Higher-order Cognition Research Articles

0266 A Brief Nap During a Period of Sleep Deprivation Does Not Mitigate Cognitive Deficits

Abstract Introduction Sleep deprivation consistently impairs vigilant attention and placekeeping, which is the ability to maintain place in a sequence of steps without skipping or repeating steps. Placekeeping is a broadly important component of higher-order cognition. Previously, we found that caffeine benefitted vigilant attention but had no effect on placekeeping for most individuals. Here, we investigated the extent to which another intervention, brief naps, mitigated deficits in vigilant attention and placekeeping during a period of sleep deprivation. Methods In the evening, participants completed assessments of placekeeping and vigilant attention, the UNRAVEL task and Psychomotor Vigilance Task (PVT), respectively. Participants were then randomly assigned to either stay awake in the laboratory overnight (Sleep-deprived) or sleep at home (Rested). Sleep-deprived participants were also randomly given a 0, 30, or 60 minute nap opportunity. During the naps, participants were setup with partial polysomnography. In the morning, Rested participants returned and everyone completed UNRAVEL and PVT again. Results Sleep deprivation increased placekeeping errors, particularly following interrupted performance, and increased attentional lapses. A brief nap opportunity did not mitigate placekeeping or vigilant attention deficits. Polysomnography data showed that total sleep time was negatively related to placekeeping errors following an interruption; participants who slept more made fewer post-interruption errors. Slow wave sleep (SWS) was negatively related to attentional lapses and placekeeping errors on non-interruption trials; participants who obtained more SWS made fewer lapses and non-interruption errors. Sleep latency was also negatively related to attentional lapses, such that participants who fell asleep quickly, an indication of greater sleepiness, had more attentional lapses. Conclusion A brief nap during a period of sleep deprivation is not a viable intervention and longer naps may be required before observable performance benefits emerge. However, specific aspects of sleep architecture were related to performance on the two tasks, suggesting domain-specific deficits due to sleep deprivation. Support Funding received by the Office of Naval Research N00014-16-1-2841.

M66. FACILITATIVE EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION ON SEMANTIC MEMORY EXAMINED BY TEXT-MINING ANALYSIS IN PATIENTS WITH SCHIZOPHRENIA

BackgroundTranscranial direct current stimulation (tDCS) is a neurophysiological therapy which modulates neural activities in the brain with weak electrical current. The beneficial effects of tDCS are relevant to positive and negative symptoms, as well as cognition and functional capacity in patients with schizophrenia (Narita et al, 2017). However, whether tDCS would improve higher-order cognition, e.g. semantic memory organization, has remained unclear. Recently, text-mining analyses have been proven to be effective to reveal semantic memory in patients with schizophrenia (Sung et al., 2012; Sumiyoshi et al., 2018). The purpose of the study was to investigate effects of tDCS to improve semantic memory, as evaluated by text-mining analyses of category fluency data, in patients with schizophrenia.MethodsTwenty-eight patients meeting DSM-5 criteria for schizophrenia entered the study. All subjects gave written informed consent, and the study was approved by the Ethical Committee of National Center of Neurology and Psychiatry and the Ethical Committee of Osaka university. Data from healthy control subjects (N=335) were also used. The tDCS was conducted according to the previous study (Narita et al., 2017). tDCS was administered twice a day in 5 consecutive days. The Brief Assessment of Cognition in Schizophrenia, (BACS) was administered at baseline and one month after the last tDCS session. Verbal outputs of the category fluency task in the BACS were submitted to the singular valued decomposition (SVD) analysis. Semantic memory structures were estimated by calculating cosine values (i.e. similarities) among frequent items in the six-dimensional solution. These values were compared between healthy controls vs. patients at baseline and follow-up using Pearson’s correlational coefficients.ResultsThe correlational coefficient for the frequent items (DOG, CAT, ELEPAHANT, GIRAFFE, LION, TIGER) between patients and healthy controls was considerably higher at the follow-up (r=0.58) compared to that at base line (r=0.12), reaching a marginal significance (p=0.058). A visual inspection for the cosine profiles of frequent items indicated that distinct clusters of Pet (DOG, CAT), Wild-Herbivorous (ELEPAHANT, GIRAFFE), and Wild-Carnivorous (LION, TIGER) in patients at follow-up, as in the case for healthy controls.DiscussionTo our knowledge, this is the first study reporting a facilitative effect of tDCS on higher-order of cognition in patients with schizophrenia. Semantic memory in the patients became structurally similar to that for healthy controls after administration of tDCS. Furthermore, animal names frequently produced were meaningfully clustered in patients at follow-up, similar to the pattern of healthy controls. These results may explain the efficacy of tDCS for improving other domains of cognitive function in patients with schizophrenia. We also could demonstrate that text-mining analysis is a powerful tool to elucidate higher-order cognition in people with mental disorders.ReferencesNarita, Z et al. 2017a. Front. Psychiatry, 8:184. doi: 10.3389/fpsyt.2017.00184.Sung, K. et al. 2012. J Int Neuropsychol Soc.,18, 565-57Sumiyoshi, C. et al. 2018. Front. Psychiatry, 9:87. doi: 10.3389/fpsyt.2018.00087

