Modeling the effects of treatment resistance and anticholinergic burden on cognitive function domains in patients with schizophrenia.

The contribution of anticholinergic burden to cognitive function in patients with treatment resistant schizophrenia (TRS) is uncertain. This case-control study aims to comprehensively examine the association between treatment resistance and cognitive functions and the contribution of anticholinergic burden in patients with schizophrenia. Anticholinergic burden of all patients was calculated using the Anticholinergic Cognitive Burden scale. Exploratory Factor Analysis of 11 cognitive assessments identified four cognitive domains: verbal memory, attention and general cognitive functions, visual memory and processing speed, and executive function. Two structural equation models (SEM) examined the relationship of TRS and these cognitive functions with, and without considering anticholinergic burden. A total of 288 participants were included (TRS N=111, non-TRS N=177). Patients with TRS performed poorer than the non-TRS group only in the executive function domain. Anticholinergic burden contributed significantly to the attention and general cognitive functions, visual memory and processing speed, and executive function. The impact of TRS on executive function was no longer significant after adding anticholinergic burden to the SEM. Results suggested that anticholinergic burden contributes to a wide range of cognitive function impairment in patients with schizophrenia and is likely to be part of the apparent differences of cognitive function between TRS and non-TRS.

Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years.

BACKGROUND AND OBJECTIVES: Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures. RESULTS: The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD. DISCUSSION: Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose. TRIAL REGISTRATION INFORMATION: The study is registered at ClinicalTrials.gov as NCT01730170.

Association between Flavonoid Intake and Cognitive Executive Function among African American and White Adults in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) Study.

Healthy dietary patterns rich in flavonoids may benefit cognitive performance over time. Among socioeconomically disadvantaged groups, the association between flavonoid intake and measures of cognition is unclear. This study sought to identify associations between flavonoid intake and cognitive performance among Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study participants (n = 1947) across three study visits. Flavonoid intakes were assessed via two 24-h dietary recalls. Cognitive performance was assessed via the Trail Making Test (TMT)-A and TMT-B, which provide measures of attention and executive function, respectively. Mixed effects linear regression was used to model TMT scores over three study visits against visit 1 (v1) flavonoid intake, time (years from v1), and the interaction between v1 flavonoid intake and time, capturing both the cross-sectional association between flavonoid intake and time at v1 as well as the longitudinal association between v1 flavonoid intake and the change in TMT scores over time. Prior to adjustment, inverse cross-sectional associations at v1 were observed between (1) anthocyanidin intake and TMT-A scores for the overall sample and (2) total flavonoid, anthocyanidin, flavan-3-ol, flavone, and flavonol intake and TMT-B scores for the overall sample and among White adults. Only the association between anthocyanidin intake and TMT-B at v1 among White adults persisted after adjustment (for demographic characteristics such as age). One possible explanation for the few significant associations is universally low flavonoid intakes resulting from the consumption of an unhealthy dietary pattern.

Investigating the relationship between prenatal alcohol exposure and children's behavioural and emotional development: analysis of the Growing Up in New Zealand study.

AIMS: To examine the relationship between prenatal alcohol exposure (PAE) and children's behavioural and emotional development in a large generalizable sample of women and their children in Aotearoa New Zealand. METHODS: Using data from the Growing Up in New Zealand longitudinal cohort, we investigated the relationship between maternal PAE and behavioural and emotional development in 8-year-old children. We explored secondary outcomes including measures of language, executive function, academic achievement, and adaptive behaviour. RESULTS: We found no significant differences in the measures of behavioural and emotional development in children 8 years old based on alcohol consumption. No significant differences in behavioural and emotional development were found based on amount of PAE and when PAE occurred, despite controlling for a range of potential confounding factors, such as neighbourhood deprivation and maternal health measures. PAE was associated with significantly higher scores for parent-rated oral language indicating better oral language. In Maori mothers, PAE was significantly associated with an increased risk of higher scores on two of the Strengths and Difficulties Questionnaire subscales. CONCLUSIONS: We did not find an association between PAE and behavioural and emotional development in children aged 8 years. PAE and behavioural and emotional development are difficult to measure accurately, and the moderating variables between them are complex. Future analyses will require larger cohorts of mothers and their children using precise measures of PAE and outcomes to enable more precise estimates of association.

