Diverse learners: learning disabilities and quality of life following mind-body and health education interventions for adults with neurofibromatosis.

PURPOSE: Neurofibromatosis (NF) is associated with low quality-of-life (QoL). Learning disabilities are prevalent among those with NF, further worsening QoL and potentially impacting benefits from mind-body and educational interventions, yet research on this population is scarce. Here, we address this gap by comparing NF patients with and without learning disabilities on QoL at baseline and QoL-related gains following two interventions. METHODS: Secondary analysis of a fully-powered RCT of a mind-body program (Relaxation Response Resiliency Program for NF; 3RP-NF) versus an educational program (Health Enhancement Program for NF; HEP-NF) among 228 adults with NF. Participants reported QoL in four domains (Physical Health, Psychological, Social Relationships, and Environmental). We compare data at baseline, post-treatment, and 12-month follow-up, controlling for intervention type. RESULTS: At baseline, individuals with NF and learning disabilities had lower Psychological (T = -3.0, p = .001) and Environmental (T = -3.8, p < .001) QoL compared to those without learning disabilities. Both programs significantly improved all QoL domains (ps < .0001-0.002) from baseline to post-treatment, regardless of learning disability status. However, those with learning disabilities exceeded the minimal clinically important difference in only one domain (Psychological QoL) compared to three domains in individuals without learning disabilities. Moreover, those with learning disabilities failed to sustain statistically significant gains in Psychological QoL at 12-months, while those without learning disabilities sustained all gains. CONCLUSION: Adults with NF and learning disabilities have lower Psychological and Environmental QoL. While interventions show promise in improving QoL regardless of learning disabilities, additional measures may bolster clinical benefit and sustainability among those with learning disabilities.

Learning difficulties often not documented in newly diagnosed focal epilepsy.

OBJECTIVE: A previous investigation of people with newly diagnosed focal epilepsy participating in the Human Epilepsy Project 1 (HEP1) revealed an association between learning difficulties and structural brain differences, suggesting an underlying relationship prior to seizure onset. To investigate physicians' practices of documentation learning difficulties during clinical encounters, we conducted a review of initial epileptologist encounter notes from HEP1 participants who self-reported early life learning difficulties separately as part of study enrollment. METHODS: HEP1 enrolled 67 North American participants between June 2012 and November 2017 who self-reported one or more difficulties with learning (i.e., having repeated grade, receiving learning support/remediation, and/or formal diagnosis of a learning disability) prior to epilepsy diagnosis as part of the study enrollment. The epileptologist's initial encounter note was then reviewed in detail for each of these participants. Documentation of learning issues and specific diagnoses of learning disabilities was compared to participant characteristics. Regression analysis was used to test for any independent associations between participant characteristics and physician documentation of learning difficulties. RESULTS: There were significant independent relationships between age, sex, and physician documentation of learning difficulties. On average, participants ages 22 and younger were 12.12 times more likely to have their learning difficulties documented compared to those 23 years and older (95 % CI: 2.226 to 66.02, p = 0.004). Additionally, male participants had 7.2 times greater odds of having their learning difficulty documented compared to female participants (95 % CI: 1.538 to 33.717, p = 0.012). There were no significant independent associations between race, language, employment, or geographical region. SIGNIFICANCE: These findings highlight disparities in physician documentation for people with newly diagnosed focal epilepsy and a history of learning difficulties. In the HEP1 cohort, physicians were more likely to document learning difficulties in males and in younger individuals. Systematic practice standards are important for reducing healthcare disparities across populations, improving clinical care to individuals, as well as enabling more accurate retrospective study of clinical phenomenon.

Disruption of neonatal Purkinje cell function underlies injury-related learning deficits.

It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury. Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex.

A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster.

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/ß neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

Cognitive deficits and impaired hippocampal long-term potentiation in KATP-induced DEND syndrome.

ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic ß-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF.

Learning disabilities in children with hearing loss: A systematic review.