S142. NOVEL CONCEPTS OF SOCIAL IMPAIRMENTS IN SCHIZOPHRENIA

BackgroundSocial deficits are a well-known phenotype of schizophrenia, which strongly influence the clinical progress of patients. A core substrate of these dysfunctions are altered Theory of Mind (ToM) processes which critically shape social interactions and can impress in an exaggerated and atrophied form in the disorder. Although there is a well-established link between clinical outcome measures and ToM deficits, less evidence exists about the neural and behavioral mechanisms underlying a specific core function responsible for forming interpersonal mental representations, which in turn aid to optimize social interactions. Along this line, an urgent clinical issue is how alterations in these interpersonal predictive processes translate into clinical issues and whether they can be positively influenced by psychological group interventions.MethodsIn a set of different studies, we used functional and structural magnetic resonance imaging and a dynamic social interactive task, a modified prisoner’s dilemma game, in which the participants can form mental representations of different interaction partners in order to optimize their joint interaction sequences. Methodologically, we have drawn on several sophisticated methods ranging from graph theoretic network indices, functional and effective connectivity to structural covariance analyses and linked them with behavioral and clinical outcome measures.ResultsOur data shows a central relevance of the right temporo-parietal junction (rTPJ) in forming mental representations in healthy subjects, given the region integrates memory processing streams during social interactions. Further behavioral analyses indicate that these mechanisms are relevant for interpersonal adaptive processes during social interactions. In patients with schizophrenia, we have found dysfunctions in this important mechanism, indicated by a reduced integration of neural pathways from the temporal lobe, such as the hippocampus. These alterations are associated with behavioral indices of dysfunctions in generating mental representations during an interpersonal interaction. When we examined neural computations in the entire ToM network, we found for the first time that the rTPJ has reduced out-going effective connections to brain regions linked with higher-order cognition, such as the dmPFC, in patients. On a conceptual level, this finding might be associated with dysfunctional updating processes from brain regions located in the temporal lobe, which will be an ongoing empirical question.DiscussionOur results indicate a central pathological relevance of the rTPJ for social dysfunctions in schizophrenia. First, the regions seem to be less informed by memory processing streams, relevant to update social information by previous information. Additionally, we have shown that in the core mentalizing network the region integrates to a lesser extent into the dmPFC, which might be associated with our previous findings. Our results show concrete targets for specific interventions to improve the clinical important social-cognitive dysfunctions occurring in the disorder. Hence, we suggest approaches to enhance the functioning of brain mechanisms relevant for human connections that can facilitate the patients’ clinical outcome.

A neural mechanism of the relationship between impulsivity and emotion dysregulation in patients with Internet gaming disorder.

Impulsivity and emotion dysregulation have been known to be risk factors for Internet gaming disorder (IGD), but their underlying neural mechanisms are not yet fully understood. Given that the prefrontal cortex has a key role in higher order cognition and addiction, the present study aimed to investigate emotional influences on response inhibition in situations with different cognitive demands. A total of 41 young male adults (20 with and 21 without IGD) were scanned while performing two versions of an emotional go/no-go task with demands on low and high working memory load. Patients with IGD showed a failure in response inhibition and increased activation of widespread brain regions, including prefrontal, motor-sensory, parietal, occipital, insula, and striatal regions across tasks. Among these regions, involvement of the dorsolateral prefrontal cortex and ventral striatum was observed only during the task with high demands on working memory. Moreover, it was also only during the high-load task that interaction between response inhibition and emotional states was observed in the dorsomedial prefrontal cortex, with observations revealing that its alteration in patients with IGD was associated with number of hours spent on Internet gaming. Our findings highlight a failure of response inhibition and dysfunction within the inhibitory control network. The special significance of our study is that dysfunctional dorsomedial prefrontal cortex may mediate abnormal emotional influences on response inhibition in patients with IGD.