Executive function deficits in patients with the first episode of late-life depression before and after SSRI treatment: A pilot fMRI study.

BACKGROUND: Executive function deficits (EFD) in late-life depression (LLD) has been reported to be associated with antidepressant treatment resistance, increased disability, and poor quality of life. However, the underlying neutral mechanisms of EFD in patients with the first episode of LLD remains unclear. METHODS: A total of 27 patients with first-episode, drug-naive LLD and 27 non-depressed controls (NC) were recruited for the present research. Participants underwent the Trail Making Test, the 17-item Hamilton depression rating scale (HAMD-17) test, and task-state functional magnetic resonance imaging scans under the neutral Stroop task. LLD patients' executive functions, depressive symptoms, and brain activity were examined again after 6 months of antidepressant treatment. RESULTS: Of the 27 LLD patients, 16 cases completed 6-month follow-ups. Patients in the LLD baseline group spent more time on the Trail Making Test A test than those in the NC group (p < 0.05). In the presence of an incongruency between the word color and meaning, the accuracy rate of the neutral Stroop task in the LLD baseline group was lower, and the reaction time was greater than that in the NC group, with statistically significant difference (p < 0.05). The HAMD-17 score in the LLD follow-up group was significantly lower than that in the LLD baseline group (p < 0.05). More activated brain regions were present in the LLD baseline group than in the NC group when performing the neutral Stroop task. Compared with the LLD baseline group, abnormal activation of relevant brains in the cingulate-prefrontal-parietal network of LLD patients still existed in the LLD follow-up group. CONCLUSIONS: LLD patients engaged more brain areas than the NC group while performing the neutral Stroop task. Abnormal activation of the cingulate-prefrontal-parietal network could be a contributing factor to EFD in LLD. TRIAL REGISTRATION: ChiCTR, ChiCTR2100042370 (Date of registration: 21/01/2021). LIMITS: We didn't enroll enough first-episode, LLD patients, the robustness of the findings need to be confirmed by large sample clinical trials.

Wild Blueberry Extract Intervention in Healthy Older Adults: A Multi-Study, Randomised, Controlled Investigation of Acute Cognitive and Cardiovascular Effects.

BACKGROUND: Circadian and homeostatic declines in cognitive performance are observed during the day, most commonly at 14:00. Additionally, postprandial reductions in cognitive ability have been widely demonstrated 1 h after lunch consumption, affecting domains of executive functioning (EF), episodic memory (EM), and attention. Existing evidence shows that anthocyanin-rich foods such as berries may improve or attenuate the decline in EF and EM in ageing adults. Further research is required to assess whether extracts such as wild blueberry extract (WBE) may be beneficial for cognitive function across an acute timeframe, including known periods of reduced functioning. OBJECTIVES: (1) Study 1: ROAB: To investigate the efficacy of WBE in maintaining EF and EM throughout the day alongside measures of cardiovascular outcomes in healthy older adults. A range of WBE doses were utilised to identify the optimal dose at which cognitive and cardiovascular effects occur. (2) Study 2: BEAT: To replicate alleviation of cognitive decline during a predicted post-lunch dip whilst also improving cardiovascular outcomes following acute WBE 222 mg supplementation. METHODS: Both studies employed a randomised, double-blind, cross-over, placebo-controlled design to explore the effects of WBE intervention versus placebo on several outcomes, including EM, EF, blood pressure, and heart rate in a healthy older adult population (aged 68-75). In ROAB, 28 participants received a single dose of WBE 111 mg, 222 mg, 444 mg, or 888 mg or placebo over a 5-week period, each separated by a 1-week washout. Outcomes were measured at 0 h, 2 h, 4 h, and 6 h post intervention, with intervention occurring immediately after baseline (0 h). In BEAT, 45 participants received WBE 222 mg and placebo (1-week washout). Outcomes were measured at 0 h and 6 h (14:00) when a post-lunch dip was anticipated. This was further enhanced by consumption of lunch 1 h prior to cognitive testing. The WBE 222 mg intervention aligned with known peaks in plasma blueberry polyphenol metabolites at 2 h post dosing, which would coincide with a predicted drop in post-lunch performance. RESULTS: ROAB: A significant dip in executive function was apparent at the 4 h timepoint for placebo only, indicating attenuation for WBE doses. Strikingly, WBE 222 mg produced acute reductions in both systolic and diastolic blood pressure compared with placebo. BEAT: EF reaction time was found to be significantly faster for WBE 222 compared to placebo at the predicted post-lunch dip (14:00), with no other notable benefits on a range of cognitive and cardiovascular outcomes. CONCLUSION: These two studies indicate that WBE may have cardiovascular benefits and attenuate the natural cognitive decline observed over the course of the day, particularly when a decline is associated with a circadian rhythm-driven postprandial dip. However, it is important to acknowledge that effects were subtle, and benefits were only observed on a small number of outcomes. Further research is required to explore the utility of WBE in populations already experiencing mild cognitive impairments.

