Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models.

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine. Appeared originally in Front Neurosci 2020; 14:43.

Lavender Essential Oil Inhalation Improves Attentional Shifting and Accuracy: Evidence from Dynamic Changes of Cognitive Flexibility and Power Spectral Density of Electroencephalogram Signals.

Background: Cognitive flexibility, a vital component of executive function, entails the utilization of extended brain networks. Olfactory stimulation has been shown to influence various brain functions, particularly cognitive performance. Method: To investigate aroma inhalation's effects on brain activity dynamics associated with cognitive flexibility, 20 healthy adults were recruited to complete a set-shifting task during two experimental conditions: no aroma stimuli vs. lavender essential oil inhalation. Using Thomson's multitaper approach, the normalized power spectral density (NPSD) was assessed for five frequency bands. Results: Findings confirm that aroma inhalation significantly affects behavioral indices (i.e., reaction time (RT) and response accuracy) and electroencephalogram (EEG) signatures, especially in the frontal lobe. Participants showed a tremendous increase in theta and alpha NPSD, associated with relaxation, along with beta NPSD, associated with clear and fast thinking after inhaling the aroma. NPSD of the delta band, an indicator of the unconscious mind, significantly decreased when stimulated with lavender essential oil. Further, participants exhibited shorter RT and more accurate responses following aroma inhalation. Conclusion: Our findings revealed significant changes in oscillatory power and behavioral performance after aroma inhalation, providing neural evidence that olfactory stimulation with lavender essential oil may facilitate cognitive flexibility.

The effect of transcranial alternating current stimulation on cognitive flexibility and attention of children with intellectual disability: a case report.

BACKGROUND: Intellectual disability is a neurodevelopmental disorder characterized by significant impairments in intellectual functioning and adaptive behavior. Cognitive flexibility and attention are crucial cognitive domains often affected in children with intellectual disability. This case report explores the novel use of transcranial alternating current stimulation, a noninvasive brain stimulation technique, to enhance these cognitive functions. The study's novelty lies in its focus on alpha-wave frequency transcranial alternating current stimulation targeting specific Brodmann areas and its potential sustained impact on cognitive flexibility and attention in the pediatric population with intellectual disability. CASE PRESENTATION: The case study involved two elementary school students, both 7 years old with mild intellectual disability, one male and one female, both with Turkic ethnicity, from Shahid Fahmideh School for Exceptional Children in Khosrowshah, Iran. Both participants underwent a 2-week intervention with daily 20-minute sessions of transcranial alternating current stimulation at an alpha-wave frequency (10 Hz), targeting Brodmann areas F3 and P3. Cognitive flexibility and attention were assessed using the Wisconsin Card Sorting Test and the Clock Test, administered at four time points: pre-intervention, week 1, week 2, and 1 month post-intervention. Statistical analysis showed significant improvements in both Wisconsin Card Sorting Test and Clock Test scores for both participants compared with baseline, with sustained enhancement over time. CONCLUSION: The findings from this case report indicate that transcranial alternating current stimulation may be a promising intervention for improving cognitive flexibility and attention in children with intellectual disability. The significant and sustained improvements observed suggest that transcranial alternating current stimulation could have a meaningful clinical impact on the cognitive development of this population. However, further research is needed to confirm the efficacy of transcranial alternating current stimulation and to explore its broader applicability and long-term effects in larger, more diverse populations.

Relationships between cognitive flexibility performance and adaptive behavior outcomes in survivors of pediatric brain tumor.