Working memory load-dependent changes in cortical network connectivity estimated by machine learning

Working memory engages multiple distributed brain networks to support goal-directed behavior and higher order cognition. Dysfunction in working memory has been associated with cognitive impairment in neuropsychiatric disorders. It is important to characterize the interactions among cortical networks that are sensitive to working memory load since such interactions can also hint at the impaired dynamics in patients with poor working memory performance. Functional connectivity is a powerful tool used to investigate coordinated activity among local and distant brain regions. Here, we identified connectivity footprints that differentiate task states representing distinct working memory load levels. We employed linear support vector machines to decode working memory load from task-based functional connectivity matrices in 177 healthy adults. Using neighborhood component analysis, we also identified the most important connectivity pairs in classifying high and low working memory loads. We found that between-network coupling among frontoparietal, ventral attention and default mode networks, and within-network connectivity in ventral attention network are the most important factors in classifying low vs. high working memory load. Task-based within-network connectivity profiles at high working memory load in ventral attention and default mode networks were the most predictive of load-related increases in response times. Our findings reveal the large-scale impact of working memory load on the cerebral cortex and highlight the complex dynamics of intrinsic brain networks during active task states.

Insula Structure in Psychotic Disorders and Youth With Psychosis Spectrum Symptoms

Reduced insula volume is consistently observed in psychotic disorders. High-risk individuals who later transition to psychosis also exhibit smaller insula, suggesting a developmental origin. The insula is a complex structure comprised of agranular, dysgranular, and granular areas which differ in their cytoarchitecture and are implicated in distinct functions; however differential alterations in these areas are rarely investigated. In particular, the agranular and dysgranular insula are critical for higher-order cognition, which is often a pre-morbid marker of psychosis risk.

A Preliminary Study for the Development of Informant-Report Scale on Cognitive-Linguistic Abilities of the Elderly: Focused on Mild Cognitive Impairment and Alzheimer’s Disease

Purpose: Subjective cognitive-linguistic test is used to supplement various objective tests and increase a diagnostic accuracy. The purpose of this preliminary study was to develop and standardize the Informant-report Scale on Cognitive-Linguistic abilities of the Elderly (ISCOLE), and investigate the correlation between ISCOLE and objective test in individuals with neurological disease. Methods: People with mild cognitive impairment (MCI) (n = 30) and Alzheimer’s disease (AD) (n = 32) completed the objective cognitive-linguistic test. Informants of these patients (n = 62) and controls (n = 35) provided ratings of ISCOLE. Results: The main findings were as follows. Firstly, there was a significant difference among three groups in all subdomains and total score of ISCOLE. Secondly, several domains like attention, higher-order cognition, and language of ISCOLE were significantly associated with the objective performances in tow groups. Thirdly, memory, language, and total score of ISCOLE were a predictor of memory in MCI group. AD’s higher-order cognition was also predicted by attention, language and higher-order cognition of ISCOLE. Conclusion: This study is expected to help confirm the overall correlations between ISCOLE and objective test, and present the predictors of objective cognitive-linguistic performances in MCI and AD. The findings have implications for the use of ISCOLE in clinical settings. We also showed evidence that the ISCOLE is an informant-based measure of cognitive-linguistic decline providing a relevant contribution to the diagnostic and prognostic investigation of patients with MCI and AD.

Subcortical Brain Volume Abnormalities in Individuals With an At-risk Mental State.

Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology.

