Personalized Prediction of Postconcussive Working Memory Decline: A Feasibility Study

Concussion, also known as mild traumatic brain injury (mTBI), commonly causes transient neurocognitive symptoms, but in some cases, it causes cognitive impairment, including working memory (WM) deficit, which can be long-lasting and impede a patient’s return to work. The predictors of long-term cognitive outcomes following mTBI remain unclear because abnormality is often absent in structural imaging findings. The purpose of the study was to determine whether machine learning-based models using functional magnetic resonance imaging (fMRI) biomarkers and demographic or neuropsychological measures at baseline could effectively predict 1-year cognitive outcomes of concussion. We conducted a prospective, observational study of patients with mTBI who were compared with demographically-matched healthy controls enrolled between September 2015 to August 2020. Baseline assessments were collected within the first week of injury, and follow-ups were conducted at 6 weeks, 3 months, 6 months, and 1 year. Potential demographic, neuropsychological, and fMRI features were selected according to the significance of correlation with the estimated changes in WM ability. The support vector machine classifier was trained using these potential features and estimated changes in WM between the predefined time periods. Patients demonstrated significant cognitive recovery at the third month, followed by worsened performance after 6 months, which persisted until 1 year after concussion. Approximately half of the patients experienced prolonged cognitive impairment at 1-year follow up. Satisfactory predictions were achieved for patients whose WM function did not recover at 3 months (accuracy=87.5%), 6 months (accuracy=83.3%), 1 year (accuracy=83.3%), and performed worse at 1-year follow-up compared to baseline assessment (accuracy=83.3%). This study demonstrated the feasibility of personalized prediction for long-term postconcussive WM outcomes based on baseline fMRI and demographic features, opening a new avenue for early rehabilitation intervention in selected individuals with possible poor long-term cognitive outcomes.

Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency

Duchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3’ end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research.To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 DMD, mean age 9.7±1.8 years; 25 Controls, mean age 9.6±1.4 years). Trials of two neutral visual stimuli were presented to participants: one ‘safe’ cue presented alone; one ‘threat’ cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response, SCR; heart rate, HR). Retention of conditioned physiological responses was subsequently tested with presentation of both cues without the aversive noise in an ‘extinction’ phase. Primary outcomes were the magnitude of the initial unconditioned SCR and HR change responses to the aversive ‘threat’ and acquisition and retention of conditioned responses after conditioning. Secondary outcomes were neuropsychological measures and genotype associations.The initial (unconditioned) mean SCR to threat was greater in DMD than Controls (Mean difference 3.0 µS (95% CI 1.0, 5.1), P=.004), associated with a significant threat-induced bradycardia only in the DMD group (mean difference -5.6 bpm (95% CI 0.51, 16.9); P=.04). DMD participants found the task more aversive than Controls, consequently early termination during the extinction phase occurred in 26% of the DMD group (vs. 0% Controls; P=.007).This study provides the first evidence that boys with DMD show increased unconditioned startle responses to threat, similar to the mdx mouse phenotype that also responds to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.

Sepsis and Cognitive Assessment

Sepsis disproportionally affects people over the age of 65, and with an exponentially increasing older population, sepsis poses additional risks for cognitive decline. This review summarizes published literature for (1) authorship qualification; (2) the type of cognitive domains most often assessed; (3) timelines for cognitive assessment; (4) the control group and analysis approach, and (5) sociodemographic reporting. Using key terms, a PubMed database review from January 2000 to January 2021 identified 3050 articles, and 234 qualified as full text reviews with 18 ultimately retained as summaries. More than half (61%) included an author with an expert in cognitive assessment. Seven (39%) relied on cognitive screening tools for assessment with the remaining using a combination of standard neuropsychological measures. Cognitive domains typically assessed were declarative memory, attention and working memory, processing speed, and executive function. Analytically, 35% reported on education, and 17% included baseline (pre-sepsis) data. Eight (44%) included a non-sepsis peer group. No study considered sex or race/diversity in the statistical model, and only five studies reported on race/ethnicity, with Caucasians making up the majority (74%). Of the articles with neuropsychological measures, researchers report acute with cognitive improvement over time for sepsis survivors. The findings suggest avenues for future study designs.

Neuropsychological Functioning in Users of Serotonergic Psychedelics – A Systematic Review and Meta-Analysis

Background: Serotonergic psychedelics (SPs) like LSD, psilocybin, DMT, and mescaline are a heterogeneous group of substances that share agonism at 5-HT2a receptors. Besides the ability of these substances to facilitate profoundly altered states of consciousness, persisting psychological effects have been reported after single administrations, which outlast the acute psychedelic effects. In this review and meta-analysis, we investigated if repeated SP use associates with a characteristic neuropsychological profile indicating persisting effects on neuropsychological function.Methods: We conducted a systematic review of studies investigating the neuropsychological performance in SP users, searching studies in Medline, Web of Science, embase, ClinicalTrials.gov, and EudraCT. Studies were included if they reported at least one neuropsychological measurement in users of SPs. Studies comparing SP users and non-users that reported mean scores and standard deviations were included in an exploratory meta-analysis.Results: 13 studies (N = 539) published between 1969 and 2020 were included in this systematic review. Overall, we found that only three SPs were specifically investigated: ayahuasca (6 studies, n = 343), LSD (5 studies, n = 135), and peyote (1 study, n = 61). However, heterogeneity of the methodological quality was high across studies, with matching problems representing the most important limitation. Across all SPs, no uniform pattern of neuropsychological impairment was identified. Rather, the individual SPs seemed to be associated with distinct neuropsychological profiles. For instance, one study (n = 42) found LSD users to perform worse in trials A and B of the Trail-Making task, whereas meta-analytic assessment (5 studies, n = 352) of eleven individual neuropsychological measures indicated a better performance of ayahuasca users in the Stroop incongruent task (p = 0.03) and no differences in the others (all p > 0.05).Conclusion: The majority of the included studies were not completely successful in controlling for confounders such as differences in non-psychedelic substance use between SP-users and non-users. Our analysis suggests that LSD, ayahuasca and peyote may have different neuropsychological consequences associated with their use. While LSD users showed reduced executive functioning and peyote users showed no differences across domains, there is some evidence that ayahuasca use is associated with increased executive functioning.