Objective: Survivors of pediatric brain tumors are at increased risk of executive function (EF) and adaptive behavior difficulties. While previous research suggests that executive dysfunction impacts suboptimal adaptive outcomes, the specific elements of EF influencing this relationship remain unexplored. This study examines the relationship between cognitive flexibility and adaptive behavior in survivors compared to healthy controls. Methods: 86 survivors (Mage(SD)=23.41(4.24), 44 females) and 86 controls (Mage(SD)=23.09(4.50), 44 females) completed the Delis-Kaplan Executive Function System Trail Making Test (TMT) and Verbal Fluency Test (VFT). The Letter-Number Sequencing (LNS) and Category Switching (CS) conditions were isolated as measures of cognitive flexibility. Informants provided responses to obtain adaptive behavior ratings using the Scales of Independent Behavior-Revised (SIB-R). Linear regressions explored relationships between cognitive flexibility and SIB-R scores in survivors compared to controls. Results: For both TMT and VFT, the relationship between cognitive flexibility and adaptive behavior was significantly different between survivors and controls for SIB-R scores in Social Communication, Community Living, and Personal Living Skills (p<.0125). Survivors' better LNS performance predicted greater SIB-R scores across the same 3 domains (all p= <.001, r2semipartial=.08). Similarly, survivors' better CS performance predicted greater SIB-R scores across the same 3 domains (p = 0.002 to .02, r2semipartial =.03 to .04). No significant relationships were found in controls (all p >.05). After adjusting for working memory and inhibitory control, most relationships remained significant in survivors (p= <.001 to .046, r2semipartial=.02 to .08). Conclusion: These findings reveal a robust, positive relationship between cognitive flexibility performance and adaptive behaviors specific to survivors.

[Coin tossing: Development of a computerized test to assess cognitive flexibility in older adults]. / Lanzando la moneda. Desarrollo de una prueba informática para evaluar la flexibilidad cognitiva en las personas mayores.

BACKGROUND: The aging population is increasing. Aging has been associated with some degree of cognitive decline, especially in functions such as cognitive flexibility. The voluntary task-switching paradigm is a novel model for studying this function. The aim of this work was to design and test a computerized instrument to assess cognitive flexibility with this paradigm. METHODS: A non-probabilistic and intentional sample of individuals aged 60 and above (N=57; M=70; SD=7.5), 72% of whom were women, was utilized. A general cognitive screening test (ACE III) and the "Coin Tossing" task, a computerized program consisting of four levels of complexity, were administered. RESULTS: A Wilcoxon test was used to contrast parity versus size responses (z(56)=-1.16, P=.24). To assess repetition bias, a Wilcoxon test was conducted between new and repeated responses (TR: z(56)=-1.81, P=.07 // Accuracy: z(56)=-6.33, P=.00). A repeated measures ANOVA was performed between reaction times before, during, and after a response change, F(1.02)=59.6, P<.01, η2=.937, B-1=1. And a repeated measures ANOVA between mean RTs per level, F(3)=7.92, P<.001, η2=.128, B-1=.98. CONCLUSIONS: The test was designed with a progressive structure across levels. The theoretical assumptions of the paradigm were partially demonstrated, showing its utility for the assessment and training of cognitive flexibility.

Assessment of Cognitive Flexibility in Jordanian Diabetic Patients by Wisconsin Card Sorting and Trail Making Tests: Implications with Demographic, Anthropometric and Therapeutic Variables.

Purpose: Cognitive flexibility is a mental ability that aids in smoothly alternating between them tasks in the brain. Diabetes Mellitus (DM) is a, common disorder that has been associated with impairments in cognitive functions. This research is a retrospective case-control study aimed at establishing a clear relationship between cognitive flexibility and diabetes among Jordanians, considering demographic, anthropometric, and therapeutic variables. Patients and Methods: The Wisconsin Card Sorting Test (WCST)-64 item and the Trail Making Test (TMT) assessed cognitive flexibility in 268 people with diabetes and healthy control. Demographic, therapeutic data were collected. We also measured waist-to-hip ratio (WHR) and body mass index (BMI). As the variables were non-normally distributed, non-parametric statistical tests were used to examine differences (Kruskal-Wallis) and correlation (Spearman) between variables. Results: The patient group did worse on the WCST In contrast to the control group, patients exhibited more significant delays for both Part A and Part B of the TMT (p<0.05). Males had higher WCST conceptual level responses than females. In addition, participants with professional jobs showed less delay in TMT Part A (p<0.05). Age was positively correlated with WCST's total errors and TMT's Parts A and B (p<0.05). BMI was negatively correlated with the WCST's conceptual level of responses and positively correlated with TMT's Part B (p<0.05). In addition, urea and albumin levels were positively correlated with TMT's Part A (p<0.05). Furthermore, creatinine was positively correlated with WCST's total errors and TMT's Part A (p<0.05). Conclusion: Some measures of cognitive flexibility are associated with DM status in the studied sample of Jordanians and other variables (educational levels, occupation, lifestyle, average duration of illness, and age).