Toward Integrative Reading Science: The Direct and Indirect Effects Model of Reading

The authors propose an integrative theoretical model of reading called the direct and indirect effects model of reading (DIER) that builds on and extends several prominent theoretical models of reading. According to DIER, the following skills and knowledge are involved in reading comprehension: word reading, listening comprehension, text reading fluency, background knowledge (content knowledge and discourse knowledge), reading affect or socioemotions, higher order cognitions and regulation (e.g., inference, perspective taking, reasoning, and comprehension monitoring), vocabulary, grammatical (morphosyntactic and syntactic) knowledge, phonology, morphology, orthography, and domain–general cognitions (e.g., working memory and attentional control). Importantly, DIER also describes the nature of structural relations—component skills are hypothesized to have (a) hierarchical relations; (b) dynamic (or differential) relations as a function of text, activity (including assessment), and development; and (c) interactive relations. The authors then examined the hierarchical relations hypothesis by comparing a flat or direct relations model with hierarchical relations (or direct and indirect effects) models. Structural equation model results from 201 Korean-speaking first graders supported the hierarchical relations hypothesis and revealed multichanneled direct and indirect effects of component skills. These results are discussed in light of DIER, including instructional and assessment implications for reading development and reading difficulties.

Individual Variation in Functional Topography of Association Networks in Youth

The spatial distribution of large-scale functional networks on the cerebral cortex differs between individuals and is particularly variable in association networks that are responsible for higher-order cognition. However, it remains unknown how this functional topography evolves in development and supports cognition. Capitalizing on advances in machine learning and a large sample imaged with 27min of high-quality functional MRI (fMRI) data (n= 693, ages 8-23 years), we delineate how functional topography evolves during youth. We found that the functional topography of association networks is refined with age, allowing accurate prediction of unseen individuals' brain maturity. The cortical representation of association networks predicts individual differences in executive function. Finally, variability of functional topography is associated with fundamental properties of brain organization, including evolutionary expansion, cortical myelination, and cerebral blood flow. Our results emphasize the importance of considering the plasticity and diversity of functional neuroanatomy during development and suggest advances in personalized therapeutics.

Multisensory Gains in Simple Detection Predict Global Cognition in Schoolchildren

The capacity to integrate information from different senses is central for coherent perception across the lifespan from infancy onwards. Later in life, multisensory processes are related to cognitive functions, such as speech or social communication. During learning, multisensory processes can in fact enhance subsequent recognition memory for unisensory objects. These benefits can even be predicted; adults’ recognition memory performance is shaped by earlier responses in the same task to multisensory – but not unisensory – information. Everyday environments where learning occurs, such as classrooms, are inherently multisensory in nature. Multisensory processes may therefore scaffold healthy cognitive development. Here, we provide the first evidence of a predictive relationship between multisensory benefits in simple detection and higher-level cognition that is present already in schoolchildren. Multiple regression analyses indicated that the extent to which a child (N = 68; aged 4.5–15years) exhibited multisensory benefits on a simple detection task not only predicted benefits on a continuous recognition task involving naturalistic objects (p = 0.009), even when controlling for age, but also the same relative multisensory benefit also predicted working memory scores (p = 0.023) and fluid intelligence scores (p = 0.033) as measured using age-standardised test batteries. By contrast, gains in unisensory detection did not show significant prediction of any of the above global cognition measures. Our findings show that low-level multisensory processes predict higher-order memory and cognition already during childhood, even if still subject to ongoing maturation. These results call for revision of traditional models of cognitive development (and likely also education) to account for the role of multisensory processing, while also opening exciting opportunities to facilitate early learning through multisensory programs. More generally, these data suggest that a simple detection task could provide direct insights into the integrity of global cognition in schoolchildren and could be further developed as a readily-implemented and cost-effective screening tool for neurodevelopmental disorders, particularly in cases when standard neuropsychological tests are infeasible or unavailable.

Retraction Notice to: How birds outperform humans inmulti-component behavior.

Recent years have witnessed an astonishing flurry of studies demonstrating that some bird species show higher-order cognitive processes on par with primates [1-3]. As birds have no neocortex, cortical processing cannot be a requirement for higher order cognition [1,4]. Although birds have more neurons than expected from their small brain weights [5], their absolute neuron count is still lower compared to cortical neuron numbers of primates. How, then, is it possible that pigeons reach performance levels in, for example, abstract numerical competence and orthographic processing, that are comparable to that of macaques [6]? While the subpallium is very similar, the organization of the pallium differs tremendously between birds and mammals [1]; moreover, the avian pallium is characterized by small, extremely tightly packed neurons [5]. It is conceivable that signal processing could be faster in such a brain as a result of a higher speed of propagation of activation between neighboring assemblies, resulting in faster switch times between neighboring networks and neuronal representations of behavioral goals. This is important, as behavioral goals in real-life situations are often achieved by a series of sub-tasks [7,8], and especially when sub-tasks supersede each other and show little overlap in processing resources, neocortical (pallial) structures are involved [7,8]. We now report that pigeons are on par with humans when a task demands simultaneous processing resources; importantly, pigeons show faster responses than humans when sub-tasks are separated such that fast switches between processes are required.