PURPOSE: The main aim of this systematic review was to investigate the possible association between hearing loss [and/or history of otitis media with effusion (OME)] and learning difficulties in children. Secondary aims were to: (i) investigate if deaf and hard of hearing (DHH) children with learning difficulties might show different clinical and neuropsychological features compared with those with other neurodevelopmental disorders; (ii) identify possible predictors of learning difficulty in DHH children. METHODS: A review was conducted of the scientific literature reported by Pubmed, Cochrane and Scopus databases. The following inclusion criteria were used: (i) studies published after 2000; (ii) studies conducted considering subjects with age < 18 years; (iii) studies considering patients who showed both learning difficulties and hearing loss and/or episodes of OME; (iv) articles written in English. The exclusion criteria were: (i) presence in the studied cohort of any other proven comorbidities, other than hearing loss and/or OME; (ii) non-original studies. RESULTS: A total of 924 studies were identified. Four were reviewed after applying the above criteria. From their analysis it emerged that: (i) children with hearing loss who had undergone a diagnostic and rehabilitation program before 6 months of age had better levels of K readiness and language and literacy skills compared to those who had undergone it after 6 months; (ii) higher frequency of episodes of OME and the presence of a conductive hearing loss during the period of language acquisition was associated to lower scores in reading skills; (iii) reading difficulties found in subjects with hearing loss had similar characteristics to those with language difficulties. CONCLUSIONS: There is a dearth of information about this topic. Further investigations are therefore necessary on children of various ages with hearing loss to disclose learning difficulties in reading and writing abilities using current diagnostic tools.

From vision to cognition: potential contributions of cerebral visual impairment to neurodevelopmental disorders.

Vision has a crucial role to play in human development and functioning. It is, therefore, not surprising that vision plays a fundamental role in the development of the child. As a consequence, an alteration in visual function is, therefore, likely to hinder the child's development. Although ocular disorders are well known, diagnosed and taken into account, cerebral visual impairments (CVI) resulting from post-chiasmatic damage are largely underdiagnosed. However, among the disorders resulting from an episode of perinatal asphyxia and/or associated with prematurity, or neonatal hypoglycaemia, CVIs are prominent. In this article, we focus on the role of the possible effects of CVI on a child's learning abilities, leading to major difficulty in disentangling the consequences of CVI from other neurodevelopmental disorders (NDD) such as dyslexia, dyscalculia, dysgraphia, attention-deficit/hyperactivity disorder (ADHD), developmental coordination disorder (DCD) and autism spectrum disorders (ASD). Although we focus here on the possible overlap between children with CVI and children with other NDD, De Witt et al. (Wit et al. Ear Hear 39:1-19, 2018) have raised exactly the same question regarding children with auditory processing disorders (the equivalent of CVI in the auditory modality). We underline how motor, social and cognitive development as well as academic success can be impaired by CVI and raise the question of the need for systematic evaluation for disorders of vision, visual perception and cognition in all children presenting with a NDD and/or previously born under adverse neurological conditions.

Strengths and difficulties in children with specific learning disabilities.

BACKGROUND: The study aims to investigate the social, emotional, and behavioral challenges in children with a specific learning disability (SLD) and to identify the factors that accompany these problems by screening with the Strengths and Difficulties Questionnaire (SDQ). METHODS: The descriptive study was conducted on 278 children with SLD. Strengths and difficulties in children were evaluated by the SDQ applied to their mothers. The percentage of cases above the cut-off limits of the SDQ was calculated. Chi-square test and multiple logistic regression analysis were used for analysis. RESULTS: The mean (SD) total SDQ score was 15.8 (6.5). The percentage of scores of abnormal total difficulties in SLD was 47.8%. Multivariate analysis revealed that cases exposed to antenatal smoking had higher odds ratio of abnormal emotional symptoms and abnormal total difficulties; cases with poor familial income and the presence of a history of antenatal smoking exposure showed considerably higher odds ratio of conduct problems; cases with younger age at the diagnosis of SLD, dyscalculia, extreme duration of preschool screen time (≥4 h), and history of hospitalization had significantly higher odds ratio for hyperactivity-inattention problems; and cases having shorter breastfeeding duration had higher odds ratio of peer problems compared to counterparts. CONCLUSION: Children with SLD have a high score on the SDQ. Practitioners could especially give guidance and support to families with financial problems and those having a child with an early age at diagnosis, exposure to antenatal smoking, short breastfeeding period, early age of the first screen use, and long screen exposure duration during the preschool period.