The association of chemotherapy-induced peripheral neuropathy with reduced executive function in chemotherapy-treated cancer survivors: A cross-sectional study.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN. MATERIALS AND METHODS: This cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function. RESULTS: Cancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03). DISCUSSION: In this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors.

Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

BACKGROUND: PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications. OBJECTIVE: To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD). METHODS: Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test (n = 172) in the off-medication and "best on" medication states. ANCOVA was used to test for differences between off-medication and on-medication scores corrected for age and years of education. RESULTS: After administration of symptomatic medications, scores worsened on the SDMT (F = 11.70, P < 0.001, d = -0.13), improved on the Stroop color (F = 26.89, P < 0.001, d = 0.184), word (F = 6.25, P = 0.013, d = 0.09), and color-word (F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio-based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color-word scores; however, longer disease duration and higher levodopa-equivalents correlated with higher Stroop difference-based interference scores. CONCLUSIONS: Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.

The neural oscillations serving task switching are altered in cannabis users.

BACKGROUND: Regular cannabis is known to impact higher-order cognitive processes such as attention, but far less is known regarding cognitive flexibility, a component of executive function. Moreover, whether such changes are related to aberrations in the neural oscillatory dynamics serving flexibility remains poorly understood. AIMS: Quantify the neural oscillatory dynamics serving cognitive flexibility by having participants complete a task-switching paradigm during magnetoencephalography (MEG). Probe whole-brain maps to identify alterations in chronic cannabis users relative to nonusers and determine how these alterations relate to the degree of cannabis use involvement. METHODS: In all, 25 chronic cannabis users and 30 demographically matched nonuser controls completed neuropsychological testing, an interview regarding their substance use, a urinalysis, and a task switch paradigm during MEG. Time-frequency windows of interest were identified using a data-driven statistical approach and these were imaged using a beamformer. Whole-brain neural switch cost maps were computed by subtracting the oscillatory maps of the no-switch condition from the switch condition per participant. These were examined for group differences. RESULTS: Cannabis users had weaker theta switch cost responses in the dorsolateral and dorsomedial prefrontal cortices, while nonusers showed the typical pattern of greater recruitment during switch relative to no switch trials. In addition, theta activity in the dorsomedial prefrontal cortex was significantly correlated with cannabis use involvement. CONCLUSIONS: Cannabis users exhibited altered theta switch cost activity compared to nonusers in prefrontal cortical regions, which are critical for cognitive flexibility. This activity scaled with cannabis use involvement, indicating a link between cannabis use and aberrant oscillatory activity underlying cognitive flexibility.

A biphasic response to blueberry supplementation on depressive symptoms in emerging adults: a double-blind randomized controlled trial.

