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Item Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent(Frontiers Media, 2019-02-20) Kasten, Chelsea R.; Zhang, Yanping; Boehm, Stephen L., II; Department of Psychology, School of ScienceThe rise in cannabinoid legalization and decriminalization in the US has been paired with an increase in adolescents that perceive marijuana as a "no risk" drug. However, a comprehensive review of human literature indicates that cannabinoid usage may have both beneficial and detrimental effects, with adolescent exposure being a critical window for harming cognitive development. Although the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are often used together for recreational and medical purposes, no study has previously observed the acute and long-lasting effects of THC+CBD in a battery of behavioral assays analogous to subjective human reports. The current study observed the acute and long-term effects of THC, CBD, and THC+CBD on object recognition memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes. Acute THC alone and in combination with CBD resulted in robust effects on anxiety-like and locomotor behavior. A history of repeated cannabinoid treatment followed by a period without drug administration resulted in minimal effects in these behavioral assays. Most notably, the strongest effects of repeated cannabinoid treatment were seen in adult females administered THC+CBD, which significantly impaired their object recognition. No effects of repeated cannabinoid history were present on hippocampal protein expression. These studies represent a detailed examination of age- and sex-effects of acute and repeated cannabinoid administration. However, the acute and long-term effects of THC with and without CBD on additional behaviors in adolescents and adults will need to be examined for a more complete picture of these drug effects.Item Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria(Springer Nature, 2019-05-21) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Idro, Richard; Ssenkusu, John M.; Datta, Dibyadyuti; Hodges, James S.; Morgan, Catherine; John, Chandy C.; Pediatrics, School of MedicineBACKGROUND: Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. METHODS: Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. RESULTS: The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. CONCLUSIONS: AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.Item Adjunctive yoga training for persons with schizophrenia: who benefits?(Cambridge University Press, 2021) Bhatia, Triptish; Gujral, Swathi; Sharma, Vikas; Kumari, Nupur; Wood, Joel; Wesesky, Maribeth A.; Jones, Jacquelynn; Davis, Louanne W.; Iyenger, Satish; Haas, Gretchen L.; Nimgaonkar, Vishwajit L.; Deshpande, Smita N.; Psychiatry, School of MedicineObjective: The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ). Methods: We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers. Results: Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148). Conclusions: YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.Item Admission Clinical and EEG Features Associated With Mortality and Long-term Neurologic and Cognitive Outcomes in Pediatric Cerebral Malaria(Wolters Kluwer, 2023) Clark, Daniel J.; Bond, Caitlin; Andrews, Alexander; Muller, Daniel J.; Sarkisian, Angela; Opoka, Robert O.; Idro, Richard; Bangirana, Paul; Witten, Andy; Sausen, Nicholas J.; Birbeck, Gretchen L.; John, Chandy C.; Postels, Douglas G.; Pediatrics, School of MedicineBackground and objectives: For children with cerebral malaria, mortality is high, and in survivors, long-term neurologic and cognitive dysfunctions are common. While specific clinical factors are associated with death or long-term neurocognitive morbidity in cerebral malaria, the association of EEG features with these outcomes, particularly neurocognitive outcomes, is less well characterized. Methods: In this prospective cohort study of 149 children age 6 months to 12 years who survived cerebral malaria in Kampala, Uganda, we evaluated whether depth of coma, number of clinical seizures, or EEG features during hospitalization were associated with mortality during hospitalization, short-term and long-term neurologic deficits, or long-term cognitive outcomes (overall cognition, attention, memory) over the 2-year follow-up. Results: Higher Blantyre or Glasgow Coma Scores (BCS and GCS, respectively), higher background voltage, and presence of normal reactivity on EEG were each associated with lower mortality. Among clinical and EEG features, the presence of >4 seizures on admission had the best combination of negative and positive predictive values for neurologic deficits in follow-up. In multivariable modeling of cognitive outcomes, the number of seizures and specific EEG features showed independent association with better outcomes. In children younger than 5 years throughout the study, seizure number and presence of vertex sharp waves were independently associated with better posthospitalization cognitive performance, faster dominant frequency with better attention, and higher average background voltage and faster dominant background frequency with better associative memory. In children younger than 5 years at CM episode but 5 years or older at cognitive testing, seizure number, background dominant frequency, and the presence of vertex sharp waves were each associated with changes in cognition, seizure number and variability with attention, and seizure number with working memory. Discussion: In children with cerebral malaria, seizure number is strongly associated with the risk of long-term neurologic deficits, while seizure number and specific EEG features (average background voltage, dominant rhythm frequency, presence of vertex sharp waves, presence of variability) are independently associated with cognitive outcomes. Future studies should evaluate the predictive value of these findings.Item Advancing cognitive engineering methods to support user interface design for electronic health records(Elsevier, 2014-04) Thyvalikakath, Thankam