Altered structure and functional connectivity of the hippocampus are associated with social and mathematical difficulties in nonverbal learning disability.

The hippocampus is known to play a critical role in a variety of complex abilities, including visual-spatial reasoning, social functioning, and math. Nonverbal learning disability (NVLD) is a neurodevelopmental disorder characterized by deficits in visual-spatial reasoning that are accompanied by impairment in social function or mathematics, as well as motor or executive function skills. Despite the overlap between behaviors supported by the hippocampus and impairments in NVLD, the structure and function of the hippocampus in NVLD has not been studied. To address this gap in the literature, we first compared hippocampal volume and resting-state functional connectivity in children with NVLD (n = 24) and typically developing (TD) children (n = 20). We then explored associations between hippocampal structure, connectivity, and performance on measures of spatial, social, and mathematical ability. Relative to TD children, those with NVLD showed significant reductions in left hippocampal volume and greater hippocampal-cerebellar connectivity. In children with NVLD, reduced hippocampal volume associated with worse mathematical problem solving. Although children with NVLD exhibited more social problems (social responsiveness scale [SRS]) and higher hippocampal-cerebellar connectivity relative to TD children, greater connectivity was associated with fewer social problems among children with NVLD but not TD children. Such an effect may suggest a compensatory mechanism. These structural and functional alterations of the hippocampus may disrupt its putative role in organizing conceptual frameworks through cognitive mapping, thus contributing to the cross-domain difficulties that characterize NVLD.

A rare disease and education: Neurofibromatosis type 1 decreases educational attainment.

Rare heritable syndromes may affect educational attainment. Here, we study education in neurofibromatosis 1 (NF1) that is associated with multifaceted medical, social and cognitive consequences. Educational attainment in the Finnish population-based cohort of 1408 individuals with verified NF1 was compared with matched controls using Cox proportional hazards model with delayed entry and competing risk for death. Moreover, models accounting for the effects of cancer at age 15-30 years, parental NF1 and developmental disorders were constructed. Overall, the attainment of secondary education was reduced in individuals with NF1 compared to controls (hazard ratio 0.83, 95%CI 0.74-0.92). History of cancer and developmental disorders were major predictors of lack of secondary education. Individuals with NF1 obtained vocational secondary education more often than general upper secondary education. Consequently, NF1 decreased the attainment of Bachelor's and Master's degrees by 46%-49% and 64%-74%, respectively. Surprisingly, the non-NF1 siblings of individuals with NF1 also had lower educational attainment than controls, irrespective of parental NF1. In conclusion, NF1 is associated with reduced educational attainment and tendency for affected individuals to obtain vocational instead of academic education. Individuals living with NF1, especially those with cancer, developmental disorders or familial NF1, need effective student counseling and learning assistance.

Influence of Special Education, ADHD, Autism, and Learning Disorders on ImPACT Validity Scores in High School Athletes.

OBJECTIVE: The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is commonly used to assist with post-concussion return-to-play decisions for athletes. Additional investigation is needed to determine whether embedded indicators used to determine the validity of scores are influenced by the presence of neurodevelopmental disorders (NDs). METHOD: This study examined standard and novel ImPACT validity indicators in a large sample of high school athletes (n = 33,772) with or without self-reported ND. RESULTS: Overall, 7.1% of athletes' baselines were judged invalid based on standard ImPACT validity criteria. When analyzed by group (healthy, ND), there were significantly more invalid ImPACT baselines for athletes with an ND diagnosis or special education history (between 9.7% and 54.3% for standard and novel embedded validity criteria) when compared to athletes without NDs. ND history was a significant predictor of invalid baseline performance above and beyond other demographic characteristics (i.e., age, sex, and sport), although it accounted for only a small percentage of variance. Multivariate base rates are presented stratified for age, sex, and ND. CONCLUSIONS: These data provide evidence of higher than normal rates of invalid baselines in athletes who report ND (based on both the standard and novel embedded validity indicators). Although ND accounted for a small percentage of variance in the prediction of invalid performance, negative consequences (e.g., extended time out of sports) of incorrect decision-making should be considered for those with neurodevelopmental conditions. Also, reasons for the overall increase noted here, such as decreased motivation, "sandbagging", or disability-related cognitive deficit, require additional investigation.