PURPOSE: The aim of the present study was to examine the acute and chronic effects of wild blueberry supplementation on mood, executive function, and serum biomarkers of neuroplasticity, inflammation, and oxidative stress in emerging adults with moderate-to-severe depressive symptoms. METHODS: In this double-blind trial, 60 emerging adults (Mage = 20.0 years, 32% male) with self-reported depressive symptoms were randomly assigned to receive a single blueberry drink (acute phase), followed by 6 weeks of daily blueberry supplementation (chronic phase), or a matched placebo drink. The primary outcome was Beck Depression Inventory-II (BDI-II) scores at 6-week follow-up. Further measures included momentary affect (PANAS-X) and accuracy on an executive function task. The data were analyzed using ANCOVAs adjusted for baseline values, sex, and habitual fruit and vegetable intake. Estimated marginal means were calculated to compare the treatment arms. RESULTS: The blueberry drink significantly improved positive affect (p = 0.026) and executive function (p = 0.025) at 2 h post-ingestion, with change scores being positively correlated in the blueberry group (r = 0.424, p = 0.017). However, after six weeks of supplementation the reduction in BDI-II scores was greater in the placebo group by 5.8 points (95% CI: 0.8-10.7, p = 0.023). Generalized anxiety and anhedonia also decreased significantly more in the placebo group. No significant differences were found for any of the biomarkers. CONCLUSIONS: Six weeks of wild blueberry supplementation were inferior to placebo in reducing depressive symptoms. Nevertheless, the correlated improvements in positive affect and executive function after a single dose of blueberries point to a beneficial, albeit transient, psychological effect. These contrasting results suggest a biphasic, hormetic-like response that warrants further investigation. TRIAL REGISTRATION: NCT04647019, dated 30 November, 2020.

Doxepin is more effective than zolpidem in improving executive function in patients with insomnia disorder.

BACKGROUND : Insomnia disorder is associated with an impairment in cognitive performance. Doxepin and zolpidem have been found to be effective in improving sleep. In this study, we aimed to compare the effects of doxepin and zolpidem on sleep structure and executive function in patients with insomnia disorder. METHODS: Patients with primary insomnia were randomly assigned to receive doxepin 6 mg/day orally or zolpidem 5-10 mg/day orally. Polysomnography (PSG) and the Pittsburgh Sleep Quality Index (PSQI) were used at baseline and after the 8-week treatment to compare clinical efficacy in the two groups. Safety was assessed using the Treatment Emergent Symptom Scale (TESS). Executive function was evaluated using the Wisconsin sorting card test (WSCT). RESULTS: Of 120 patients enrolled in the study, 60 participants were assigned to each group. A total of 109 participants (53 in the doxepin group and 56 in the zolpidem group) completed the study. After treatment, the wake after sleep onset (WASO) and total sleep time (TST) values in the doxepin group were 80.3 ± 21.4 min and 378.9 ± 21.9 min, respectively, which were significantly better than those in the zolpidem group (132.9 ± 26.5 min and 333.2 ± 24.2 min, respectively; (P < 0.05)). The sleep onset latency (SOL) value in the zolpidem group (20.3 ± 4.7 min) was significantly better than that in the doxepin group (28.2 ± 5.6 min; P < 0.05). The sleep efficiency (SE) in the doxepin group was 77.8 ± 4.2%, which was significantly better than that in the zolpidem group (68.6 ± 5.0%; P < 0.05). The PSQI score of the doxepin group was 6.1 ± 1.1, which was significantly lower than that in the zolpidem group (7.9 ± 1.9; P < 0.05). The treatment adverse events in the doxepin group was 23.3%, which was significantly higher than that in the zolpidem group (13.3%; P < 0.05). The WSCT showed a significant improvement in persistent errors (PE), random errors (RE), and categories in the two groups after 8-week treatment, and the improvement in RE and the categories was more obvious in the doxepin group (P < 0.05). CONCLUSIONS: Both doxepin and zolpidem were found to be effective in improving sleep quality, but the effects exhibited different patterns. Doxepin improved executive function more effectively than zolpidem in patients with insomnia disorder.