The mechanisms linking perceived stress to pilots' safety attitudes: a chain mediation effect of job burnout and cognitive flexibility.

Introduction: Pilots' safety attitude is crucial for aviation safety. Current research shows a correlation between perceived stress and safety attitude, yet the mechanism underlying this association remains unclear. Against the backdrop of heightened attention to pilots' stress, this study aims to thoroughly explore the inherent connection between pilot safety attitudes and their perceived stress, offering targeted insights into preventing and addressing safety attitude issues arising from pilot stress. Methods: Through path analysis of questionnaire data from 106 civil aviation pilots in China, this study systematically investigates the roles of job burnout and cognitive flexibility in the relationship between perceived stress and safety attitude. The study reveals the chain-mediated mechanism of these two factors. Results: The results demonstrate a significantly negative correlation between pilots' perceived stress and safety attitude, with cognitive flexibility and job burnout fully mediating this relationship, and cognitive flexibility affecting job burnout. A detailed analysis of the three dimensions of job burnout reveals varying impacts of emotional exhaustion, depersonalization, and reduced personal accomplishment on the aforementioned path. The research model exhibits a good fit (GFI=0.902), providing new theoretical perspectives on the association between pilots' perceived stress and safety attitude. Discussion: The findings offer practical implications for improving pilots' safety attitude by proposing targeted measures to alleviate the adverse impacts of perceived stress on safety attitude, thereby promoting aviation safety.

Differences in inhibitory control in two species of Tanganyikan bower-building cichlids contrasting in building flexibility.

A central challenge in understanding the evolution of cognition is the ability to compare a set of species differing in a trait of interest while being ecologically and phylogenetically close. Here, we examine whether differences in bower-building flexibility are related to differences in cognitive flexibility between two Tanganyikan cichlids. Cognitive flexibility enables animals to modify their decision rules when faced with new situations, and inhibitory control, the ability to inhibit a normally favoured response, is an essential component of this capacity. We tested male Aulonocranus dewindti and Cyathopharynx furcifer in a choice-against-preference paradigm. Both species clean their bowers of foreign objects and we found that both preferred to remove a snail shell over a stone. We tested their ability to modify this preference and learned to preferably select the stone instead of the shell. Although neither species showed clear learning of the new preference rule, both demonstrated inhibitory control through increased decision times and manipulations of the objects when selecting the stone. Specifically, A. dewindti, the species exhibiting greater behavioural flexibility in the construction of their bowers, selected the stone in fewer trials than C. furcifer, providing support for a link between behavioural flexibility in bower construction and cognitive flexibility.

Efficacy of a Remote Play-Based Intervention for Children With Prader-Willi Syndrome.

The current study examines the efficacy of an 8-week pretend play intervention targeting social-cognitive abilities in children with Prader-Willi syndrome (PWS), ages 6-9. PWS is a rare disorder associated with various social, emotional, and cognitive challenges linked to pretend play impairments, and for which interventions are sparse. Nineteen children were quasi-randomized to receive the intervention or be part of a waitlist control group. Participants who received the intervention (n = 10) demonstrated significant improvements in various components of pretend play, most notably in organization of play, which may generalize to broader social-cognitive gains. These findings provide evidence of the intervention's efficacy in enhancing pretend play skills and related social-cognitive abilities during this critical period of development for children with PWS.

Cognitive Correlates of Risky Decision-Making in Individuals with and without ADHD: A Meta-analysis.

This meta-analytic study aims to investigate the cognitive correlates of risky decision-making in individuals with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) individuals. A systematic analysis of existing literature was conducted, encompassing 38 studies (496 ADHD and 1493 TD). Findings revealed a consistent propensity for riskier decision-making in individuals with ADHD, supported by significant correlations with attention, cognitive flexibility, inhibitory control, time perception, and working memory. The study underscores the relevance of these cognitive functions in shaping decision-making tendencies, with nuanced patterns observed within the ADHD and TD subgroups. Individuals with ADHD often demonstrate altered patterns of correlation, reflecting the specific cognitive challenges characteristic of the disorder.