Severity of Ongoing Post-Concussive Symptoms as a Predictor of Cognitive Performance Following a Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury. METHOD: 203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8-18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1-11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (~4 months) phase. RESULTS: Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not. CONCLUSIONS: The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.

Outcomes in Hirschsprung's disease with coexisting learning disability.

This study describes functional and health-related quality of life (HRQoL) outcomes in patients with Hirschsprung's disease (HSCR) with associated learning disability or neurodevelopmental delay (LD), completing a core outcome set for HSCR. This was a cross-sectional study from a tertiary pediatric surgery center. Patients treated between 1977 and 2013 were prospectively contacted to complete an outcomes survey. Children under 12 and older patients with LD were assisted to complete these by a proxy. Bowel and urologic function were assessed (Rintala's BFS and modified DanPSS) along with HRQoL (PedsQL/GIQLI/SF-36). Thirty-two patients with LD were compared to 186 patients with normal cognition. Patients with LD had 76% survival over the follow-up period, compared to 99% in the remainder of the cohort. Poor functional outcomes were common in the patients with LD, considerably higher than cognitively normal patients: with weekly issues withholding stool, soiling and fecal accidents in over half of patients surveyed (44-60%), and urinary incontinence in 46%. Use of permanent stoma was significantly higher (22% vs. 4%; p = 0.001). HRQoL was worse in domains of physical functioning in adults and children but not for social or emotional domains in adults. Subgroup analysis of patients with Down syndrome suggested similar functional results but better QoL. Multivariate analysis demonstrated a dramatically higher incidence of poor continence outcomes in patients with LD (adjusted OR 9.6 [4.0-23]).Conclusions: We provide LD-specific outcomes showing inferior function but similar HRQoL to other patients with HSCR, this is much needed in the counselling of families of these children. What is Known: • Hirschsprung's disease is commonly associated with syndromes or other anomalies with resultant cognitive impairments. • The outcomes for these patients specifically have been poorly described in the literature. What is New: • Objective functional and quality of life surveys demonstrate significant differences from patients without cognitive impairment. • Patients with learning disability Patients with associated LD were almost ten times more likely to have an associated poor functional outcome, with very little impact on proxy-reported quality of life.

Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia.

Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects.

Predictive Value of the Global School Adaptation Questionnaire at 5 Years of Age and Educational Support at 7 Years of Age in Very Preterm Children.

OBJECTIVE: To assess the Global School Adaptation (GSA) questionnaire of children's abilities and classroom behavior administered to teachers of very preterm children at 5 years of age as a predictor of the need for educational support (grade retention, special class, learning support) at age 7. STUDY DESIGN: We assessed 858 very preterm children (<33 weeks of gestation) at 5 years of age using the GSA and again at 7 years to determine the use of educational support. We examined the association between the GSA score and educational support at 7 years and performed a receiver operating characteristic curve analysis. RESULTS: At 7 years of age, 130 children had educational support (15.2%). Children with a nonoptimal GSA score (<45) at 5 years required educational support more often (57.7%) than children with a GSA score of 45 or greater (15.4%) (OR, 7.5; 95% CI, 5.02-11.21). The need for educational support was associated with male sex; a low parent socioeconomic level; lower birth weight, birth head circumference, or gestational age (28-30 weeks of gestation); severe neurologic complications; patent ductus arteriosus ligation; and the use of therapy services at 5 years of age. After adjustment, only the GSA score was associated with educational support at 7 years of age (OR, 0.86; 95% CI, 0.84-0.88). A receiver operating characteristic curve analysis of the GSA performance revealed an optimal cut-off at 48, with a sensitivity of 70.8%, a specificity of 73.5%, and an area under the curve of 0.79. CONCLUSIONS: Using a cut-off score of 48, the GSA at 5 years of age may be a useful tool to identify children born preterm at risk of school-based learning difficulties.