Intervenciones cognitivas en niños y niñas: aportes desde el marco de la diversidad del desarrollo / Cognitive training interventions in children: contributions from a developmental diversity view

En las últimas décadas se ha generado un creciente interés en el diseño de intervenciones cognitivas orientadas a promover el desarrollo de procesos ejecutivos y autorregulatorios en niños y niñas de diversas edades. Sin embargo, la evidencia muestra que no todas las intervenciones alcanzan sus objetivos. En el presente escrito se propone, por un lado, repensar los discursos que fundamentan el diseño e implementación de intervenciones cognitivas en pos de evitar nociones normativistas del desarrollo. Por otro lado, se buscará abordar las limitaciones de las intervenciones cogniti-vas desde una perspectiva relacional que comprenda al desarrollo de los/as niños/as en términos de su complejidad y diversidad. Por último, se enunciarán algunos abordajes y direcciones futuras que podrían beneficiar al avance del área.

In the last decades, there has been a flourishing interest in the design of cognitive training interventions aimed to promote executive and self-regulatory development in children. However, evidence suggests that the aims of the studies are not always achieved. The present work proposes to analyze the discourses that ground the design and implementation of cognitive training interventions in order to avoid normative views of cognitive development. In addition, this work proposes to approach some of the problems of the area from a relational view, understanding development in a complex and diverse way. Finally, some possible future approaches and directions will be addressed.

Evidence on the acute and residual neurocognitive effects of cannabis use in adolescents and adults: a systematic meta-review of meta-analyses.

BACKGROUND: Cannabis is among the most consumed psychoactive substances world-wide. Considering changing policy trends regarding the substance, it is crucial to understand more clearly its potential acute and residual adverse effects from a public health viewpoint. Cognitive function is one of the targeted areas with conflicting findings. This meta-review measured the magnitude of acute and residual effects of cannabis on cognition in adolescents and adults provided by meta-analyses and evaluated quality of evidence. METHODS: A systematic search was performed in PubMed, PsycINFO, Web of Science and Google Scholar. Meta-analyses were included if they quantitatively examined the performances of users from the general population on cognitive tasks. RESULTS: The search retrieved 10 eligible meta-analyses (71 effects sizes, n = 43 761) with evidence ranging from low to moderate quality, which were categorized into domains of cognitive functions: executive functions (k = 7), learning and memory (k = 5), attention (k = 4), processing speed (k = 5), perceptual motor function (k = 2) and language (k = 2). Verbal learning and memory displayed the most robust evidence and were most impaired by acute cannabis intoxication that persisted after intoxication passed. Small-to-moderate acute and residual adverse effects were reported for executive functioning. Cannabis use led to small deficits in inhibitory processes and flexibility, whereas small-to-moderate deficits were reported for working memory and decision-making. Evidence regarding processing speed and attention has shown that cannabis administration induced small-to-moderate adverse effects and residual neurocognitive deficits were observed in heavy cannabis-using youths. Results showed no significant difference between cannabis users and non-users on language, and small-to-moderate effects for simple motor skills. CONCLUSION: Meta-analytical data on the acute effects of cannabis use on neurocognitive function have shown that cannabis intoxication leads to small to moderate deficits in several cognitive domains. These acute impairments accord with documented residual effects, suggesting that the detrimental effects of cannabis persist beyond acute intake.

Posterior fronto-medial atrophy reflects decreased loss aversion, but not executive impairment, in alcohol use disorder.

Decreased punishment sensitivity in alcohol use disorder (AUD) might reflect a reduction in the typical human tendency to overweigh negative choice outcomes compared with equivalent positive ones, that is, 'loss aversion.' While this hypothesis is supported by previous reports of reduced loss aversion in AUD, it is still unknown whether such decreased sensitivity to prospective losses represents a specific facet of altered decision-making or a secondary effect of executive/working-memory impairments. We addressed this issue by assessing whether lower loss aversion in 22 AUD patients compared with 19 healthy controls is explained by their differential executive or working-memory performance and by investigating its neural basis in terms of grey matter density and cortical thickness via voxel- and surface-based morphometry, respectively. A significant decrease of loss aversion in patients, unrelated to their impaired executive/working-memory performance, reflected the reduction of posterior fronto-medial grey matter density and right frontopolar cortical thickness. Rather than their executive deficits, patients' reduced loss aversion reflects the structural damage of the posterior fronto-medial cortex previously associated with solving conflicts at the response level, where earlier functional magnetic resonance imaging (fMRI) studies have shown a 'neural loss aversion' pattern of steeper deactivation for losses than activation for gains, and of the frontopolar cortex in charge of managing competing goals. These findings highlight possible directions for addressing AUD patients' high relapse rate, for example, cognitive-behavioural rehabilitative interventions enhancing the awareness of the adverse outcomes of addiction or neurostimulation protocols targeting the regions processing their salience.

