Physiological correlates of intellectual function in children with sickle cell disease: hypoxaemia, hyperaemia and brain infarction

Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain. We investigated the relationship between daytime oxyhaemoglobin saturation (SpO2), cerebral blood flow velocity (CBFV) and intellectual function (IQ) using path-analysis in 30 adolescents with sickle cell disease (mean age 17.4 years, SD 4.2). Initial analyses revealed that the association between SpO2 and Full Scale IQ (FSIQ) was fully mediated by increased CBFV, whereby SpO2 was negatively correlated with CBFV and CBFV was negatively correlated with FSIQ, i.e. decreases in oxygen saturation are associated with increases in velocity, and increased velocity is associated with lowered IQ scores. The mediated relationship suggests that lowered IQ may be a function of abnormal oxygen delivery to the brain. Further analyses showed that the association between CBFV and IQ was significant for verbal but not for performance IQ. The pathophysiology characteristic of SCD can interfere with brain function and constrain intellectual development, even in the absence of an infarct. This supports the hypothesis that lowered intellectual function is partly explained by chronic hypoxia, and has wider implications for our understanding of SCD pathophysiology.     

Hypoxia and Inflammation in Children with Sickle Cell Disease: Implications for Hippocampal Functioning and Episodic Memory

Children with sickle cell disease (SCD) suffer from systemic processes (e.g., chronic anemia, recurrent hypoxic-ischemic events, chronic inflammation) that have been associated with neurocognitive impairment in a range of clinical populations, but which have been largely understudied in relation to specific domains of cognitive functioning in children with SCD. This review focuses on episodic memory, as the hippocampus may be especially vulnerable to the systemic processes associated with SCD. The first part of the paper outlines the pathophysiology of SCD and briefly reviews the extant literature on academic and cognitive functioning in children with SCD, emphasizing the dearth of research on episodic memory. Next, the complex systemic processes of hypoxia and inflammation associated with SCD are reviewed, along with research that has associated these processes with hippocampal damage and memory impairment. The paper concludes with suggestions for future research that are informed, in part, by the literature on developmental amnesia.     

The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease.

This study examined potential cognitive benefits of oral hydroxyurea therapy for children with sickle cell disease (SCD). Cognitive abilities of 15 children with SCD on hydroxyurea were compared to 50 other children with SCD, controlling for demographics and hematocrit. Children on hydroxyurea scored significantly higher on tests of verbal comprehension, fluid reasoning, and general cognitive ability than children not on the drug. The data therefore provide preliminary evidence of cognitive benefits of hydroxyurea. Mechanisms for this effect may be improved blood/oxygen supply to the brain or reduced fatigue and illness.     

Impulsivity and control of inhibition in Benign Focal Childhood Epilepsy (BFCE)

Childhood epilepsy represents abnormal brain functioning and may affect cognitive functions that depend on the late development of the frontal lobes. This study addresses the possible consequences of benign epilepsy on frontal functions, specifically action regulation and inhibition in the absence of explicit frontal neurological signs. Thirteen children (8 males; 6-12 years old) with benign epilepsy were matched to 13 controls. They performed tasks designed to measure impulsivity and control of inhibition: CPT, Stop Signal Paradigm, Stroop test, and Matching Familiar Figures Test (MFFT). Children with epilepsy made more errors on the MFFT (p < .02), made more errors in the interference condition on the Stroop test (p < .01), and had a longer response time to the Stop Signal (p < .05) than controls, with no differences on nonexecutive functions measures. Thus, children with benign epilepsy have a deficit on some measures of impulsivity and inhibition, which may reflect poor frontal lobe functioning.     

癫痫儿童认知功能障碍诊断中的问题

癫痫是小儿常见的神经系统慢性疾病,相当一部分儿童伴有认知功能损伤,早期诊断是正确干预、改善预后的前提。但在癫痫儿童认知功能障碍诊断中存在许多的问题,给相关研究带来困难。认知理论尚不完善;认知损伤与修复的机理不清;影响因素众多,而且各不相同;更主要的是方法学上的问题。目前研究趋势是分离不同的认知成分,早期诊断某些特定的认知损伤,国内在这方面的研究起步较晚。     

Sickle cell disease as a neurodevelopmental disorder

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which typically manifest as deficits in specific cognitive domains and academic difficulties. We discuss SCD as a neurodevelopmental disorder by reviewing the mechanisms of neurological morbidity in SCD, the timing of these mechanisms, the types of cognitive and behavioral morbidity that is typical, and the interaction of social-environmental context with disease processes. The impact of the disease on families shares many features similar to other neurodevelopmental disorders; however, social-environmental factors related to low socioeconomic status, worry and concerns about social stigma, and recurrent, unpredictable medical complications can be sources of relatively higher stress in SCD. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life.     

