Thalamic stimulation has emerged as a promising neuromodulation target for treating disorders of consciousness. Impaired consciousness, a debilitating outcome in temporal lobe epilepsy (TLE) remains a central problem for patients whose seizures cannot be treated pharmacologically and cannot be stopped with conventional surgery or responsive hippocampal stimulation. Although prior studies suggest an essential role of the thalamic intralaminar central lateral (CL) nucleus in arousal and sleep, evidence for a direct effect of thalamic intralaminar stimulation on human arousal has been limited. To address these gaps, the START (stimulation of the thalamus for arousal restoral in TLE) clinical trial investigated the efficacy of bilateral CL thalamic stimulation to restore consciousness during human sleep and TLE seizures. Five patients with medically refractory mesial temporal lobe epilepsy were implanted with an investigational neurostimulator, the Medtronic Summit RC+STM. Optimal CL stimulation parameters were obtained through individualized titration in slow wave sleep, evaluated through analysis of patient movement from video recordings and electrophysiology from simultaneously recorded scalp and hippocampal electroencephalography (EEG). We found that bilateral CL stimulation led to robust arousal from sleep characterized by increased body movements and decreased low frequency power (2-15 Hz) in both cortical and hippocampal EEG during 5 minute epochs of stimulation compared to baseline slow wave sleep. We evaluated impaired consciousness during seizures using verbal and non-verbal behavioral tests administered automatically by smartwatch, and found significant behavioral impairment in three of five patients during seizures with hippocampal stimulation. Administering CL stimulation in patients with impaired consciousness during TLE seizures showed significant improvement in behavioral outcomes in two of three patients, with one patient reaching their baseline performance comparable to non-seizure times. Overall, we found that stimulation of the thalamic CL in TLE patients increased arousal during both sleep and seizures. These findings demonstrate the potential of CL as a therapeutic target for mitigating impaired consciousness in TLE and can serve as a foundation for additional studies to test generalizability of CL stimulation effects on other disorders of consciousness. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04897776 ### Funding Statement This work was supported by NIH/NINDS UG3/UH3 NS112826. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Yale University School of Medicine, Mayo Clinic, and Dartmouth-Hitchcock medical center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated in the present study will be made available from the corresponding author upon reasonable request.

Abstract Objective Children with developmental disorders including attention deficit/hyperactivity disorder (ADHD), autism (ASD), and learning disabilities (LD) often exhibit different profiles of everyday executive function (EF) strengths and weakness. This has not been tested in adults. We examined profiles of self- and informant-reported EF in adults with these developmental disorders on the BRIEF2A. Method Ratings on the BRIEF2A scales (Inhibit, Self-Monitor, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, Task-Monitor, Organization of Materials) were within-subjects dependent variables in a profile analysis with diagnostic group (ADHD, ASD, LD) as the between-subjects factor in two MANOVAs (self and informant). 79 adults diagnosed with ADHD, 35 with ASD, and 24 with LD along with 165 demographically-matched healthy adults completed Self-Report forms, and 57 with ADHD, 36 with ASD, 24 with LD, and 132 healthy adults completed Informant Report forms. Results All effects were significant (p.40) for both self- and informant reports. Profiles of scale elevations differed between diagnostic groups for self- (ŋ2 > 0.10) and informant (ŋ2 > 0.13) reports. Adults with ADHD had highest elevations on the Working Memory and Plan/Organize scales, with the LD group showing a similar profile but to a lesser degree. Adults with ASD were characterized by highest elevations on the Shift scale. Conclusions Individuals with common developmental disorders report distinguishable patterns of everyday EF. Those with ADHD report substantial difficulty sustaining working memory, planning, and organizing, while those with ASD report greatest difficulty adapting to change. Individuals with LD show similar profiles to ADHD but to a lesser degree.