Neuronal Nitric Oxide Inhibitor 7-Nitroindazole Improved Brain-Derived Neurotrophic Factor and Attenuated Brain Tissues Oxidative Damage and Learning and Memory Impairments of Hypothyroid Juvenile Rats.

Hypothyroidism-associated learning and memory impairment is reported to be connected to oxidative stress and reduced levels of brain-derived neurotrophic factor (BDNF). The effects of neuronal nitric oxide inhibitor 7-nitroindazole (7NI) on brain tissues oxidative damage, nitric oxide (NO), BDNF and memory impairments in hypothyroid juvenile rats were investigated. Male Wistar juvenile rats (20 days old) were divided into five groups, including Martinez et al. (J Neurochem 78 (5):1054-1063, 2001). Control in which vehicle was injected instead of 7NI, (Jackson in Thyroid 8 (10):951-956, 1998) Propylthiouracil (PTU) where 0.05% PTU was added in drinking water and vehicle was injected instead of 7NI, (Gong et al. in BMC Neurosci 11 (1):50, 2010; Alva-Sánchez et al. in Brain Res 1271:27-35, 2009; Anaeigoudari et al. in Pharmacol Rep 68 (2): 243-249, 2016) PTU-7NI 5, PTU-7NI 10 and PTU-7NI 20 in which 5, 10, or 20 mg/kg7NI was injected intraperitoneally (i.p.). Following 6 weeks, Morris water maze (MMW) and passive avoidance learning (PAL) tests were used to evaluate the memory. Finally, the hippocampus and the cortex of the rats were removed after anesthesia by urethane to be used for future analysis. The escape latency and traveled path in MWM test was increased in PTU group (P < 0.001). PTU also reduced the latency to enter the dark box of PAL and the time spent and the distance in the target quadrant in MWM test (P < 0.001 and P < 0.01). Treatment with 7NI attenuated all adverse effects of PTU (P < 0.05 to P < 0.001). PTU lowered BDNF and thiol content and superoxide dismutase (SOD) and catalase (CAT) activities in the brain but increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. In addition, 7NI improved thiol, SOD, CAT, thiol, and BDNF but attenuated MDA and NO metabolites. The results of the current study showed that 7NI improvement in the learning and memory of the hypothyroid juvenile rats, which was accompanied with improving of BDNF and attenuation of NO and brain tissues oxidative damage.

Neurodevelopmental, behavioral, and emotional symptoms in Becker muscular dystrophy.

INTRODUCTION: Becker muscular dystrophy (BMD) results in decreased dystrophin with implications for mental health. METHODS: This is a retrospective case series of neurodevelopmental, behavioral, and emotional symptoms and respective pharmacotherapies of 70 patients with BMD. RESULTS: Fifty-four (77.1%) patients exhibited at least one symptom, and 19 (27.1%) patients exhibited four or more symptoms. The most prevalent symptoms were specific learning disabilities or special education needs (31.4%), inattention/hyperactivity (35.7%), language/speech delays (35.7%), and emotional or behavioral dysregulation (38.6%). Fisher's exact tests indicated that anxiety was more prevalent with mutations upstream of exon 30 (P = .049), but the prevalence of other symptoms did not differ with respect to mutation sites. Similarly, the number of symptoms individual patients with BMD exhibited did not differ with respect to mutation sites. Seventeen (24.3%) patients required pharmacotherapy to manage symptoms. DISCUSSION: Neurodevelopmental, behavioral, and emotional symptoms are prevalent in patients with BMD regardless of dystrophin gene mutation site.

Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice.