Psychological aspects of multiple sclerosis and its treatment: toward a biopsychosocial perspective

Multiple sclerosis (MS) is a chronic, progressive neurological disease that produces demyelination of the CNS nerve fibers. With onset most often in young adulthood, the disease produces a variety of neurological symptoms and follows an unpredictable course characterized by exacerbations and remissions. This article reviews the literature on psychological aspects of MS including early psychoanalytic studies and more current psychosocial research. Literature on the relationship between stress and symptoms, and the extent of cognitive impairment experienced is reviewed. A view of psychosocial adjustment to MS based upon an adaptive coping model, and a psychological treatment approach suited to the special needs of individuals with MS are discussed. Finally, a biopsychosocial research model is recommended due to the complex, interactive nature of MS and unique research difficulties it presents.     

Association between biological markers of sickle cell disease and cognitive functioning amongst Cameroonian children

Background: Some of the major complications of sickle cell disease (SCD) occur in the brain and apart from overt stroke, patients also present with cognitive impairments. We sought to evaluate the prevalence of cognitive deficits as well as their biological predicting factors in young SCD patients in Cameroon.

Methods: The cognitive performances of Cameroonian SCD young patients were evaluated using a neuropsychological test battery assessing four domains of cognitive functioning (executive functions, attention, memory, and sensory-motor skills) previously adapted and normalized on healthy subjects in Yaoundé.

Findings: Up to 37.5% of the 96 SCD patients aged 6 to 24 years (M?=?13.5, SD?=?4.9) had mild-to-severe cognitive deficits. The cognitive deficits tend to increase with age. There was a significant effect of SCD on executive functions and attention, whereas SCD patients performed as well as controls on memory and sensory-motor skills tests. Structural equation models showed a significant association between (a) severe anemia and lower executive functioning, (b) low fetal hemoglobin levels and lower executive functioning and attention, (c) history of cerebrovascular accidents and lower performances in executive functioning, sensory-motor skills, and memory, (d) pathological electroencephalogram and lower attention, and (e) abnormal Transcranial Doppler and lower memory.

Conclusion: SCD patients in Cameroon presented a very high prevalence of cognitive deficits, with a specific impairment of executive functions and attention. Routine neuropsychological evaluation for early detection of cognitive deficits in SCD patients could represent a cost-effective tool to implement in resource-limited contexts such as in sub-Saharan Africa.     

Parental Problem-Solving Abilities and the Association of Sickle Cell Disease Complications with Health-Related Quality of Life for School-Age Children

Children with sickle cell disease (SCD) are at risk for poor health-related quality of life (HRQOL). The current analysis sought to explore parent problem-solving abilities/skills as a moderator between SCD complications and HRQOL to evaluate applicability to pediatric SCD. At baseline, 83 children ages 6–12 years and their primary caregiver completed measures of child HRQOL. Primary caregivers also completed a measure of social problem-solving. A SCD complications score was computed from medical record review. Parent problem-solving abilities significantly moderated the association of SCD complications with child self-report psychosocial HRQOL (p = .006). SCD complications had a direct effect on parent proxy physical and psychosocial child HRQOL. Enhancing parent problem-solving abilities may be one approach to improve HRQOL for children with high SCD complications; however, modification of parent perceptions of HRQOL may require direct intervention to improve knowledge and skills involved in disease management.     

Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs

Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.     

Atypicalities in sleep and semantic consolidation in autism

Sleep is known to support the neocortical consolidation of declarative memory, including the acquisition of new language. Autism spectrum disorder (ASD) is often characterized by both sleep and language learning difficulties, but few studies have explored a potential connection between the two. Here, 54 children with and without ASD (matched on age, nonverbal ability and vocabulary) were taught nine rare animal names (e.g., pipa). Memory was assessed via definitions, naming and speeded semantic decision tasks immediately after learning (pre‐sleep), the next day (post‐sleep, with a night of polysomnography between pre‐ and post‐sleep tests) and roughly 1 month later (follow‐up). Both groups showed comparable performance at pre‐test and similar levels of overnight change on all tasks; but at follow‐up children with ASD showed significantly greater forgetting of the unique features of the new animals (e.g., pipa is a flat frog). Children with ASD had significantly lower central non‐rapid eye movement (NREM) sigma power. Associations between spindle properties and overnight changes in speeded semantic decisions differed by group. For the TD group, spindle duration predicted overnight changes in responses to novel animals but not familiar animals, reinforcing a role for sleep in the stabilization of new semantic knowledge. For the ASD group, sigma power and spindle duration were associated with improvements in responses to novel and particularly familiar animals, perhaps reflecting more general sleep‐associated improvements in task performance. Plausibly, microstructural sleep atypicalities in children with ASD and differences in how information is prioritized for consolidation may lead to cumulative consolidation difficulties, compromising the quality of newly formed semantic representations in long‐term memory.     