The Mini-mental State Examination (MMSE) is a commonly used screening tool for cognitive impairment. Lenient scoring of spatial orientation errors (SOEs) on the MMSE is common and negatively affects its diagnostic utility. We examined the effect of lenient SOE scoring on MMSE classification accuracy in a consecutive case series of 103 older adults (age 60 or above) clinically referred for neuropsychological evaluation. Lenient scoring of SOEs on the MMSE occurred in 53 (51.4%) patients and lowered the sensitivity by 7% to 18%, with variable gains in specificity (0% to 11%) to psychometrically operationalized cognitive impairment. Results are consistent with previous reports that lenient scoring is widespread and attenuates the sensitivity of the MMSE. Given the higher clinical priority of correctly detecting early cognitive decline over specificity, a warning against lenient scoring of SOEs (on the MMSE and other screening tools) during medical education and in clinical practice is warranted.

Abstract Objective Adults with persisting symptoms after mild (mTBI) or moderate-to-severe (msTBI) TBI may show problems with executive functions (EF) on testing and, in some studies, in everyday life. We examined self- and informant-report EF in mTBI and msTBI using the BRIEF2A. Method Participants were 62 patients with persisting symptoms after mTBI (57 self-, 22 informant report) and 31 with msTBI (28 self, 17 informant) seen for neuropsychological evaluation at least one-year post-injury, compared to demographically-matched healthy adults (HA) from the standardization sample. BRIEF2A scales are Inhibit (INHIB), Self-Monitor (SM), Shift (SHFT), Emotional Control (EC), Initiate (INIT), Working Memory (WM), Plan/Organize (P/O), Task-Monitor (TM), and Organization of Materials (OM). Results mTBI self-ratings were higher than HA on all scales, especially WM, SM, INHIB, and SHFT. The majority of patients had elevated scores on 6/9 scales, most notably WM (82.5%) and P/O (64.9%). Informants also scored higher than HA on all scales, most commonly elevating on WM (77.3%), INIT (54.5%), SHFT and P/O (50%). In msTBI, greater self-rated difficulty than HA on all scales except OM, most common elevations being WM and INHIB (46.4%). msTBI Informant report was higher for the same 8/9 scales, especially elevating on WM (82%), P/O (76.5%), EC and SM (70.6%). Conclusions Patients and informants of those with persisting symptoms after mTBI and msTBI commonly endorse executive dysfunction in their everyday lives. Those persons with msTBI self-endorsed fewer problems with EF than seen in mTBI, contrasting with msTBI informants who observe a broader range of challenges than self-report, possibly related to reduced self-awareness.

Background and Hypothesis Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis.Study Design Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed.Study Results Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory.Conclusions In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Steeper delay discounting (DD) reflects greater impulsivity and has been reported in individuals with schizophrenia (SCZ) and those with substance use disorder, who also tend to report high psychological stress. We sought to compare DD in people with SCZ, cannabis use disorder (CUD), and comorbid SCZ-CUD, and determine its relationship to psychological stress in these groups, to inform treatment improvements. Participants were healthy controls (HC; n=31) and individuals with DSM-IV diagnoses of SCZ (n=21), CUD (n=61), and comorbid SCZ-CUD (n=40). After one week or more of verified abstinence from substances, participants completed the Delay Discounting Questionnaire and the Perceived Stress Scale. DD and perceived stress were greater in all three clinical groups compared to HC, though the clinical groups did not differ. Analyses did not detect a consistent relationship between stress and DD in any group, though females showed greater DD with increased stress when all clinical groups were combined. Findings indicate that, overall, perceived stress cannot account for steeper DD in patients with SCZ, CUD, and SCZ-CUD; thus, interventions for stress would not be expected to impact DD.