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals.

BACKGROUND: Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans. AIM: Evaluate changes in resting-state functional connectivity (RSFC) at 1 week and 3 months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures. METHODS: Participants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state functional magnetic resonance imaging (fMRI) scans at baseline, 1-week and 3-month post-administration and [11C]Cimbi-36 PET scans at baseline and 1 week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding. RESULTS: Psilocybin was well tolerated and produced positive changes in well-being. At 1 week only, executive control network (ECN) RSFC was significantly decreased (Cohen's d = -1.73, pFWE = 0.010). We observed no other significant changes in RSFC at 1 week or 3 months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at 1 week predicted increased mindfulness at 3 months (r = -0.65). CONCLUSIONS: These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic 'afterglow' period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at 3 months, when personality changes are observed, remain to be identified.

Brain functional connectivity in patients with hyperthyroidism after anti-thyroid treatment.

Thyroid disease is known to affect brain metabolism and cognitive function, although the recovery of thyroid-induced brain functional changes after treatment remains unclear. We aimed to investigate the alteration in brain functional connectivity and its correlation with neuropsychological variables in hyperthyroid patients before and after anti-thyroid treatment using a resting-state functional magnetic resonance imaging (rsfMRI) technique. This is a follow-up rsfMRI study of previous work that showed impaired brain functional connectivity in hyperthyroid patients compared to healthy controls. We included rsfMRI and neuropsychological data from 21 hyperthyroid patients out of an original cohort of 28 patients, before and after anti-thyroid treatment for 30 weeks. Functional connectivity analysis and neuropsychological scores were compared using paired t tests in patients at baseline and at follow-up. Patients showed an improvement in some of the memory (p < .05) and executive, visuospatial and motor (p < .001) functions after treatment, and also showed increased functional connectivity in the regions of the right fronto-parietal network, left fronto-parietal network, and default mode network (DMN) (p < .05). At follow-up, the functional connectivity of the right fronto-parietal network showed a significantly positive correlation with the recognition of objects memory score. The overall findings suggest that anti-thyroid treatment with carbimazole improves the functional connectivity within some of the resting state networks in the hyperthyroid patients, whereas the remaining networks still show impairment.

Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial.

Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg. OBJECTIVE: To determine the acute and short-term (7-day) effects of varying doses of PXN on cognitive function and side effects. METHODS: In a double blind, placebo-controlled, crossover, and counterbalanced manner, 12 healthy male and female volunteers (22.7 ± 4 years, 165 ± 7 cm, 66.5 ± 11 kg, 24.4 ± 3 kg/m2) ingested 200 mg of a placebo (PLA), 50 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.) + 150 mg PLA, 100 mg PXN + 100 mg PLA, or 200 mg of PXN. With each treatment experiment, participants completed side effect questionnaires and donated a fasting blood sample. Participants then performed a series of tests assessing cognition, executive function, memory, and reaction time. Participants then ingested one capsule of PLA or PXN treatments. Participants then completed side effects and cognitive function tests after 1, 2, 3, 4, 5, and 6 h of treatment ingestion. Participants continued ingesting one dose of the assigned treatment daily for 6-days and returned to the lab on day 7 to donate a fasting blood sample, assess side effects, and perform cognitive function tests. Participants repeated the experiment while ingesting remaining treatments in a counterbalanced manner after at least a 7-day washout period until all treatments were assessed. RESULTS: The Sternberg Task Test (STT) 4-Letter Length Present Reaction Time tended to differ among groups (p = 0.06). Assessment of mean changes from baseline with 95% CI's revealed several significant differences among treatments in Berg-Wisconsin Card Sorting Correct Responses, Preservative Errors (PEBL), and Preservative Errors (PAR Rules). There was also evidence of significant differences among treatments in the Go/No-Go Task tests in Mean Accuracy as well as several time points of increasing complexity among STT variables. Finally, there was evidence from Psychomotor Vigilance Task Test assessment that response time improved over the series of 20 trials assessed as well as during the 6-h experiment in the PXN treatment. Acute and short-term benefits compared to PLA were seen with each dose studied but more consistent effects appeared to be at 100 mg and 200 mg doses. No significant differences were observed among treatments in clinical chemistry panels or the frequency or severity of reported side effects. Results provide evidence that acute ingestion of 100 mg and 200 mg of PXN may affect some measures of cognition, memory, reasoning, and response time as well as help sustain attention. Additionally, that acute and daily ingestion of PXN for 7 days is not associated with any clinically significant side effects. CONCLUSIONS: PXN may serve as an effective nootropic agent at doses as low as 50 mg.

Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress.

Prenatal adversity or stress can have long-term consequences on developmental trajectories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional implications. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. As these insults can have sex-specific effects on biological outcomes, we analyzed epigenome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may reflect the sex-specific effects of prenatal insults on long-term functional and health outcomes and have important implications for understanding possible mechanisms underlying fetal alcohol spectrum disorder and other neurodevelopmental disorders.

Effects of Inositol-Enhanced Bonded Arginine Silicate Ingestion on Cognitive and Executive Function in Gamers.

Inositol stabilized arginine silicate (ASI) ingestion has been reported to increase nitric oxide levels while inositol (I) has been reported to enhance neurotransmission. The current study examined whether acute ASI + I (Inositol-enhanced bonded arginine silicate) ingestion affects cognitive function in e-sport gamers. In a double blind, randomized, placebo controlled, and crossover trial, 26 healthy male (n = 18) and female (n = 8) experienced gamers (23 ± 5 years, 171 ± 11 cm, 71.1 ± 14 kg, 20.7 ± 3.5 kg/m2) were randomly assigned to consume 1600 mg of ASI + I (nooLVL®, Nutrition 21) or 1600 mg of a maltodextrin placebo (PLA). Prior to testing, participants recorded their diet, refrained from consuming atypical amounts of stimulants and foods high in arginine and nitrates, and fasted for 8 h. During testing sessions, participants completed stimulant sensitivity questionnaires and performed cognitive function tests (i.e., Berg-Wisconsin Card Sorting task test, Go/No-Go test, Sternberg Task Test, Psychomotor Vigilance Task Test, Cambridge Brain Sciences Reasoning and Concentration test) and a light reaction test. Participants then ingested treatments in a randomized manner. Fifteen minutes following ingestion, participants repeated tests (Pre-Game). Participants then played their favorite video game for 1-h and repeated the battery of tests (Post-Game). Participants observed a 7-14-day washout period and then replicated the study with the alternative treatment. Data were analyzed by General Linear Model (GLM) univariate analyses with repeated measures using weight as a covariate, paired t-tests (not adjusted to weight), and mean changes from baseline with 95% Confidence Intervals (CI). Pairwise comparison revealed that there was a significant improvement in Sternberg Mean Present Reaction Time (ASI + I vs. PLA; p < 0.05). In Post-Game assessments, 4-letter Absent Reaction Time (p < 0.05), 6-letter Present Reaction Time (p < 0.01), 6-letter Absent Reaction Time (p < 0.01), Mean Present Reaction Time (p < 0.02), and Mean Absent Reaction Time (p < 0.03) were improved with ASI + I vs. PLA. There was a non-significant trend in Pre-Game Sternberg 4-letter Present Reaction time in ASI + I vs. PLA (p < 0.07). ASI + I ingestion better maintained changes in Go/No-Go Mean Accuracy and Reaction Time, Psychomotor Vigilance Task Reaction Time, and Cambridge Post-Game Visio-spatial Processing and Planning. Results provide evidence that ASI + I ingestion prior to playing video games may enhance some measures of short-term and working memory, reaction time, reasoning, and concentration in experienced gamers.