P.; Dziabiak, Michael P.; Johnson, Raymond; Torres-Urquidy, Miguel Humberto; Acharya, Amit; Yabes, Jonathan; Schleyer, Titus K.; Department of Cariology, Operative Dentistry and Dental Public Health, IU School of DentistryBackground Despite many decades of research on the effective development of clinical systems in medicine, the adoption of health information technology to improve patient care continues to be slow, especially in ambulatory settings. This applies to dentistry as well, a primary care discipline with approximately 137,000 practitioners in the United States. A critical reason for slow adoption is the poor usability of clinical systems, which makes it difficult for providers to navigate through the information and obtain an integrated view of patient data. Objective In this study, we documented the cognitive processes and information management strategies used by dentists during a typical patient examination. The results will inform the design of a novel electronic dental record interface. Methods We conducted a cognitive task analysis (CTA) study to observe ten general dentists (five general dentists and five general dental faculty members, each with more than two years of clinical experience) examining three simulated patient cases using a think-aloud protocol. Results Dentists first reviewed the patient’s demographics, chief complaint, medical history and dental history to determine the general status of the patient. Subsequently, they proceeded to examine the patient’s intraoral status using radiographs, intraoral images, hard tissue and periodontal tissue information. The results also identified dentists’ patterns of navigation through patient’s information and additional information needs during a typical clinician-patient encounter. Conclusion This study reinforced the significance of applying cognitive engineering methods to inform the design of a clinical system. Second, applying CTA to a scenario closely simulating an actual patient encounter helped with capturing participants’ knowledge states and decision-making when diagnosing and treating a patient. The resultant knowledge of dentists’ patterns of information retrieval and review will significantly contribute to designing flexible and task-appropriate information presentation in electronic dental records.Item Age of First Concussion and Cognitive, Psychological, and Physical Outcomes in NCAA Collegiate Student Athletes(Springer, 2022) Moody, Jena N.; Hayes, Jasmeet P.; Buckley, Thomas A.; Schmidt, Julianne D.; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael; Pasquina, Paul F.; Caccese, Jaclyn B.; Psychiatry, School of MedicineObjective: Concussions are common among youth athletes and could disrupt critical neurodevelopment. This study examined the association between age of first concussion (AFC) and neurocognitive performance, psychological distress, postural stability, and symptoms commonly associated with concussion in healthy collegiate men and women student athletes. Methods: Participants included 4267 collegiate athletes from various contact, limited-contact, and non-contact sports (1818 women and 2449 men) who completed baseline assessments as part of the Concussion Assessment, Research and Education (CARE) Consortium. Psychological distress was assessed with the Brief Symptom Inventory 18; neurocognitive performance was assessed with the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT); symptoms commonly associated with concussion were assessed with the ImPACT Post-Concussion Symptom Scale; postural stability was assessed with the Balance Error Scoring System. Generalized linear models were used to examine the effects of AFC on clinical outcomes separately in men and women. Results: Later AFC was associated with lower global (Exp(B) = 0.96, P = 0.001) and somatic (Exp(B) = 0.96, P = 0.002) psychological distress on the Brief Symptom Inventory 18 and faster ImPACT reaction time (B = - 0.003, P = 0.001) in women. AFC was not associated with any clinical outcomes in men. Conclusion: Younger AFC was associated with some differences in psychological distress and reaction time among women but not men; however, these results are likely not clinically meaningful. Sociodemographic disparities, pre-existing conditions, and sport type may impact clinical and cognitive outcomes in collegiate athletes more than concussion history. Future work should examine the relationship between AFC and lifespan-related outcomes.Item Aircraft noise, like heat stress, causes cognitive impairments via similar mechanisms in male mice(Elsevier, 2021) Sun, Gang; Lin, Xiaojing; Yi, Xueqing; Zhang, Peng; Liu, Ruoxu; Fu, Bo; Sun, Yating; Li, Jing; Jiao, Shuxin; Tian, Tian; Xu, Xiao-Ming; Tseng, Kuang-Wen; Lin, Cheng-Hsien; Neurological Surgery, School of MedicineTo our knowledge, little evidence is available about effects of aircraft noise (AN), a non-chemical stressor, on cognitive function. Again, it is unknown whether or not the heat stress (HS)-induced cognitive deficits can be exacerbated by AN. The adult male mice were assigned to four groups: group 1 mice exposed to non-HS (24-26 °C 2 h daily for 4 consecutive days) and white noise (WN) (2 h daily for 4 consecutive days), group 2 mice exposed to WN and HS (32-34 °C 2 h daily for 4 consecutive days), group 3 mice exposed to AN and non-HS (2 h daily for 4 consecutive days) and group 4 mice exposed to AN and HS (2 h daily for consecutive 4 days). Cognitive function were determined by passive avoidance, Y-maze, Morris water maze, and novel object recognition tests. Gut barrier and blood-brain-barrier (BBB) permeability, upload of lipopolysaccharide (LPS) translocation, systemic and central inflammation, and stress reactions were examined. Heat stressed mice displayed both increased stress reactions and learning and memory loss. Heat stress also caused gut barrier hyperpermeability, increased upload of LPS translocation, systemic inflammation, BBB disruption and hippocampal neuroinflammation. Aircraft noise stressed mice did not display systemic