Abstract Objective The Identi-Fi is a test of visuospatial organization with overall performance represented by the Visual Organization Index (VOI). Though untimed, the Professional Manual indicates administration takes ~10 minutes in the standardization sample. We examined Identi-Fi time of completion (TOC) in a mixed clinical sample and explored whether TOC and VOI are differentially associated with other neuropsychological measures. Method Participants were 240 adults referred for clinical neuropsychological evaluation, 78.3% being aged 60+ (M = 64.50 ± 12.38 years, range = 21–79), male (54.6%), with 14.80 ± 2.89 years of education (range = 7–21). They completed the Identi-Fi and other cognitive tests (WAIS-IV Block Design and Digit Span; Trail Making Test; Boston Naming Test; D-KEFS Color-Word Interference). Correlation and linear regression were used to examine relationships. Results Overall, VOI was low average (M = 85.61 ± 19.00, range = 40–125). TOC was slightly longer (M = 12.92 ± 6.04 minutes, range = 4.07–47.78) than reported in the manual. VOI was correlated with visuoconstruction, confrontation naming, attention, processing speed and executive functions (all p ≤ 0.001), as well as TOC (r = −0.195, p = 0.002) and education (r = 0.136, p = 0.035). TOC was corelated with age (r. = 384, p < 0.001), education (r = 0.141, p = 0.029), processing speed (TMT-A: r = −0.329, p < 0.001; CW1: r = −0.171, p = 0.014), cognitive flexibility (r = −0.230, p = 0.001), and response inhibition (r = −0.269, p < 0.001). TOC was predicted by processing speed (β = −4.986, p = 0.049) even after accounting for age and education. Conclusion TOC may be longer in clinical populations, though this may reflect the older age of this sample. Although time and accuracy on the Identi-Fi correlated with processing speed, accuracy was also associated with other cognitive abilities. Further research into the clinical utility of Identi-Fi TOC is warranted.

BackgroundCognitive symptoms are often reported by those with a history of COVID-19 infection. No comprehensive meta-analysis of neurocognitive outcomes related to COVID-19 exists despite the influx of studies after the COVID-19 pandemic. This study meta-analysed observational research comparing cross-sectional neurocognitive outcomes in adults with COVID-19 (without severe medical/psychiatric comorbidity) to healthy controls (HCs) or norm-referenced data.MethodsData were extracted from 54 studies published between January 2020 and June 2023. Hedges’ g was used to index effect sizes, which were pooled using random-effects modelling. Moderating variables were investigated using meta-regression and subgroup analyses.ResultsOmnibus meta-analysis of 696 effect sizes extracted across 54 studies (COVID-19 n=6676, HC/norm-reference n=12 986; average time since infection=~6 months) yielded a small but significant effect indicating patients with COVID-19 performed slightly worse than HCs on cognitive measures (g=−0.36; 95% CI=−0.45 to –0.28), with high heterogeneity (Q=242.30, p<0.001, τ=0.26). Significant within-domain effects was yielded by cognitive screener (g=−0.55; 95% CI=−0.75 to –0.36), processing speed (g=−0.44; 95% CI=−0.57 to –0.32), global cognition (g=−0.40; 95% CI=−0.71 to –0.09), simple/complex attention (g=−0.38; 95% CI=−0.46 to –0.29), learning/memory (g=−0.34; 95% CI=−0.46 to –0.22), language (g=−0.34; 95% CI=−0.45 to –0.24) and executive function (g=−0.32; 95% CI=−0.43 to –0.21); but not motor (g=−0.40; 95% CI=−0.89 to 0.10), visuospatial/construction (g=−0.09; 95% CI=−0.23 to 0.05) and orientation (g=−0.02; 95% CI=−0.17 to 0.14). COVID-19 samples with elevated depression, anxiety, fatigue and disease severity yielded larger effects.ConclusionMild cognitive deficits are associated with COVID-19 infection, especially as detected by cognitive screeners and processing speed tasks. We failed to observe clinically meaningful cognitive impairments (as measured by standard neuropsychological instruments) in people with COVID-19 without severe medical or psychiatric comorbidities.