Neural anomalies during vigilance in schizophrenia: Diagnostic specificity and genetic associations

Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N = 48), bipolar disorder patients (N = 26), first-degree biological relatives of schizophrenia patients (N = 55) and bipolar disorder patients (N = 28), as well as healthy controls (N = 68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.

Structural relations of language and cognitive skills, and topic knowledge to written composition: A test of the direct and indirect effects model of writing.

Writing involves multiple processes, drawing on a number of language, cognitive, and print-related skills, and knowledge. According to the Direct and Indirect Effects model of Writing (DIEW; Kim & Park, 2019, Reading and Writing, 32, 1319), these multiple factors have hierarchical, interactive, and dynamic relations. I examined the hierarchical relations of language and cognitive skills to written composition as well as the relation of topic knowledge to written composition, using DIEW as a theoretical framework. One hundred thirty-two English-speaking students in Grade 4 were assessed on written composition, topic knowledge, oral language (vocabulary, grammatical knowledge, discourse-level oral production), higher order cognitions (inference, perspective taking [theory of mind], monitoring), domain-general cognitions (working memory and attention), and transcription skills (spelling and handwriting fluency). Structural equation modelling was used to compare hierarchical relations models with a direct or flat relations model. The hierarchical relations model was supported. Discourse oral language skills and transcription skills completely mediated the relations of the other component skills to written composition, and the included component skills explained 82% of variance in written composition. Substantial total effects were found for discourse language, transcription, attention, working memory, vocabulary, theory of mind, and grammatical knowledge. Topic knowledge was moderately related to writing, but this relation became weak once the other skills were accounted for. Component skills have hierarchical structural relations and make direct and indirect contributions to written composition. Furthermore, the role of topic knowledge in written composition appears constrained by language and transcription skills for developing writers.

Oscillatory biomarkers of early auditory information processing predict cognitive gains following targeted cognitive training in schizophrenia patients

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by “bottom-up” enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Single session high definition transcranial direct current stimulation to the cerebellum does not impact higher cognitive function.

The prefrontal cortex is central to higher order cognitive function. However, the cerebellum, generally thought to be involved in motor control and learning, has also been implicated in higher order cognition. Recent work using transcranial direct current stimulation (tDCS) provides some support for right cerebellar involvement in higher order cognition, though the results are mixed, and often contradictory. Here, we used cathodal high definition tDCS (HD-tDCS) over the right cerebellum to assess the impact of HD-tDCS on modulating cognitive performance. We predicted that stimulation would result in performance decreases, which would suggest that optimal cerebellar function is necessary for cognitive performance, much like the prefrontal cortex. That is, it is not simply a structure that lends support to complete difficult tasks. While the expected cognitive behavioral effects were present, we did not find effects of stimulation. This has broad implications for cerebellar tDCS research, particularly for those who are interested in using HD-tDCS as a way of examining cerebellar function. Further implications, limitations, and future directions are discussed with particular emphasis on why null findings might be critical in developing a clear picture of the effects of tDCS on the cerebellum.

Evaluating the relationship between psychometric intelligence and cognitive functions in paediatric multiple sclerosis.

BackgroundProcessing speed is frequently reduced in patients suffering from multiple sclerosis (MS). Reduced processing speed can also lead to impaired working memory capacity (WMC) in adult MS patients. Less is known about the interplay of cognitive deficits in paediatric MS patients.ObjectivesIn the present study, we investigated whether processing speed and WMC are reduced in paediatric MS patients compared with healthy controls and whether reduced processing speed and WMC might explain potential differences in psychometric intelligence between MS patients and healthy controls.MethodsTwenty-one paediatric MS patients and 21 healthy controls completed a reaction time (RT) task, a working memory task, and Cattell’s Culture Fair Test (CFT20-R).ResultsPatients with MS had slower RT and lower intelligence scores than healthy controls. We could find no significant differences for WMC. An analysis of covariance revealed that group differences in intelligence could be partially explained by processing speed differences.ConclusionThe results indicate that processing speed is a good marker for MS-related impaired efficiency and increased error-proneness of the central nervous system in higher-order cognition as required by Cattell’s CFT20-R.