Radiation therapy and concomitant temozolomide chemotherapy are commonly used in treatment of brain tumors, but they may also result in behavioral impairments such as anxiety and cognitive deficit. The present study sought to investigate the effect of fluoxetine on the behavioral impairments caused by radiation and temozolomide treatment. C57BL/6J mice were subjected to a single cranial radiation followed by 6-wk cyclic temozolomide administration and were then treated with chronic administration of fluoxetine. Behavioral tests were carried out to determine the anxiety-like behavior and cognition function of these animals. Long-term potentiation (LTP) in the hippocampus was measured by electrophysiology, and neurogenesis in the dentate gyrus was evaluated by immunohistochemistry. Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment, along with LTP impairment and neurogenesis deficit. Chronic fluoxetine administration could reverse the behavioral dysfunction, enhance LTP, and increase neurogenesis in the hippocampus. NEW & NOTEWORTHY Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment. Chronic fluoxetine administration could reverse the behavioral dysfunction. The effect of fluoxetine might be via rescuing the neurogenesis deficit caused by radiation and temozolomide treatment.

Longitudinal increases in structural connectome segregation and functional connectome integration are associated with better recovery after mild TBI.

Traumatic brain injury damages white matter pathways that connect brain regions, disrupting transmission of electrochemical signals and causing cognitive and emotional dysfunction. Connectome-level mechanisms for how the brain compensates for injury have not been fully characterized. Here, we collected serial MRI-based structural and functional connectome metrics and neuropsychological scores in 26 mild traumatic brain injury subjects (29.4 ± 8.0 years, 20 males) at 1 and 6 months postinjury. We quantified the relationship between functional and structural connectomes using network diffusion (ND) model propagation time, a measure that can be interpreted as how much of the structural connectome is being utilized for the spread of functional activation, as captured via the functional connectome. Overall cognition showed significant improvement from 1 to 6 months (t25 = -2.15, p = .04). None of the structural or functional global connectome metrics was significantly different between 1 and 6 months, or when compared to 34 age- and gender-matched controls (28.6 ± 8.8 years, 25 males). We predicted longitudinal changes in overall cognition from changes in global connectome measures using a partial least squares regression model (cross-validated R2 = .27). We observe that increased ND model propagation time, increased structural connectome segregation, and increased functional connectome integration were related to better cognitive recovery. We interpret these findings as suggesting two connectome-based postinjury recovery mechanisms: one of neuroplasticity that increases functional connectome integration and one of remote white matter degeneration that increases structural connectome segregation. We hypothesize that our inherently multimodal measure of ND model propagation time captures the interplay between these two mechanisms.

Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway.

BACKGROUND: Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinflammation. Moreover, CatC can induce chemokine production in brain inflammatory processes. In vitro studies further confirmed that CatC is secreted extracellularly from LPS-treated microglia. However, the mechanisms of CatC affecting neuroinflammatory responses are not known yet. METHODS: CatC over-expression (CatCOE) and knock-down (CatCKD) mice were treated with intraperitoneal and intracerebroventricular LPS injection. Morris water maze (MWM) test was used to assess the ability of learning and memory. Cytokine expression in vivo was detected by in situ hybridization, quantitative PCR, and ELISA. In vitro, microglia M1 polarization was determined by quantitative PCR. Intracellular Ca2+ concentration was determined by flow cytometry, and the expression of NR2B, PKC, p38, IkBα, and p65 was determined by western blotting. RESULTS: The LPS-treated CatCOE mice exhibited significantly increased escape latency compared with similarly treated wild-type or CatCKD mice. The highest levels of TNF-α, IL-1ß, and other M1 markers (IL-6, CD86, CD16, and CD32) were found in the brain or serum of LPS-treated CatCOE mice, and the lowest levels were detected in CatCKD mice. Similar results were found in LPS-treated microglia derived from CatC differentially expressing mice or in CatC-treated microglia from wild-type mice. Furthermore, the expression of NR2B mRNA, phosphorylation of NR2B, Ca2+ concentration, phosphorylation of PKC, p38, IκBα, and p65 were all increased in CatC-treated microglia, while addition of E-64 and MK-801 reversed the phosphorylation of above molecules. CONCLUSION: The data suggest that CatC promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. CatC may be one of key molecular targets for alleviating and controlling neuroinflammation in neurological diseases.