inflammation but caused gut barrier hyperpermeability, increased upload of LPS translocation, increased stress reactions, BBB disruption, hippocampal neuroinflammation and cognitive deficits. Aircraft noise exposure further exacerbated the heat stress-induced cognitive deficits and its complications. Our data suggest that AN, like HS, causes cognitive impairments via similar mechanisms in male mice.Item Alexa, let's train now! - A systematic review and classification approach to digital and home-based physical training interventions aiming to support healthy cognitive aging(Elsevier, 2023) Herold, Fabian; Theobald, Paula; Gronwald, Thomas; Kaushal, Navin; Zou, Liye; de Bruin, Eling D.; Bherer, Louis; Müller, Notger G.; Health Sciences, School of Health and Human SciencesBackground There is mounting evidence that regular physical activity is an important prerequisite for healthy cognitive aging. Consequently, the finding that almost one-third of the adult population does not reach the recommended level of regular physical activity calls for further public health actions. In this context, digital and home-based physical training interventions might be a promising alternative to center-based intervention programs. Thus, this systematic review aimed to summarize the current state of the literature on the effects of digital and home-based physical training interventions on adult cognitive performance. Methods In this pre-registered systematic review (PROSPERO; ID: CRD42022320031), 5 electronic databases (PubMed, Web of Science, PsycInfo, SPORTDiscus, and Cochrane Library) were searched by 2 independent researchers (FH and PT) to identify eligible studies investigating the effects of digital and home-based physical training interventions on cognitive performance in adults. The systematic literature search yielded 8258 records (extra 17 records from other sources), of which 27 controlled trials were considered relevant. Two reviewers (FH and PT) independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX scale). Results Of the 27 reviewed studies, 15 reported positive effects on cognitive and motor-cognitive outcomes (i.e., performance improvements in measures of executive functions, working memory, and choice stepping reaction test), and a considerable heterogeneity concerning study-related, population-related, and intervention-related characteristics was noticed. A more detailed analysis suggests that, in particular, interventions using online classes and technology-based exercise devices (i.e., step-based exergames) can improve cognitive performance in healthy older adults. Approximately one-half of the reviewed studies were rated as having a high risk of bias with respect to completion adherence (≤85%) and monitoring of the level of regular physical activity in the control group. Conclusion The current state of evidence concerning the effectiveness of digital and home-based physical training interventions is mixed overall, though there is limited evidence that specific types of digital and home-based physical training interventions (e.g., online classes and step-based exergames) can be an effective strategy for improving cognitive performance in older adults. However, due to the limited number of available studies, future high-quality studies are needed to buttress this assumption empirically and to allow for more solid and nuanced conclusions.Item Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial(Mary Ann Liebert, 2018-10-01) Hammond, Flora M.; Sherer, Mark; Malec, James F.; Zafonte, Ross D.; Dikmen, Sureyya; Bogner, Jennifer; Bell, Kathleen R.; Barber, Jason; Temkin, Nancy; Physical Medicine and Rehabilitation, School of MedicineDespite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p = 0.002) and Learning Memory Index (p = 0.001), but not Attention/Processing Speed Index (p = 0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100 mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.Item Anticholinergic Exposure During Rehabilitation: Cognitive and Physical Function Outcomes in Patients with Delirium Superimposed on Dementia(Elsevier, 2015-12) Kolanowski, Ann; Mogle, Jacqueline; Fick, Donna M.; Campbell, Noll; Hill, Nikki; Mulhall, Paula; Behrens, Liza; Colancecco, Elise; Boustani, Malaz; Clare, Linda; Department of Medicine, IU School of MedicineOBJECTIVES: We examined the association between anticholinergic medication exposure and subsequent cognitive and physical function in patients with delirium superimposed on dementia during rehabilitation. We also examined length of stay and discharge disposition by anticholinergic medication exposure. DESIGN: In this secondary analysis we used control group data from an ongoing randomized clinical trial. SETTING/PARTICIPANTS: Participants with delirium and dementia were enrolled at admission to post-acute care. These 99 participants had a mean age of 86.11 (±6.83) years; 67.6% were women; 98% were Caucasian; and 33% were positive for at least one APOE e4 allele. MEASURES: We obtained daily measures of cognitive and physical function using: Digit Span; memory, orientation and attention items from the Montreal Cognitive Assessment; CLOX; the Confusion Assessment Method; and the Barthel Index. Anticholinergic medication exposure was measured weekly using the Anticholinergic Cognitive Burden Scale. RESULTS: Using multilevel models for time we found that greater use of clinically relevant anticholinergic medications in the previous week reduced cognitive and physical function, as measured by Digit Span Backwards and the Barthel index, in the current week. There was no effect of anticholinergic medication use on delirium severity, and APOE status did not moderate any outcomes. Greater use of clinically relevant anticholinergic medications was related to longer length of stay but not discharge disposition. CONCLUSIONS: For vulnerable older adults, anticholinergic exposure represents a potentially modifiable risk factor for poor attention, working memory, physical function, and greater length of stay during rehabilitation.