Assessment of prospective memory after stroke utilizing virtual reality

Prospective Memory (PM) is the ability to remember to do something in the future. It is often impaired after stroke and can impact on an individual’s level of independence and daily functioning. PM tasks have been criticized for their lack of ecological validity wherein test results may not be related to actual performance in daily life. With ecological validity in mind, the Virtual Reality Prospective Memory Shopping Task (VRPMST) was designed to assess two types of PM, time- and event-based. This study aimed to examine the ecological and convergent validity of the VRPMST in comparison to an experimental (Lexical Decision PM Task) and clinical measure of PM (Cambridge PM Test). Twelve individuals with stroke and 12 controls were administered three PM measures, three neuropsychological measures, and two user-friendliness questionnaires, one for the experimental PM measure and one for the VRPMST. Individuals with stroke showed impairments in PM compared to controls on all three PM measures, particularly time-based PM. Individuals with stroke were found to monitor time significantly less than controls on both the experimental PM measure and the VRPMST. The VRPMST was found to be sensitive in measuring PM, have better ecological validity when compared to the experimental PM measure, and good convergent validity. The findings of this study have helped to clarify that PM impairment does exist after stroke, possibly due to a problem in strategic monitoring. In addition, we have demonstrated how VR technology can be used to design a measure of cognitive function commonly impaired after stroke.

A-197 Trail Making Test Normative Data from the National Alzheimer’s Coordinating Center: A Comparison of Regression and Non-Regression Methods

Objective Various methods are used to derive normative data for neuropsychological assessment measures. The National Alzheimer’s Coordinating Center (NACC) regression norms (2011) are frequently used within Alzheimer’s Disease Research Centers, yet little research exists comparing these norms to similar regression/non-regression-based norms. Normative data for the widely-used Trail Making Test (TMTA&B) was compared between two regression-based normative data methods (Mitrushina and NACC) and traditional normative methods (i.e., Mayo’s Older Americans Normative Studies [MOANS]). Method TMTA&B data were obtained from 14,873 cognitively normal NACC participants (ages: 50–89; education: M = 15.81, SD = 2.90). T-scores for TMTA&B scores based on Mitrushina, NACC, and MOANS norms were computed. T-scores for regression norms were bounded from 20 to 80. Cohen’s d effect sizes were used to compare differences in scores. Results MOANS and Mitrushina norms produced similar normative scores in the overall sample (TMTA T-score difference = 1.06, d = 0.112, TMTB T-score difference = 1.4, d = 0.144). NACC-derived scores were ~ 0.5 SD below MOANS (TMTA T-score difference = −5.3, d = 0.553, TMTB T-score difference = −4.1, d = 0.427) and Mitrushina scores (TMTA T-score difference = −6.3, d = 0.736, TMTB T-score difference = −5.6, d = 0.615). NACC data produced the lowest average TMTA&B T-scores across all 5-year age band groups. Conclusions Significantly lower TMT scores were obtained using NACC’s regression-based norms compared to both MOANS norms and Mitrushina regression norms. These results underscore that the choice of norms may under and/or overestimate cognitive functioning, and comparison norms must be chosen carefully when making decisions about patients’ cognitive status. Future research applying NACC’s regression-based norms to other commonly used neuropsychological measures is warranted.

A-171 An Evaluation of Remotely Administered Reaction Time Subtests

Objective Due to the COVID-19 pandemic, many services attempted to quickly transition to a remote format. A need to incorporate and evaluate a remote delivery of neuropsychological measures arose. TestMyBrain (TMB) from the Many Brains Project has been utilizing teleneuropsychology in research since 2017. Method Volunteer research participants (N = 176, Mage = 29, Medu = 15 years, 64.7% white, 54.2% female, 83.2% right-handed) were administered TMB Simple Reaction Time and Choice Reaction Time subtest as part of a larger battery via zoom. Participants were able to choose between completing these measures using a keyboard, mouse, or a touch screen. There were no significant differences among demographic variables across the different completion methods. Results An ANCOVA indicated there was not a significant difference in simple reaction time across the different response F(2,168) = 0.482, p = 0.618, ηp2 = 0.006. There was however a significant difference in choice reaction time across the different response methods F(2,168) = 11.486, p < 0.001, ηp2 = 0.120. Conclusion Results suggest different response methods maybe suitable for simpler tasks, yet there lacks consistency in response methods for more complex tasks. This medium effect size may have occurred as a result of the lack of sensitivity for devices to detect taps on different portions of the screen as effectively as various keys on a keyboard. Administrators must be aware of the limitations response methods may introduce into results. Limitation to this analysis include limited samples and not controlling for other factors that may potentially influence reaction time such as internet connection. Future research should focus on creating a standardized method for teleneuropsychology administration.