The organization of functional neurocognitive networks in focal epilepsy correlates with domain-specific cognitive performance

Understanding and diagnosing cognitive impairment in epilepsy remains a prominent challenge. New etiological models suggest that cognitive difficulties might not be directly linked to seizure activity, but are rather a manifestation of a broader brain pathology. Consequently, treating seizures is not sufficient to alleviate cognitive symptoms, highlighting the need for novel diagnostic tools. Here, we investigated whether the organization of three intrinsic, resting-state functional connectivity networks was correlated with domain-specific cognitive test performance. Using individualized EEG source reconstruction and graph theory, we examined the association between network small worldness and cognitive test performance in 23 patients with focal epilepsy and 17 healthy controls, who underwent a series of standardized pencil-and-paper and digital cognitive tests. We observed that the specific networks robustly correlated with test performance in distinct cognitive domains. Specifically, correlations were evident between the default mode network and memory in patients, the central-executive network and executive functioning in controls, and the salience network and social cognition in both groups. Interestingly, the correlations were evident in both groups, but in different domains, suggesting an alteration in these functional neurocognitive networks in focal epilepsy. The present findings highlight the potential clinical relevance of functional brain network dysfunction in cognitive impairment.Peer reviewe

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children

BACKGROUND: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex. MATERIAL AND METHODS: This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles. RESULTS: PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups. CONCLUSIONS: Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association - and need for replication.This research was funded by the Research Council of Norway (MILJØFORSK, project no. 267984/E50 “NeuroTox”), National Institutes of Health (NIH) R01ES021777, and National Institute of Environmental Health Sciences (NIEHS) P30 ES010126. The ADHD Study, from which the present data were drawn, was supported by funds and grants from the Norwegian Ministry of Health, the Norwegian Health Directorate, the South-Eastern Health Region, G&PJ Sorensen Fund for Scientific Research, and from the Norwegian Resource Centre for ADHD, Tourette syndrome and Narcolepsy. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH, and National Institute of Neurological Disorders and Stroke (NINDS) (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1). We are grateful to all the participating families in Norway who take part in this on-going cohort study, and to the staff of the ADHD Study.publishedVersio

Executive function in young preschool children with symptoms of ADHD

The overarching goal of research presented in this thesis was to provide new knowledge about basic, self-regulatory skills- or executive function (EF)- in young preschool children with behavioral symptoms characteristic of Attention-Deficit/Hyperactivity Disorder (ADHD). Etiological models of ADHD emphasize an onset during kindergarten and preschool years, and neuropsychological theories have converged on deficits in early developing EF processes as a possible developmental pathway towards ADHD. Despite a growing interest in EF development and the introduction of several developmentally appropriate methods of EF measurement for use with the youngest age groups, studies addressing EF in young children with elevated levels of ADHD symptoms are still scarce. Research hypotheses in this thesis had thus to be based on theoretical models of EF development, together with findings from the preschool group as a whole (pooled data from children aged 3 –6 years), and from older children. We hypothesized that EF structure in early preschool years would differ from that described in older children (Paper II), but that associations between deficiencies in early emerging EF processes and symptoms of ADHD would be identifiable. This was expected to hold both when EF was assessed through neuropsychological tests (Paper I), and by use of parents’ ratings of EF behavior in everyday settings (Paper III). The relationship between clinically administered tests of EF and parents’ ratings of EF behavior was specifically addressed in an additional empirical chapter. Our results indicate that at age three, some differentiation has taken place, which is measurable both by neuropsychological tasks and ratings of EF behavior in everyday settings. Labels used to define EF subcomponents in school-aged children and adolescents may not map directly onto emerging EF skills during early preschool years. Performance on neuropsychological tests of inhibition and working memory were related to symptoms of ADHD in our sample. Effect sizes were small, limiting the measures’ clinical utility at this early stage in development. Behavioral ratings of EF in these two domains were more closely related to symptoms of ADHD than the performance-based measures. According to parent ratings of EF, children meeting diagnostic criteria for ADHD presented with higher problem scores across EF domains, and a different EF profile relative to children with internalizing problems and typically developing controls. We found that performance-based measures of EF and ratings of EF behavior were related in our sample. These two methods of measurement are likely to tap into different aspects of early EF and should not be used interchangeably as parallel measures of EF

Parent ratings of executive function in young preschool children with symptoms of attention-deficit/-hyperactivity disorder

