden of delirium symptoms than the other motor subtypes. Hyperactive delirium was associated with younger age, drug withdrawal and the DEC category other systemic aetiologies (p<0.001). Mixed delirium showed the greatest symptom burden and was more often associated with drug intoxication and metabolic disturbance (p<0.001). All three delirium motor subtypes had similar levels of impairment in attention and visuospatial functioning but differed significantly when compared with no subtype (p<0.001). Conclusions: This study indicates a pattern of aetiology and symptomatology of delirium motor subtypes across a large international sample that had previously been lacking. It serves to improve our understanding of this complex condition and has implications in terms of early detection and management of delirium.Item Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking(MDPI, 2021-04-06) Radke, Anna K.; Sneddon, Elizabeth A.; Frasier, Raizel M.; Hopf, Frederic W.; Psychiatry, School of MedicineAlcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.Item Individual associations of adolescent alcohol use disorder versus cannabis use disorder symptoms in neural prediction error signaling and the response to novelty(Elsevier, 2021-04) Aloi, Joseph; Crum, Kathleen I.; Blair, Karina S.; Zhang, Ru; Bashford-Largo, Johannah; Bajaj, Sahil; Schwartz, Amanda; Carollo, Erin; Hwang, Soonjo; Leiker, Emily; Filbey, Francesca M.; Averbeck, Bruno B.; Dobbertin, Matthew; Blair, R. James R.; Psychiatry, School of MedicineTwo of the most commonly used illegal substances by adolescents are alcohol and cannabis. Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with poorer decision-making in adolescents. In adolescents, level of AUD symptomatology has been negatively associated with striatal reward responsivity. However, little work has explored the relationship with striatal reward prediction error (RPE) representation and the extent to which any augmentation of RPE by novel stimuli is impacted. One-hundred fifty-one adolescents participated in the Novelty Task while undergoing functional magnetic resonance imaging (fMRI). In this task, participants learn to choose novel or non-novel stimuli to gain monetary reward. Level of AUD symptomatology was negatively associated with both optimal decision-making and BOLD response modulation by RPE within striatum and regions of prefrontal cortex. The neural alterations in RPE representation were particularly pronounced when participants were exploring novel stimuli. Level of CUD symptomatology moderated the relationship between novelty propensity and RPE representation within inferior parietal lobule and dorsomedial prefrontal cortex. These data expand on an emerging literature investigating individual associations of AUD symptomatology levels versus CUD symptomatology levels and RPE representation during reinforcement processing and provide insight on the role of neuro-computational processes underlying reinforcement learning/decision-making in adolescents.Item Keeping the inner voice inside the head, a pilot fMRI study(Wiley, 2021-04) Stephane, Massoud; Dzemidzic, Mario; Yoon, Gihyun; Psychiatry, School of MedicineIntroduction: The inner voice is experienced during thinking in words (inner speech) and silent reading and evokes brain activity that is highly similar to that associated with external voices. Yet while the inner voice is experienced in internal space (inside the head), external voices (one's own and those of others) are experienced in external space. In this paper, we investigate the neural basis of this differential spatial localization. Methods: We used fMRI to examine the difference in brain activity between reading silently and reading aloud. As the task involved reading aloud, data were first denoised by removing independent components related to head movement. They were subsequently processed using finite impulse response basis function to address the variations of the hemodynamic response. Final analyses were carried out using permutation-based statistics, which is appropriate for small samples. These analyses produce spatiotemporal maps of brain activity. Results: Reading silently relative to reading aloud was associated with activity of the "where" auditory pathway (Inferior parietal lobule and middle temporal gyrus), and delayed activity of the primary auditory cortex. Conclusions: These pilot data suggest that internal space localization of the inner voice depends on the same neural resources as that for external space localization of external voices-the "where" auditory pathway. We discuss the implications of these findings on the possible mechanisms of abnormal experiences of the inner voice as is the case in verbal hallucinations.