Subjective Cognitive Impairment Can Be Detected from the Decline of Complex Cognition: Findings from the Examination of Remedes 4 Alzheimer's (R4Alz) Structural Validity.

R4Alz is utilized for the early detection of minor neurocognitive disorders. It was designed to assess three main dimensions of cognitive-control abilities: working-memory capacity, attentional control, and executive functioning. OBJECTIVES: To reveal the cognitive-control dimensions that can differentiate between adults and older adults with healthy cognition, people with subjective cognitive impairment, and people diagnosed with mild cognitive impairment by examining the factorial structure of the R4Alz tool. METHODS: The study comprised 404 participants: (a) healthy adults (n = 192), (b) healthy older adults (n = 29), (c) people with SCI (n = 74), and (d) people diagnosed with MCI (n = 109). The R4Alz battery was administered to all participants, including tests that assess short-term memory storage, information processing, information updating in working memory, and selective, sustained and divided attention), task/rule-switching, inhibitory control, and cognitive flexibility. RESULTS: A two-factorial structural model was confirmed for R4Alz, with the first factor representing "fluid intelligence (FI)" and the second factor reflecting "executive functions (EF)". Both FI and EFs discriminate among all groups. CONCLUSIONS: The R4Alz battery presents sound construct validity, evaluating abilities in FI and EF. Both abilities can differentiate very early cognitive impairment (SCI) from healthy cognitive aging and MCI.

Testing associations between assessments of cognitive flexibility and eating disorder symptoms in adolescent bulimia nervosa.

OBJECTIVE: Cognitive rigidity, or difficulty adapting to changing demands, is commonly observed in anorexia nervosa. Less is known, however, about cognitive flexibility (CF) in bulimia nervosa (BN) and, particularly, adolescence. Clarifying this relation and best assessment practices may guide informed clinical decision-making. The current study compared how two measures of CF (i.e., Wisconsin Card Sort Task [WCST] and Trail Making Task [TMT]) relate to BN symptoms among adolescents. METHODS: Data from a subsample (n = 78) of adolescents with BN were analyzed. Linear and hurdle regressions were used to compare the effects of WCST perseverative errors and TMT performance on Eating Disorder Examination Global Scores, objective binge episodes, and self-induced vomiting episodes (SVEs) at baseline and end-of-treatment (EOT). RESULTS: Neither CF measure associated with baseline BN symptoms. TMT performance positively associated with the likelihood of engaging in SVEs at EOT (𝛽 = 0.47, p = 0.01, 95% confidence interval [CI] = [0.11-0.84]) and, among adolescents who endorsed ≥1 SVE at EOT, WCST perseverative errors (𝛽 = 0.05, p = 0.005, 95% CI = [0.01-0.08]) positively associated with SVE frequency at EOT. DISCUSSION: The overall lack of associations between CF and outcomes suggests that cognitive rigidity may not be as relevant to the clinical profile of adolescent BN as for anorexia nervosa. In the few significant associations that emerged, the WCST and TMT uniquely predicted the severity of vomiting at EOT in this sample. Given the lack of CF deficits, future work should aim to test the role of other executive functions (e.g., impulsivity), in addition to CF, to determine which deficits are present in adolescent BN and may predict outcomes. PUBLIC SIGNIFICANCE: Patients with eating disorders often have difficulties thinking flexibly, which may interfere with their recovery. We tested two ways of measuring flexible thinking in adolescents with BN. Overall, flexible thinking was not associated with symptom-level outcomes. However, less flexible thinking at the start of treatment predicted self-induced vomiting at EOT. If findings are replicable, then assessing and addressing flexible thinking could improve outcomes for adolescents with BN.

Anterior Cingulate Cortex Causally Supports Meta-Learning.