27.1 NEURAL STRUCTURE IS INDEPENDENTLY PREDICTED BY DEPRIVATION AND THREAT IN EARLY CHILDHOOD

The impact of childhood adversity on risk for psychopathology is commonly examined using a cumulative risk model. In a recently proposed alternative approach, the dimensional model of adversity and psychopathology (DMAP), different dimensions of adversity are hypothesized to impact health and well-being through different neural pathways. We expect deprivation to impact thickness in areas of cortex involved in higher-order cognition such as the prefrontal cortex. In contrast, we expect threat to selectively impact subcortical structures associated with increased reactivity to emotional stimuli.

Translating neural stem cells to neurons in the mammalian brain.

The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higher-order cognition. During mammalian embryogenesis, radial glial precursor cells sequentially give rise to diverse populations of excitatory cortical neurons, followed by astrocytes and oligodendrocytes. A subpopulation of these embryonic neural precursors persists into adulthood as neural stem cells, which give rise to inhibitory interneurons and glia. Although the intrinsic mechanisms instructing the genesis of these distinct progeny have been well-studied, most work to date has focused on transcriptional, epigenetic, and cell-cycle control. Recent studies, however, have shown that posttranscriptional mechanisms also regulate the cell fate choices of transcriptionally primed neural precursors during cortical development. These mechanisms are mediated primarily by RNA-binding proteins and microRNAs that coordinately regulate mRNA translation, stability, splicing, and localization. Together, these findings point to an extensive network of posttranscriptional control and provide insight into both normal cortical development and disease. They also add another layer of complexity to brain development and raise important biological questions for future investigation.

The Abused Inhalant Toluene Impairs Medial Prefrontal Cortex Activity and Risk/Reward Decision-Making during a Probabilistic Discounting Task

Inhalant (e.g., toluene) misuse is linked to behavioral and cognitive deficits in humans, yet preclinical studies of the effect of inhalants on higher-order cognition are limited. We addressed this gap in the literature by examining the effect of toluene vapor exposure on risk/reward decision-making in male and female Sprague-Dawley rats using a probabilistic discounting task. In this task, rodents chose a risky/large reward or a safe/small reward, with the odds of risky reinforcement descending or ascending throughout the test session. We observed a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting caused by acute toluene exposure. Rats exposed to toluene vapor during adolescence and tested as adults performed comparably to air-treated controls and were susceptible to the effects of an acute toluene challenge. These behavioral flexibility deficits observed suggests dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients in real-time using in vivo fiber photometry. mPFC activity peaked before either lever press during free-choice trials in toluene- and air-treated animals. During forced-choice trials, GCaMP6f transients shifted from pre-risky to pre-safe choice, an effect mitigated by acute toluene exposure. mPFC activity decreased during rewarded trials, with larger decreases following risky/large wins compared with safe/small wins. Toluene-treated animals also had decreased mPFC activity during rewarded trials, but there was no distinction between risky/large wins and safe/small wins. These results provide physiological evidence for mPFC-dependent behavioral deficits caused by toluene.SIGNIFICANCE STATEMENT Inhalants (e.g., toluene) are an understudied class of drugs of abuse that cause devastating behavioral and cognitive deficits in humans. Understanding the neurobiological interactions of toluene vapor using animal models is important for developing effective treatment strategies for inhalant addicts. Here we find that toluene vapor reduces behavioral flexibility in rodents making risk/reward-based decisions. The medial prefrontal cortex (mPFC) drives behavioral flexibility during this type of decision-making and we show that toluene reduces the ability of mPFC neurons to track optimal choices as reward probabilities change. Toluene also reduces these neurons' ability to distinguish between small and large rewards. A combination of these factors likely leads to the impaired performance in probabilistic discounting following acute toluene exposure.