Dyspneic-fear and catastrophic cognitions in hyperventilatory panic attacks

The tenability of cognitive explanations of the experience of fear during panic attacks (viz. Ley's misattribution-of-symptoms hypothesis and Beck's and Clark's catastrophic-misinterpretation-of-symptoms hypotheses) is seriously questioned by findings from three independent lines of research: (a) Wolpe and Rowan's observation that catastrophic cognitions follow fear, (b) Rachman, Levitt and Lopatka's reports of panic attacks without fearful cognitions, and (c) reports of panic attacks during sleep occurring predominately during non-dreaming stages of sleep. Recognition of these findings led Ley to reject his misattribution-of-symptoms hypothesis in favor of an innate emotional-respiratory-response explanation. The revised hyperventilation theory now maintains that fear experienced during a hyperventilatory panic attack is caused by severe dyspnea in the context of little or no perceived control over the causes of the dyspnea (i.e. dyspneic-fear). Cognitions during panic attacks are discussed in terms of the cognitive deficit that results from the cerebral hypoxia produced by hyperventilation. Implications for theory and treatment are discussed.     

Performance on the Test of Memory Malingering in children with neurological conditions

Despite increasing interest in the use of performance validity tests with youth, relatively little is known about how children and adolescents with neurological diagnoses perform on these measures. The purpose of this study was to examine performance on the Test of Memory Malingering (TOMM) in a general pediatric neurologic sample. Data were obtained from 266 consecutive patients (mean age = 13.0, SD = 3.7, range = 5–18) referred for a neuropsychological assessment in a tertiary care pediatric hospital. As part of a broader neuropsychological battery, patients were administered the TOMM. In this sample, 94% of children passed the TOMM. Pass rate was 87% for 5–7 year-olds but was ≥ 90% for all other ages. Children with a history of stroke had the lowest pass rate (86%), with other diagnostic groups scoring ≥ 90%, including epilepsy, traumatic brain injury, and hydrocephalus. Lower TOMM performance was related to slower processing speed and weaker memory performance. The results support using the TOMM with children and adolescents who have neurological diagnoses. Caution may still be warranted when interpreting scores in those who are younger and/or who have more significant cognitive difficulty.     

Executive functions and linguistic performance in SCD older adults and healthy controls

Subjective cognitive decline (SCD) might represent the preclinical phase of Alzheimer’s disease. Given the interest to characterize it, the present study explores (1) if there are differences in lexical retrieval (LexR) and sentence comprehension (SComp) between SCD and matched controls, and (2) the predictive value of demographic variables and executive functions in relation to LexR and SComp in each group. A sample of 135 participants voluntarily took part in this study (66 with SCD). They all completed the Trail Making, the Stroop, the Boston Naming, and the ECCO-Senior tests, as well as verbal fluency tasks (VF). Results show that (1) groups differ in LexR and in inhibition efficiency, and (2) VF is explained by years of formal education, particularly in the control group; SComp in the most complex items seems to rely in different strategies, related to flexibility in controls and to inhibition efficiency in SCD patients.     

Consolidation of vocabulary is associated with sleep in typically developing children,but not in children with dyslexia

Sleep is known to play an active role in consolidating new vocabulary in adults; however, the mechanisms by which sleep promotes vocabulary consolidation in childhood are less well understood. Furthermore, there has been no investigation into whether previously reported differences in sleep architecture might account for variability in vocabulary consolidation in children with dyslexia. Twenty‐three children with dyslexia and 29 age‐matched typically developing peers were exposed to 16 novel spoken words. Typically developing children showed overnight improvements in novel word recall; the size of the improvement correlated positively with slow wave activity, similar to previous findings with adults. Children with dyslexia showed poorer recall of the novel words overall, but nevertheless showed overnight improvements similar to age‐matched peers. However, comparisons with younger children matched on initial levels of novel word recall pointed to reduced consolidation in dyslexics after 1 week. Crucially, there were no significant correlations between overnight consolidation and sleep parameters in the dyslexic group. This suggests a reduced role of sleep in vocabulary consolidation in dyslexia, possibly as a consequence of lower levels of learning prior to sleep, and highlights how models of sleep‐associated memory consolidation can be usefully informed by data from typical and atypical development.     

Evidence for the Syndrome of Nonverbal Learning Disabilities in Children with Brain Tumors

This study examined the predicted utility of the Nonverbal Learning Disabilities syndrome (NLD) (Rourke, 1995) for characterizing neurocognitive and psychosocial outcomes in 123 children with brain tumors. Children with brain tumors were found to be at high risk of having a specific academic deficit, particularly in arithmetic. Children with arithmetic deficit evidenced a higher rate of impairment on nonverbal tasks than on verbal tasks, whereas children with reading deficit evidenced a higher rate of impairment on verbal tasks than on nonverbal tasks. However, significant differences between children with arithmetic and reading deficits were not found for all of the component features of the NLD syndrome, and arithmetic deficit was not related to treatment with irradiation.     