In dynamic environments with volatile rewards the anterior cingulate cortex (ACC) is believed to determine whether a visual object is relevant and should be chosen. The ACC may achieve this by integrating reward information over time to estimate which objects are worth to explore and which objects should be avoided. Such a higher-order meta-awareness about which objects should be explored predicts that the ACC causally contributes to choices when the reward values of objects are unknown and must be inferred from ongoing exploration. We tested this suggestion in nonhuman primates using a learning task that varied the number of object features that could be relevant, and by controlling the motivational value of choosing objects. During learning the ACC was transiently micro-stimulated when subjects foveated the to-be-chosen stimulus. We found that stimulation selectively impaired learning when feature uncertainty and motivational value of choices were high, which was linked to a deficit in using reward outcomes for feature-specific credit assignment. Application of an adaptive reinforcement learning model confirmed a primary deficit in weighting prediction errors that led to a meta-learning impairment to adaptively increase exploration during learning and to an impaired use of working memory to support learning. These findings provide causal evidence that the reward history traces in ACC are essential for meta-adjusting the exploration-exploitation balance and the strength of working memory of object values during adaptive behavior.

Disentangling cognitive flexibility: a model-based assessment of women with anorexia nervosa.

Cognitive flexibility (CF) has been proposed as a potential trait marker in anorexia nervosa (AN), although findings have been inconsistent. To address this inconsistency, we applied a model that distinguishes between three subtypes of CF: task switching, switching sets, and stimulus-response mapping, which we then assessed using a paradigm-based task battery. The aim of the study was to investigate how AN is associated with these three CF subtypes. Thirty-three women with AN and 37 age- and education-matched controls performed a battery of computerized cognitive tasks to assess the three CF subtypes. Compared to the control group, individuals with AN exhibited poorer performance on the task switching and switching sets subtypes, as measured by response time switch cost, but not on the stimulus-response mapping subtype. No differences were found between the groups in response accuracy. Furthermore, switching sets as compared to the task switching and stimulus-response mapping subtypes was found to better explain the differences between the groups. These findings indicate a domain-specific impairment in CF among patients with AN, reflecting deficits observed in subtypes related to the disorder's characteristics, particularly that associated with visual perception. Therefore, CF impairment in AN should not be viewed dichotomously, but rather as a relative impairment that varies depending on the specific CF subtype.

Effects of Practicing Closed- vs. Open-Skill Exercises on Executive Functions in Individuals with Attention Deficit Hyperactivity Disorder (ADHD)-A Meta-Analysis and Systematic Review.

(1) Background: Previous studies have identified discrepancies in improvements in executive functioning in typically developing children when comparing closed- and open-skill exercise interventions. However, there is limited research on executive functioning in attention deficit hyperactivity disorder (ADHD). This study aims to conduct a systematic review and meta-analysis to explore the impact of closed- and open-skill exercises on ADHD populations. (2) Methods: The PRISMA guidelines for systematic reviews were followed to search seven databases to evaluate and analyze studies published from 2013 to 2023. Prospero: CRD42023460452. (3) Results: A meta-analysis of 578 subjects with ADHD in 11 RCTs (Randomized control trial) and 3 NRS (Non-randomized studies) revealed that closed-skill exercise significantly improved executive function subdomains, including inhibitory control (standardized mean differences (SMD) = -1.00), cognitive flexibility (SMD = -1.33), and working memory (SMD = -0.85). Furthermore, open-skill exercise was found to have a positive effect on inhibitory control (SMD = -1.98) and cognitive flexibility (SMD = -0.97) in ADHD patients. Both types of exercise interventions demonstrated an improvement in executive function compared to controls, with open-skill exercises exhibiting superior effects (Qb = 6.26). (4) Conclusions: The review recommends a 12-week intervention cycle with exercise at least twice a week of moderate or higher intensity as suitable for ADHD individuals. This review also encourages individuals with ADHD to engage in exercises involving multiple motor skill types.

A Novel Approach to Measuring an Old Construct: Aligning the Conceptualisation and Operationalisation of Cognitive Flexibility.