Abstract Objective Patients with Parkinson’s disease (PD) commonly experience neuropsychiatric symptoms, often garnered through informant interview, that may be associated with poorer cognitive functioning. Recently, the Neuropsychiatric Inventory Questionnaire (NPI-Q) was found to have three factors with differential association to cognition in patients with PD. We sought to further examine this relationship in those with the condition. Method A sample of 42 patients with PD were seen for neuropsychological evaluation (85.7% male, 97.6% White, mean age 70.88 [SD = 7.16], mean years education 15.74 [SD = 2.99]). A knowledgeable informant completed the NPI-Q. Spearman correlations examined relationships between cognition (Digit Span, BVMT-R, CVLT-3, BNT-2, D-KEFS Color-Word Interference, COWAT, Animal Fluency, Trail Making Test), NPI-Q Total Severity, and severity for three factors (Mood [depression, anxiety, apathy, motor, nighttime behaviors, eating]; Hyperactivity [mania, aggression/agitation, disinhibition, irritability]; Psychotic Symptoms [delusions, hallucinations]). Results NPI-Q total severity was generally low (mean = 3.90, SD = 5.12). Total severity and severity of Mood and Hyperactivity were unrelated to cognition. More severe Psychotic Symptoms were related to worse Digit Span (r = −0.41, p = 0.008), BVMT-R Learning (r = −0.33, p = 0.03) and Delayed Recall (r = −0.34, p = 0.03), and D-KEFS Inhibition Time (r = 0.44, p = 0.006). Conclusions In a modest sample of patients with PD, severity of psychotic symptoms was related to worse auditory attention/working memory, visual learning and memory, and inhibition. No other NPI-Q score was associated with cognitive functioning. Findings support the utility of the NPI-Q in PD and the importance of considering specific neuropsychiatric factors and their implications for cognitive functioning.

The Mini-mental State Examination (MMSE) is a commonly used screening tool for cognitive impairment. Lenient scoring of spatial orientation errors (SOEs) on the MMSE is common and negatively affects its diagnostic utility. We examined the effect of lenient SOE scoring on MMSE classification accuracy in a consecutive case series of 103 older adults (age 60 or above) clinically referred for neuropsychological evaluation. Lenient scoring of SOEs on the MMSE occurred in 53 (51.4%) patients and lowered the sensitivity by 7% to 18%, with variable gains in specificity (0% to 11%) to psychometrically operationalized cognitive impairment. Results are consistent with previous reports that lenient scoring is widespread and attenuates the sensitivity of the MMSE. Given the higher clinical priority of correctly detecting early cognitive decline over specificity, a warning against lenient scoring of SOEs (on the MMSE and other screening tools) during medical education and in clinical practice is warranted.

Abstract Objective People with epilepsy (PWE) commonly have executive functioning (EF) difficulties on objective testing. However, less is known about subjective EF difficulties in everyday life. We examined self- and informant-rated EF in PWE using the Behavior Rating Inventory of Executive Function for Adults-2 (BRIEF-2A). We hypothesized that PWE and their informants would endorse greater EF difficulties relative to healthy participants. Method Participants included 43 PWE who completed comprehensive clinical neuropsychological evaluation at a large Northeastern academic medical center, which included BRIEF-2A Informant and Self Report Forms (Age M = 40.4 ± 17.2 years, 53% female, Education M = 13.0 ± 1.8 years). Twenty-four participants completed self-reports, while 19 had both self and informant reports. The comparison sample included 43 age- and gender-matched healthy controls (HC). We analyzed BRIEF-2A subscales using MANOVAs, where elevated T scores indicated worse EF. Repeated measures ANOVAs compared self and informant ratings. Multi-rater comparisons (90% CIs) and chi-squares analyzed patterns of discrepant ratings. Results Self-reported EF difficulties in PWE were elevated across all scales, compared to HC (p’s0.25), with greatest difference observed for working memory (PWE = 69.7 ± 12.7, HC = 44.5 ± 16.7, ηp2 = 0.61). Similar elevations across all scales were observed for PWE informant reports (p’s0.14). PWE rated greater self-monitoring (p = 0.03, ηp2 > 0.23) and emotional control (p = 0.08, ηp2 > 0.16) difficulties than informants. There was 42.1–68.4% concordance between self and informant reports for PWE, compared to 84–95% in HC. Patterns of self and informant ratings were similar between PWE and HC for initiation, planning/organization, and task-monitoring (p’s > 0.20). Conclusions PWE and their informants report high, yet relatively similar, levels of EF difficulties in daily life.