Background Recent research has demonstrated that deficits in basic, self-regulatory processes, or executive function (EF), may be related to symptoms of attention-deficit/hyperactivity disorder (ADHD) already during the preschool period. As the majority of studies investigating these relations in young children have been based primarily on clinically administered tests, it is not clear how early symptoms of ADHD may be related to observations of EF in an everyday context. The preschool version of the Behavior Rating Inventory of Executive Function (BRIEF-P) was developed to provide information about EF through observable, behavioral manifestations of self-regulation, and is the most commonly used rating scale for EF assessment in children. Methods Relations between symptoms of ADHD reported in the Preschool Age Psychiatric Assessment interview (PAPA), and EF as measured by the BRIEF-P (parent form), were investigated in a large, nonreferred sample of preschool children (37–47 months, n = 1134) recruited from the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. The inventory’s discriminative ability was examined in a subsample consisting of children who met the diagnostic criteria for either ADHD, oppositional defiant disorder (ODD) or anxiety disorder, and typically developing controls (n = 308). The four groups were also compared with regard to patterns of EF difficulties reported in the BRIEF-P. Results Of the five BRIEF-P subscales, Inhibit and Working Memory were the two most closely related to ADHD symptoms, together explaining 38.5% of the variance in PAPA symptom ratings. Based on their scores on the Inhibit and Working Memory subscales (combined), 86.4% of the children in the ADHD and TD groups were correctly classified. ADHD symptoms were associated with more severe difficulties across EF domains, and a different EF profile in comparison to children with other symptoms (anxiety, ODD) and to typically developing controls. Conclusions Early symptoms of ADHD were linked to parent-reported difficulties primarily within inhibition and working memory, suggesting that deficiencies within these two EF domains characterize early forms of ADHD. Our findings support the clinical utility of the BRIEF-P as a measure of EF in young preschool children with symptoms of ADHD

Factor structure of the Behavior Rating Inventory of Executive Functions (BRIEF-P) at age three years

The preschool period is an important developmental period for the emergence of cognitive self-regulatory skills or executive functions (EF). To date, evidence regarding the structure of EF in preschool children has supported both unitary and multicomponent models. The aim of the present study was to test the factor structure of early EF as measured by the Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P). BRIEF-P consists of five subscales and three broader indexes, hypothesized to tap into different subcomponents of EF. Parent ratings of EF from a nonreferred sample of children recruited from the Norwegian Mother and Child Cohort Study (N = 1134; age range 37–47 months) were subjected to confirmatory factor analyses (CFA). Three theoretically derived models were assessed; the second-order three-factor model originally proposed by the BRIEF-P authors, a “true” first-order one-factor model and a second-order one-factor model. CFA fit statistics supported the original three-factor solution. However, the difference in fit was marginal between this model and the second-order one-factor model. A follow-up exploratory factor analysis (EFA) supported the existence of several factors underlying EF in early preschool years, with a considerable overlap with the five BRIEF-P subscales. Our results suggest that some differentiation in EF has taken place at age 3 years, which is reflected in behavior ratings. The internal consistency of the BRIEF-P five clinical subscales is supported. Subscale interrelations may, however, differ at this age from those observed in the preschool group as a whole

Cognitive change after DBS in refractory epilepsy: A randomized-controlled trial

Objectives Deep brain stimulation of the anterior thalamic nucleus (ANT-DBS) reduces seizure frequency in patients with refractory epilepsy. There are, however, few studies on treatment-related changes in cognitive functions. The main objective of this study was to investigate cognitive changes in patients receiving ANT-DBS. We also explored whether possible effects were related to stimulation duration and whether change in seizure frequency was associated with cognitive changes. Materials and methods Bilateral ANT electrodes were implanted in 18 patients with refractory epilepsy, aged 18–52 years. Immediately after implantation, patients were randomized to stimulation ON (n = 8) or OFF (n = 10) for the first 6 months (blinded phase). During the following 6-month open phase, both groups received stimulation. Neuropsychological assessments were conducted before implantation (T1), at the end of the blinded period (T2), and 1 year after implantation (T3). Results Groupwise comparisons across the three time points revealed changes in performance in two of 22 cognitive test scores: motor speed and sustained attention. We found no significant group differences in cognitive change from T1 to T2. Patients reported fewer symptoms of executive dysfunction after 12 months of stimulation. Patients showing significant improvement in seizure frequency had better performance in a measure of verbal learning. Conclusion Our results indicate that ANT-DBS has very limited effects on cognitive functioning, as measured by formal tests after 6- or 12-month stimulation. ANT-DBS may have a positive influence on executive function. Our findings provide limited support for an association between change in seizure frequency and cognitive functioning

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children

Background Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex. Material and methods This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles. Results PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups. Conclusions Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association – and need for replication

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children

BACKGROUND: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex. MATERIAL AND METHODS: This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles. RESULTS: PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups. CONCLUSIONS: Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association - and need for replication