A successful adjustment to dynamic changes in one's environment requires contingent adaptive behaviour. Such behaviour is underpinned by cognitive flexibility, which conceptually is part of fluid intelligence. We argue, however, that conventional approaches to measuring fluid intelligence are insufficient in capturing cognitive flexibility. We address the discrepancy between conceptualisation and operationalisation by introducing two newly developed tasks that aim at capturing within-person processes of dealing with novelty. In an exploratory proof-of-concept study, the two flexibility tasks were administered to 307 university students, together with a battery of conventional measures of fluid intelligence. Participants also provided information about their Grade Point Averages obtained in high school and in their first year at university. We tested (1) whether an experimental manipulation of a requirement for cognitive inhibition resulted in systematic differences in difficulty, (2) whether these complexity differences reflect psychometrically differentiable effects, and (3) whether these newly developed flexibility tasks show incremental value in predicting success in the transition from high school to university over conventional operationalisations of fluid intelligence. Our findings support the notion that cognitive flexibility, when conceptualised and operationalised as individual differences in within-person processes of dealing with novelty, more appropriately reflects the dynamics of individuals' behaviour when attempting to cope with changing demands.

Neurocognitive Function Domains Are Not Affected in Active Professional Male Footballers, but Attention Deficits and Impairments Are Associated with Concussion.

OBJECTIVE: To determine the neurocognitive function of active professional male footballers, determine whether deficits/impairments exist, and investigate the association between previous concussion(s) and neurocognitive function. METHODS: An observational cross-sectional study conducted via electronic questionnaires. The CNS Vital Signs online testing system was used to evaluate neurocognitive function. RESULTS: Of the 101 participants, 91 completed the neurocognitive function testing. Neurocognitive function domain deficits or impairments were unlikely in 54.5-89.1%, slight in 5.9-21.8%, moderate in 1.0-9.9%, and likely in 4.0-14.9% of participants. A history of zero concussions found a significant association between the neurocognitive index (Odds Ratio [OR] 0.6; 95% CI 0.2-0.4) and complex attention domain (OR 0.3; 95% CI 0.1-0.9), with 40% and 70% less odds, respectively, of deficit/impairment. Among the 54.5% who reported any number of concussions, there were increased odds of neurocognitive domain deficits/impairments for complex attention (CA) [3.4 times more] and simple attention (SA) [3.1 times more]. CONCLUSION: In the active professional male footballer, most neurocognitive functions do not have significant deficits/impairments. The odds of neurocognitive function deficit/impairment were significantly increased threefold for CA and SA in those who reported a history of any concussion(s).

Unraveling symptom interplay: a network analysis of procrastination in gifted students.

BACKGROUND: This study explores the intricate web of symptoms experienced by academically gifted high school students, focusing on procrastination, rumination, perfectionism, and cognitive flexibility. The well-being of these gifted adolescents remains a pivotal concern, and understanding the dynamics of these symptoms is vital. METHODS: A diverse sample of 207 academically gifted high school students from Mashhad, Iran, participated in this study. Using convenience sampling, participants from grades 10, 11, and 12 were included, with detailed assessments conducted through questionnaires measuring the mentioned symptoms. RESULTS: Our network analysis uncovers compelling insights into the interplay of these symptoms: Procrastination, though moderately central, exerts significant influence within the network, underscoring its relevance. Cognitive flexibility, while centrally positioned, curiously exhibits a negative influence, potentially serving as a protective factor. Negative perfectionism emerges as the keystone symptom, with both high centrality and a positive influence. Rumination displays substantial centrality and a positive influence, indicating its role in symptom exacerbation. Positive perfectionism, moderately central, lacks direct influence on other symptoms. CONCLUSION: This network analysis provides a nuanced understanding of the relationships among procrastination, rumination, perfectionism, and cognitive flexibility in academically gifted adolescents. Negative perfectionism and cognitive flexibility emerge as critical factors deserving attention in interventions aimed at enhancing the well-being of this unique group. Further research should explore causal relationships to refine targeted interventions.

Probing cognitive flexibility in Shank2-deficient mice: Effects of D-cycloserine and NMDAR signaling hub dynamics.

Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2-deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2-deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2-deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility.