Deficits In Cognitive Flexibility Research Articles

Aging to 24 months increased C57BL/6J mouse social sniffing and hippocampal Neto1 levels, and impaired female spatial learning

Understanding how natural aging impacts rodent performance in translational behavior tests is critical to teasing apart impairments due to age-related decline from neurodegenerative disorder modeling. Reduced neuropilin and tolloid-like 1 (NETO1), an accessory protein of ionotropic glutamate receptors involved in synaptic plasticity, was associated with Alzheimer’s disease, yet aging effects on Neto1 remain unclear. For these reasons, our goal was to characterize how Neto1 expression corresponded with social, repetitive, and spatial learning behaviors and stress response across the C57BL/6J mouse lifespan. We measured social preferences in three-chamber tests, and motor stereotypies by marble burying. Cognitive flexibility is typically assessed in the Morris water maze (MWM), wherein C57BL/6J mice exhibit deficits with age. However, fatigue or locomotor impairment may confound interpretation of MWM performance. Therefore, we used a less arduous water T-maze (WTM) to compare spatial learning flexibility in 2, 9–15, and 24-month-old male and female mice to test the hypothesis that deficits would emerge with age. In both sexes, 9–15-month-olds made more chamber entries during social preference tests, while 2-month-olds did less social sniffing than aged mice. No age or sex differences emerged in marble burying or serum corticosterone measurements. In 24-month-olds hippocampal Neto1was increased relative to 2-month-olds, and male cognitive flexibility was strong, while spatial learning and reversal learning of 24-month-old females was impaired in WTM irrespective of Neto1 expression. The WTM is a useful alternative assessment for cognitive flexibility deficits in aged mice, and the role of hippocampal Neto1 in promoting social sniffing is of interest.

Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats.

Posttraumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), an mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and brain derived neurotrophic factor (BDNF) signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits. vHipp input to IL was silenced using a Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later. Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects were blocked by local infusion of a neutralizing anti-BDNF antibody into IL. vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress.

Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD. MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win-stay and lose-shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness. ResultsUnmedicated patients with OCD were impaired on the deterministic reversal task under punishment only at the first and third reversals compared with both control participants and medicated patients with OCD, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups. ConclusionsBoth perseveration and increased shifting can be observed in OCD, depending on test conditions including the predictability of reinforcement. Perseveration was related to clinical severity and remediated by serotonergic medication.

Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility.

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.SIGNIFICANCE STATEMENT Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning, and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPARs for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPARs required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-β cause excessive ubiquitination of GluA1, inhibiting that GluA1 ubiquitination may have the potential to ameliorate amyloid-β-induced synaptic depression in Alzheimer's disease.

Cognitive flexibility in schizophrenia: A confirmatory factor analysis of neuropsychological measures

Cognitive flexibility (CF) is the ability to adapt cognitive strategies according to the changing environment. The deficit in CF has often been linked to various neurological and psychiatric disorders including schizophrenia. However, the operationalization and assessment of CF have not been unified and the current research suggests that the available instruments measure different aspects of CF. The main objective of the present study was to compare three frequently used neuropsychological measures of CF-Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and Stroop Color and Word Test (SCWT) in a population of patients (N = 220) with first-episode schizophrenia spectrum disorders in order to evaluate their convergent validity. The hypothesis of an underlying latent construct was tested via a confirmatory factor analysis. We used a one-factor CF model with scores from WCST, SCWT and TMT as observed variables. The established model showed a good fit to the data (χ2 = 1.67, p = 0.43, SRMR = 0.02, RMSEA = 0.0, CFI = 1.00). The highest factor loading was found in WCST as CF explained most of the variance in this neuropsychological measure compared to the other instruments. On the other hand, a TMT ratio index and a SCWT interference demonstrated lowest loadings in the model. The findings suggest that not all the frequently used measures share an underlying factor of CF or may capture different aspects of this construct.

Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons

Addictive substance use impairs cognitive flexibility, with unclear underlying mechanisms. The reinforcement of substance use is mediated by the striatal direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra pars reticulata (SNr). Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs), which receive extensive striatal inhibition. Here, we hypothesized that increased dMSN activity induced by substance use inhibits CINs, reducing cognitive flexibility. We found that cocaine administration in rodents caused long-lasting potentiation of local inhibitory dMSN-to-CIN transmission and decreased CIN firing in the dorsomedial striatum (DMS), a brain region critical for cognitive flexibility. Moreover, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed flexibility of goal-directed behavior in instrumental reversal learning tasks. Notably, rabies-mediated tracing and physiological studies showed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN-to-CIN circuit mediates the reinforcement-induced deficits in cognitive flexibility.

Repeated dextromethorphan administration in adolescent rats produces long-lasting behavioral alterations

Initiation of non-medical dextromethorphan (DXM) use often occurs in adolescence, yet little is known about the consequences when use begins during this developmental period. The current experiments examined the acute response and the effects of repeated exposure to DXM in adolescence on behavior in adulthood. We examined locomotor activity, locomotor sensitization, and cognitive function, in rats that received repeated administration of DXM. Groups of adolescent (PND 30) and adult (PND 60) male rats were treated with DXM (60 mg/kg) once daily for 10 days. Locomotor activity in response to DXM was assessed following the first injection, on the 10th day of injection (adolescent – PND 39; adult – PND 69), and following 20 days of abstinence (adolescent – PND 59; adult – PND 89). Acute locomotor effects and locomotor sensitization were compared in adolescents and adults; cross-sensitization to ketamine, another dissociative with abuse potential, was also examined. In a separate group of rodents cognitive deficits were assessed following a 20 day abstinence period (adolescent – PND 59; adult – PND 89) in spatial learning and novel object recognition tasks. The locomotor stimulant effect of DXM was much greater in adolescents than adults. Also, only adolescent rats that were repeatedly administered DXM demonstrated locomotor sensitization at the end of 10 days of injection. However, sensitization occurred after the abstinence period in all rats regardless of age. Nonetheless, cross-sensitization to ketamine was only evident in adolescent-treated rats. DXM also led to an increase in perseverative errors in reversal learning only in the adolescent-treated group. We conclude that repeated use of DXM produces long-lasting neuroadaptations that may contribute to addiction. Deficits in cognitive flexibility occur in adolescents, although further work is necessary to confirm these findings. The results extend the understanding of potential long-term consequences of DXM use in adolescents and adults.

Impaired cognitive flexibility across psychiatric disorders.

Problems with cognitive flexibility have been associated with multiple psychiatric disorders, but there has been little understanding of how cognitive flexibility compares across these disorders. This study examined problems of cognitive flexibility in young adults across a range of psychiatric disorders using a validated computerized trans-diagnostic flexibility paradigm. We hypothesized that obsessive-compulsive spectrum disorders (eg, obsessive-compulsive disorder, trichotillomania, and skin-picking disorder) would be associated with pronounced flexibility problems as they are most often associated with irrational or purposeless repetitive behaviors. A total of 576 nontreatment seeking participants (aged 18-29years) were enrolled from general community settings, provided demographic information, and underwent structured clinical assessments. Each participant undertook the intra-extra-dimensional task, a validated computerized test measuring set-shifting ability. The specific measures of interest were total errors on the task and performance on the extra-dimensional (ED) shift, which reflects the ability to inhibit and shift attention away from one stimulus dimension to another. Participants with depression and PTSD had elevated total errors on the task with moderate effect sizes; and those with the following had deficits of small effect size: generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), antisocial personality disorder, and binge-eating disorder. For ED errors, participants with PTSD, GAD, and binge-eating disorder exhibited deficits with medium effect sizes; those with the following had small effect size deficits: depression, social anxiety disorder, OCD, substance dependence, antisocial personality disorder, and gambling disorder. These data indicate cognitive flexibility deficits occur across a range of mental disorders. Future work should explore whether these deficits can be ameliorated with novel treatment interventions.

Cognitive Flexibility in Mice: Effects of Puberty and Role of NMDA Receptor Subunits.

Cognitive flexibility refers to the ability to adapt flexibly to changing circumstances. In laboratory mice, we investigated whether cognitive flexibility is higher in pubertal mice than in adult mice, and whether this difference is related to the expression of distinct NMDA receptor subunits. Using the attentional set shifting task as a measure of cognitive flexibility, we found that cognitive flexibility was increased during puberty. This difference was more pronounced in female pubertal mice. Further, the GluN2A subunit of the NMDA receptor was more expressed during puberty than after puberty. Pharmacological blockade of GluN2A reduced the cognitive flexibility of pubertal mice to adult levels. In adult mice, the expression of GluN2A, GluN2B, and GluN2C in the orbitofrontal cortex correlated positively with performance in the attentional set shifting task, whereas in pubertal mice this was only the case for GluN2C. In conclusion, the present study confirms the observation in humans that cognitive flexibility is higher during puberty than in adulthood. Future studies should investigate whether NMDA receptor subunit-specific agonists are able to rescue deficient cognitive flexibility, and whether they have the potential to be used in human diseases with deficits in cognitive flexibility.

Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration.

The cognitive symptoms of schizophrenia (SZ) present a significant clinical burden. They are treatment resistant and are the primary predictor of functional outcomes. Although the neural mechanisms underlying these deficits remain unclear, pathological GABAergic signaling likely plays an essential role. Perturbations with parvalbumin (PV)-expressing fast-spiking (FS) interneurons in the prefrontal cortex (PFC) are consistently found in post-mortem studies of patients with SZ, as well as in animal models. Our studies have shown decreased prefrontal synaptic inhibition and PV immunostaining, along with working memory and cognitive flexibility deficits in the MK801 model. To test the hypothesized association between PV cell perturbations and impaired cognition in SZ, we activated prefrontal PV cells by using an excitatory DREADD viral vector with a PV promoter to rescue the cognitive deficits induced by adolescent MK801 administration in female rats. We found that targeted pharmacogenetic upregulation of prefrontal PV interneuron activity can restore E/I balance and improve cognition in the MK801 model. Our findings support the hypothesis that the reduced PV cell activity levels disrupt GABA transmission, resulting in the disinhibition of excitatory pyramidal cells. This disinhibition leads to an elevated prefrontal excitation/inhibition (E/I) balance that could be causal for cognitive impairments. Our study provides novel insights into the causal role of PV cells in cognitive function and has clinical implications for understanding the pathophysiology and management of SZ.

Identifying patterns of neurocognitive dysfunction through direct comparison of children with leukemia, central nervous system tumors, and sickle cell disease.

To quantify and compare the magnitude and type of neurocognitive dysfunction in at-risk children with central nervous system (CNS) tumors, acute lymphoblastic leukemia (ALL), and sickle cell disease (SCD) using a common instrument and metric to directly compare these groups with each other. Fifty-three participants between the ages of 7 and 12 years (n=27 ALL, n=11 CNS tumor, n=15 SCD) were enrolled and assessed using the NIH Toolbox Cognition Battery (NIHTCB). Participants with ALL or CNS tumor were 0-18 months posttherapy, while participants with SCD possessed the SS or Sβ0 genotype, took hydroxyurea, and had no known history of stroke. Independent sample t-tests showed that participants with ALL and CNS tumor experienced greatest deficits in processing speed (ALL d=-0.96; CNS tumor d=-1.2) and inhibitory control and attention (ALL d=-0.53; CNS tumor d=-0.97) when compared with NIHTCB normative data. Participants with SCD experienced deficits in cognitive flexibility only (d=-0.53). Episodic memory was relatively spared in all groups (d=-0.03 to -0.32). There were no significant differences in function when groups were compared directly with each other by analysis of variance. Use of a common metric to quantify the magnitude and type of neurocognitive dysfunction across at-risk groups of participants by disease shows that participants perform below age-expected norms in multiple domains and experience dysfunction differently than one another. This approach highlights patterns of dysfunction that can inform disease- and domain-specific interventions.

Anxiety-linked impairment in the ability to recode stimuli.

It has been proposed that elevated trait anxiety is associated with deficits in cognitive flexibility, which is required to enable people to switch between different ways of classifying information. Recent research has focused on a particular facet of cognitive flexibility that may be specifically impaired in high trait anxious individuals. This concerns the ability to recode stimulus information that has initially been categorized in terms of 1 stimulus dimension, in terms of an alternative dimension. However, limitations in previously employed assessment methodologies compromise the capacity to draw firm conclusions from prior research investigating this hypothesis. Across 2 studies we developed and delivered a novel stimulus information recoding assessment task to a sample of individuals who varied in trait anxiety, to test the hypothesis that elevated trait anxiety is specifically associated with a deficit in the ability to recode information that has already been classified. Across both studies we found evidence to support this hypothesis. The theoretical and practical implications of these findings are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ketamine in the Treatment of Delusions: A Review of the Evidence

AbstractIntroductionDelusions are defined as fixed false beliefs that are not within normal parameters of society, culture, or religion that can be part of psychotic or mood disorders. They can be difficult to treat and, for some inpatient individuals, persistent delusions can make safe discharge impossible. Ketamine is a dissociative agent that has shown promise in treating mood disorders. Despite this, clinicians hesitate to prescribe this when a patient presents with any type of psychotic symptom. There is proof that ketamine is safe to use with psychotic symptoms, and there is growing evidence that it may be a suitable treatment alternative for delusions resistant to other psychopharmacology.MethodsA literature review using articles from multiple databases was conducted to gather supporting evidence on the use of ketamine in the context of psychosis. Since there has not been a reported conducted study specifically for ketamine and delusions, a look into its use for psychosis was done to find links between the neurobiology of delusions and the mechanism of action of ketamine.ResultsCurrent literature does not demonstrate that ketamine within a therapeutic setting exacerbates psychotic symptoms in those with depression or bipolar disorder, regardless of the presence of psychotic features, nor does it reveal that predisposed patients experience lasting psychotic effects. Furthermore, although ketamine is often used to model schizophrenia, brain connectivity seen during ketamine-induced delusions is opposite to the connectivity seen in delusions in the context of chronic schizophrenia. Regardless of connectivity patterns, ketamine appears to act upon many of the same mechanisms that underlie delusions. There is evidence delusions are characterized by low belief flexibility, high prediction error, and high aberrant salience. An animal model of stress-induced cognitive dysfunction found that ketamine corrected the cognitive flexibility deficits. Ketamine has been shown to alter prediction error in those suffering from major depressive disorder, resulting in greater optimism bias when patients update maladaptive beliefs post-ketamine administration. In respect to aberrant salience, neural networks affecting this include midbrain dopaminergic neurons and their projections to striatal and frontal cortical regions. Studies have shown this effect was reduced by ketamine-induced plasticity in the orbitofrontal cortex.ConclusionPsychotic symptoms may not be an absolute contraindication for ketamine treatment. In fact, ketamine could be beneficial in the treatment of various mental illnesses with psychotic features that are not amenable to classical treatment. The dissociative properties may jump-start treatment while waiting for antipsychotics to work. This could significantly reduce hospital stays, especially for patients in long-term facilities.FundingNo Funding

GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia

BackgroundParvalbumin interneuron (PVI) activity synchronizes the medial prefrontal cortex circuit for normal cognitive function, and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for the NMDA receptor hypofunction hypothesis of SZ. However, the role of the GluN2D subunit, which is enriched in PVIs, in regulating molecular networks relevant to SZ is unknown. MethodsUsing electrophysiology and a mouse model with conditional deletion of GluN2D from PVIs (PV-GluN2D knockout [KO]), we examined the cell excitability and neurotransmission in the medial prefrontal cortex. Histochemical, RNA sequencing analysis and immunoblotting were conducted to understand molecular mechanisms. Behavioral analysis was conducted to test cognitive function. ResultsPVIs in the medial prefrontal cortex were found to express putative GluN1/2B/2D receptors. In a PV-GluN2D KO model, PVIs were hypoexcitable, whereas pyramidal neurons were hyperexcitable. Excitatory neurotransmission was higher in both cell types in PV-GluN2D KO, whereas inhibitory neurotransmission showed contrasting changes, which could be explained by reduced somatostatin interneuron projections and increased PVI projections. Genes associated with GABA (gamma-aminobutyric acid) synthesis, vesicular release, and uptake as well as those involved in formation of inhibitory synapses, specifically GluD1-Cbln4 and Nlgn2, and regulation of dopamine terminals were downregulated in PV-GluN2D KO. SZ susceptibility genes including Disc1, Nrg1, and ErbB4 and their downstream targets were also downregulated. Behaviorally, PV-GluN2D KO mice showed hyperactivity and anxiety behavior and deficits in short-term memory and cognitive flexibility. ConclusionsThese findings demonstrate that GluN2D in PVIs serves as a point of convergence of pathways involved in the regulation of GABAergic synapses relevant to SZ.

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

SummarySignificant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.

Executive functions underlie word reading and reading fluency in Chinese children with attention deficit/hyperactivity disorder, reading disabilities, and comorbid attention deficit/hyperactivity disorder and reading disabilities

ABSTRACT The current study examined the executive function (EF) deficits and their roles in reading in one hundred and four Cantonese-speaking children with typical development, reading disabilities (RD), ADHD, and comorbid ADHD and RD (ADHD + RD). Children’s EF and reading skills were measured. Analysis of variance results showed that all children with disorders manifested deficits in verbal and visuospatial short-term and working memory and behavioral inhibition. Moreover, children with ADHD and ADHD + RD also exhibited deficits in inhibition (IC and BI) and cognitive flexibility. These findings demonstrated that the EF deficits in Chinese children with RD, ADHD, and ADHD + RD are similar to those in their counterparts using alphabetic languages. However, children with ADHD + RD displayed more severe deficits in visuospatial working memory compared to children with RD and ADHD, which was inconsistent with that observed in children using alphabetic languages. Regression analysis results showed that verbal short-term memory was a significant predictor for both word reading and reading fluency in children with RD and ADHD + RD. Moreover, behavioral inhibition significantly predicted reading fluency in children with ADHD. These findings also agreed with previous studies. Collectively, the results of the current study showed that the EF deficits and their roles in reading found in Chinese children with RD, ADHD, and ADHD + RD are mainly consistent with children using alphabetic languages. However, more studies are still needed to confirm these findings, especially comparing the severity of working memory among these three disorders.

Cognitive flexibility in inpatient children and adolescents with a history of suicide attempts

An increase in suicide rates during adolescence has made it the second leading cause of death for this age group. While potential deficits in cognitive flexibility have been thought to contribute to suicidality, this factor has been evaluated in only a few studies among this age group. The current study sought to evaluate cognitive flexibility in 100 psychiatric inpatient children and adolescents (age X=14.39, SD=2.53), with (n=26) and without (n=74) a history of suicide attempts, using the Wisconsin Card Sorting Test (WCST). Results showed no differences between the groups in WCST scores. However, in a small sub-sample with mood disorders only, those with a history of a suicide attempt performed better than those without such history. These findings are contrary to our hypothesis that those who attempted suicide have worse cognitive flexibility, though consistent with earlier data in adults. Further research is needed to shed light on these findings.

Cognitive flexibility in post-traumatic stress disorder: Sustained interference associated with altered modulation of cortical oscillatory activity during task-switching

Post-traumatic stress disorder (PTSD) is associated with deficits in cognitive flexibility, with evidence suggesting that these deficits may be a risk factor for the development of core PTSD symptoms. Understanding the neurophysiological substrate of this association could aid the development of effective therapies for PTSD. In this study, we investigated the relationship between post-traumatic stress severity (PTSS) in service members with combat exposure and the modulation of cortical oscillatory activity during a test of cognitive flexibility. Participants were assigned to three groups based on PTSS scores: low (well below a threshold consistent with a diagnosis of PTSD, n = 30), moderate (n = 32), and high (n = 29) symptom severity. Magnetoencephalography data were recorded while participants performed a cued rule-switching task in which two matching rules were repeated or switched across consecutive trials. Participants with high PTSS had longer reaction times for both switch and repeat trials, and showed evidence of sustained residual interference during repeat trials. During the cue-stimulus interval, participants with moderate and high PTSS showed higher relative theta power in switch trials over left dorsolateral prefrontal cortex (DLPFC). After test-stimulus onset, participants with high PTSS showed less suppression of beta band activity, which was present over multiple prefrontal, parietal, and temporal regions in switch trials, but it was confined to ventromedial prefrontal cortex in repeat trials. Higher theta band activity is a marker of effortful voluntary shifting of attention, while lower suppression of beta band activity reflects difficulties with inhibition of competing perceptual information and courses of action. These findings are consistent with a role for altered suppression of beta band activity, which can be due to less effective top-down bias signals exerted by DLPFC, in the etiology of cognitive flexibility deficits in PTSD.

Examining the Relationship Between Task-Switching and Speech Errors in Parkinson's Disease

<h3>Research Objectives</h3> To establish the link between cognitive flexibility deficits and errors in speech production in Parkinson's disease (PD). A secondary goal is to show that this relationship exists despite the presentation of "normal" overall cognitive functioning on a standard screening test (Montreal Cognitive Battery; MoCA). <h3>Design</h3> Regression (between-subjects). <h3>Setting</h3> University. <h3>Participants</h3> Fifteen people with PD and 15 adult controls participated in this study. All were native speakers of American English, had no upper respiratory tract infections, and passed depression and hearing screenings. People with PD varied on a continuum of overall disease and speech severity. Controls had no history of hearing, speech-language, or neurological disorders. All study procedures were approved by the Institutional Review Board. <h3>Interventions</h3> N/A. <h3>Main Outcome Measures</h3> 1) Metrics of cognitive flexibility (reaction times, error rates) 2) MoCA scores, speech errors (articulation errors, stuttering-like disfluencies, and other disfluencies) and 3) Speech rate. <h3>Results</h3> Results show that people with PD would present with impaired cognitive flexibility (slower reaction times to switch demands compared to controls) despite falling within normal range on standard clinical screenings of cognition (MoCA) and that people with PD and controls show an inverse relationship between cognitive flexibility and the number of errors during speech production with group differences in both flexibility and speech error rates occurring. <h3>Conclusions</h3> Our findings suggest that impairments in cognition in PD may occur earlier than previously thought and may only be apparent on more sensitive tests of cognitive flexibility that are typically not performed as standard-of-care. A relationship between cognitive flexibility and speech errors suggests a role of cognitive flexibility during speech-motor control. These deficits should be considered when recommending therapy and designing interventions. <h3>Author(s) Disclosures</h3> Funding for this work is through an internal grant by Seton Hall University. No other relevant disclosures.

Investigating cognitive flexibility deficit in schizophrenia using task-based whole-brain functional connectivity.

Cognitive flexibility is a core cognitive control function supported by the brain networks of the whole-brain. Schizophrenic patients show deficits in cognitive flexibility in conditions such as task-switching. A large number of neuroimaging studies have revealed abnormalities in local brain activations associated with deficits in cognitive flexibility in schizophrenia, but the relationship between impaired cognitive flexibility and the whole-brain functional connectivity (FC) pattern is unclear. We investigated the task-based functional connectivity of the whole-brain in patients with schizophrenia and healthy controls during task-switching. Multivariate pattern analysis (MVPA) was utilized to investigate whether the FC pattern can be used as a feature to discriminate schizophrenia patients from healthy controls. Graph theory analysis was further used to quantify the degrees of integration and segregation in the whole-brain networks to interpret the different reconfiguration patterns of brain networks in schizophrenia patients and healthy controls. The results showed that the FC pattern classified schizophrenia patients and healthy controls with significant accuracy. Moreover, the altered whole-brain functional connectivity pattern was driven by a lower degree of network integration and segregation in schizophrenia, indicating that both global and local information transfers at the entire-network level were less efficient in schizophrenia patients than in healthy controls during task-switching processing. These results investigated the group differences in FC profiles during task-switching and not only elucidated that FC patterns are changed in schizophrenic patients, suggesting that task-based FC could be used as a potential neuromarker to discriminate schizophrenia patients from healthy controls in cognitive flexibility but also provide increased insight into the brain network organization that may contribute to impaired cognitive flexibility.