Sickle cell disease: primary stroke prevention

Stroke is an important and common complication of sickle cell disease (SCD), affecting children as well as adults. Clinically evident stroke, usually brain infarction, is usually associated with stenosis or occlusion of the intracranial arteries of the Circle of Willis, sometimes with formation of moyamoya (a Japanese word for "hazy" or "like a puff of smoke" that describes the appearance of a abnormal microvasculature on angiography believed secondary to internal carotid artery stenosis or occlusion and the resultant extensive collateralization). Several types of intracranial hemorrhage are observed but usually in older children and adults. Cerebrovascular diseases restricted to small vessels may go unrecognized but is associated with cognitive and learning problems. Prevention of recurrent stroke has been accomplished with chronic blood transfusion. A primary prevention strategy for clinical stroke, based on the Stroke Prevention in Sickle Cell Anemia Trial, has been tested in a randomized clinical trial. Over 2,000 young children with SCD were screened with transcranial Doppler ultrasound (TCD) to detect elevated blood flow velocity indicative of vessel disease and high risk of future stroke. Those randomized to standard care (no transfusion) had a 10%/year risk of stroke, which was reduced >90% with chronic transfusion. This approach is the only primary stroke prevention strategy so far tested in SCD in a randomized controlled trial. Silent lesions on magnetic resonance imaging are associated with an approximately 1.5%/year risk of clinical stroke and a trial is now starting in children with these lesions who do not meet Stroke Prevention in Sickle Cell Anemia Trial criteria for transfusion based on TCD. A controlled trial, based on intervention for nocturnal hypoxemia, is also underway. Hydroxyurea, bone marrow transplantation, antiplatelet, and antithrombotic agents may work but have not been tested in primary prevention in a systematic way. If early and repeated, TCD screening of children, as recommended by National Heart Lung and Blood Institute and the American Stroke Association, were implemented broadly the incidence of new strokes could be greatly reduced in these children.     

Association of social-environmental factors with cognitive function in children with sickle cell disease

The aim of this study was to examine the relationship between cognitive function in pediatric sickle cell disease (SCD) patients and mothers’ reports of social-environmental stress, depressive symptoms, and parenting. A total of 65 children with SCD completed comprehensive neuropsychological testing to assess several domains of cognitive functioning, including general intellectual ability, academic achievement, and executive function. Mothers reported on demographics, social-environmental stress, depressive symptoms, and parenting. As predicted, children with SCD significantly underperformed relative to normative data on measures of cognitive function. Associations between maternal social-environmental stress, maternal depressive symptoms, and parenting were mixed. The results show partial support for the hypothesis that greater stress and depressive symptoms and less positive parenting are associated with poorer cognitive function in children with SCD. Linear regression analyses showed that maternal financial stress was the strongest predictor across all domains of cognitive function. The findings replicate and extend past research, reaffirming that children with SCD are at risk for cognitive impairment across multiple domains. Additionally, social-environmental stress, particularly financial strain, is linked to mothers’ depressive symptoms and parenting behaviors as well as children’s cognitive function. Future studies using direct observations of parenting behaviors are needed. These findings, along with recent research on parenting interventions, may inform the development of concrete, teachable parenting and coping skills to improve cognitive functioning in children with SCD.     

Associations between serum cortisol, cardiovascular function and neurological outcome following acute global hypoxia in the newborn piglet

Perinatal asphyxia is a significant contributor to neonatal brain injury. However, there is significant variability in neurological outcome in neonates after global hypoxia-ischemia. The aims of this study were to identify which physiological response/s during global hypoxia-ischemia influence the severity of brain injury and to assess their relative importance. Hypoxia/hypercapnia was induced in 20 anaesthetized piglets by reducing the inspired oxygen fraction to 10% and the ventilation rate from 30 to 10 breaths per minute for 45 min. Neurological outcome was assessed using functional markers including cerebral function amplitude (via electroencephalography) and cerebral impedance, and the structural marker microtubule associated protein-2 by immunohistochemistry at 6 h post hypoxia. Significant variability in neurological outcome was observed following the constant hypoxia/hypercapnia insult. There was a high degree of variability in cardiovascular function (mean arterial blood pressure and heart rate) and serum cortisol concentrations in response to hypoxia. More effective maintenance of cardiovascular function and higher serum cortisol concentrations were associated with a better outcome. These two variables were strongly associated with neurological outcome, and together explained 68% of the variation in the severity of neurological outcome. The variability in the cardiovascular and cortisol responses to hypoxia may be a more important determinant of neurological outcome then previously recognized.