Abstract Objective Insomnia symptoms are prevalent among individuals with post-acute sequelae of COVID-19 (PASC) and may, to some extent, reflect virally-mediated neurological changes. Mood disturbance and cognitive impairment, including weaknesses in attention and processing speed, are also observed. There is limited research examining the association between insomnia, mood, and cognition in PASC, which we aimed to elucidate. Methods Patients were 69 consecutive adults (M-age = 46.5 ± 11.6 years; M-education = 15.03 ± 2.66 years; M-TOPF-SS = 104.6 ± =12.58; 69.6% female; 95.7% White) seen for neuropsychological evaluation in a PASC clinic. They completed the Conners Continuous Performance (CPT-3), Symbol Digit Modalities Test, Insomnia Severity Index, Beck Anxiety Inventory, and Beck Depression Inventory as part of a larger battery of measures. Cognitive performance was compared between patients with elevated versus non-elevated insomnia symptoms. Models were also adjusted for mood symptoms via MANCOVA. Results Group demographics were unrelated to mood, sleep, and cognition. MANOVA yielded a significant main effect (Wilks’ Λ = 0.656, F(7,61) = 4.57, p < 0.001), with more CPT-3 commission errors (p < 0.001, ηp2 = 0.247), faster reaction times (p = 0.012, ηp2 = 0.090), and more variable response speed consistency (p = 0.027, ηp2 = 0.071) in those with insomnia. Commission errors and reaction times remained significant after covarying for mood. The insomnia group displayed slower responses across block changes (p = 0.038, ηp2 = 0.065) when mood was controlled. Conclusion Patients with PASC with elevated insomnia symptoms showed greater inaccuracy and more variable reaction times on a sustained attention task, in a pattern suggesting impulsivity, even after controlling for mood symptoms. Findings suggest that improving sleep may ameliorate attention deficits in persons with PASC.

Abstract Objective The CVLT-3 is a measure of verbal learning and memory used extensively in clinical and research settings that contains an embedded performance validity indicator, a forced choice recognition trial (CVLT-3-FCR). The CVLT-2-FCR was modified for the CVLT-3-FCR, replacing abstract with concrete distractor words. To date, no one has reported independent data on failure rates in clinical populations on the CVLT-3-FCR. Method Participants were 373 patients referred for clinical neuropsychological evaluation who completed the CVLT-3 (Standard form) as part of their evaluation. Mean age was 61.20 (SD = 14.30, range = 20–86), mean education was 15.00 years (SD = 2.87, range = 6–21), 53.1% were male, and 97.6% White. Failure was defined as CVLT-3-FCR score ≤ 14. Results 85.5% of our mixed clinical sample had CVLT-3-FCR score of 16/16, and 7.5% had 15/16. Only 7% (N = 26) scored ≤14, most common primary diagnoses being mild neurocognitive disorder (N = 9) and psychiatric (N = 7), while only four had dementia of any etiology. Those who failed tended to be a little older [pass = 60.82 years (SD = 14.44), fail = 66.38 years (SD = 11.28); p = 0.055) and scored lower for CVLT-3 Total Trials 1–5, short- and long-delay free recall, recognition hits, false positives, and discriminability (all p < 0.001). Conclusions Findings indicate CVLT-3-FCR ≤ 14 is extremely rare in a large mixed clinical sample of adults and older adults, even in subsamples for whom lower scores on PVTs have been suggested (e.g., dementia). While passing the CVLT-3-FCR does not in itself confirm adequate test engagement, failure should raise concern and the need for additional PVTs in one’s assessment.