High occurrence of sleep problems in survivors of a childhood brain tumor with neurocognitive complaints: The association with psychosocial and behavioral executive functioning.

BACKGROUND: Survivors of childhood brain tumors are prone to sleep and neurocognitive problems. Effective interventions to improve neurocognitive functioning are largely lacking. In general, sleep problems are negatively related to neurocognitive functioning, but this relationship is unclear in survivors of childhood brain tumors. Therefore, the occurrence of sleep problems, potential risk factors, and the relation between sleep and executive functioning were evaluated. PROCEDURE: Baseline data of a randomized controlled trial on the effectiveness of neurofeedback were used. Childhood brain tumor survivors 8-18 years of age with parent-reported neurocognitive complaints ≥2 years after treatment were eligible. Parents completed the Sleep Disturbance Scale for Children. Executive functioning was assessed by parents and teachers (Behavior Rating Inventory of Executive Functioning). Multiple linear regression analyses were used to examine sociodemographic and medical characteristics and emotional difficulties and hyperactivity/inattention (Strength and Difficulties Questionnaire) as potential risk factors for sleep problems, and to assess the association between sleep and executive functioning. RESULTS: Forty-eight percent of survivors (n = 82, 7.0 ± 3.6 years post diagnosis, age 13.8 ± 3.2 years) had sleep problems and scored significantly worse than the norm on the subscales Initiating and Maintaining Sleep, Excessive Somnolence, and the total scale (effect sizes 0.58-0.92). Emotional problems and/or hyperactivity/inattention were independent potential risk factors. Sleep problems were associated with worse parent-reported executive functioning. CONCLUSIONS: Sleep problems occur among half of childhood brain tumor survivors with neurocognitive problems, and are associated with worse executive functioning. Future studies should focus on the development of sleep interventions for this population, to improve sleep as well as executive functioning.

Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls.

With more children surviving a brain tumor, insight into the late effects of the disease and treatment is of high importance. This study focused on profiling the neurocognitive functions that might be affected after treatment for a pediatric brain tumor, using a broad battery of computerized tests. Predictors that may influence neurocognitive functioning were also investigated. A total of 82 pediatric brain tumor survivors (PBTSs) aged 8-18 years (M = 13.85, SD = 3.15, 49% males) with parent-reported neurocognitive complaints were compared to a control group of 43 siblings (age M = 14.27, SD = 2.44, 40% males) using linear mixed models. Neurocognitive performance was assessed using measures of attention, processing speed, memory, executive functioning, visuomotor integration (VMI), and intelligence. Tumor type, treatment, tumor location, hydrocephalus, gender, age at diagnosis, and time since diagnosis were entered into regression analyzes as predictors for neurocognitive functioning. The PBTSs showed slower processing speeds and lower intelligence (range effect sizes .71-.82, p < .001), as well as deficits in executive attention, short-term memory, executive functioning, and VMI (range effect sizes .40-.57, p < .05). Older age at assessment was associated with better neurocognitive functioning (B = .450, p < .001) and younger age at diagnosis was associated with lower intelligence (B = .328, p < .05). Medical risk factors, e.g., hydrocephalus, did not show an association with neurocognitive functioning. Late effects in PBTSs include a broad range of neurocognitive deficits. The results suggest that even PBTSs that were traditionally viewed as low risk for neurocognitive problems (e.g., surgery only, no hydrocephalus) may suffer from decreased neurocognitive functioning.

Neurofeedback ineffective in paediatric brain tumour survivors: Results of a double-blind randomised placebo-controlled trial.

BACKGROUND: Many paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study). METHODS: Eligible for inclusion were PBTS with neurocognitive complaints, aged 8-18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time. RESULTS: A total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15). CONCLUSION: Results indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS.

Psychosocial profile of pediatric brain tumor survivors with neurocognitive complaints.

PURPOSE: With more children surviving a brain tumor, neurocognitive consequences of the tumor and its treatment become apparent, which could affect psychosocial functioning. The present study therefore aimed to assess psychosocial functioning of pediatric brain tumor survivors (PBTS) in detail. METHODS: Psychosocial functioning of PBTS (8-18 years) with parent-reported neurocognitive complaints was compared to normative data on health-related quality of life (HRQOL), self-esteem, psychosocial adjustment, and executive functioning (one-sample t tests) and to a sibling control group on fatigue (independent-samples t test). Self-, parent-, and teacher-report questionnaires were included, where appropriate, providing complementary information. RESULTS: Eighty-two PBTS (mean age 13.4 years, SD 3.2, 49 % males) and 43 healthy siblings (mean age 14.3, SD 2.4, 40 % males) were included. As compared to the normative population, PBTS themselves reported decreased physical, psychological, and generic HRQOL (d = 0.39-0.62, p < 0.008). Compared to siblings, increased fatigue-related concentration problems (d = 0.57, p < 0.01) were reported, although self-reported self-esteem and psychosocial adjustment seemed not to be affected. Parents of PBTS reported more psychosocial (d = 0.81, p < 0.000) and executive problems (d = 0.35-0.43, p < 0.016) in their child than parents of children in the normative population. Teachers indicated more psychosocial adjustment problems for female PBTS aged 8-11 years than for the female normative population (d = 0.69, p < 0.025), but they reported no more executive problems. CONCLUSIONS: PBTS with parent-reported neurocognitive complaints showed increased psychosocial problems, as reported by PBTS, parents, and teachers. IMPLICATIONS FOR CANCER SURVIVORS: Systematic screening of psychosocial functioning is necessary so that tailored support from professionals can be offered to PBTS with neurocognitive complaints.

Volume of white matter hyperintensities is an independent predictor of intelligence quotient and processing speed in children with sickle cell disease.

Sickle cell disease can be complicated by cerebral white matter hyperintensities (WMHs), which are associated with diminished neurocognitive functioning. The influence of the total volume of WMHs on the degree of neurocognitive dysfunction has not yet been characterized. In our study of 38 patients (mean age 12·5 years) we demonstrated that a higher volume of WMHs was associated with lower full-scale intelligence quotient (IQ), verbal IQ, Processing Speed Index and more fatigue. Our results suggest that volume of WMHs is an additional parameter to take into account when planning individual diagnostic and treatment options.

Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFßR bicyclic peptide inhibits liver fibrogenesis in vivo.

Hepatic stellate cells (HSCs), following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFNγ) is a potent anti-fibrotic cytokine, but its pleiotropic receptor expression leading to severe adverse effects has limited its clinical application. Since, activated HSC express high-level of platelet derived growth factor beta receptor (PDGFßR), we investigated the potential of PDGFßR-specific targeting of IFNγ and its signaling peptide that lacks IFNγR binding site (mimetic IFNγ or mimIFNγ) in liver fibrosis. We prepared DNA constructs expressing IFNγ, mimIFNγ or BiPPB (PDGFßR-specific bicyclic peptide)-IFNγ, BiPPB-mimIFNγ fusion proteins. Both chimeric proteins alongwith IFNγ and mimIFNγ were produced in E.coli. The expressed proteins were purified and analyzed for PDGFßR-specific binding and in vitro effects. Subsequently, these recombinant proteins were investigated for the liver uptake (pSTAT1α signaling pathway), for anti-fibrotic effects and adverse effects (platelet counts) in CCl4-induced liver fibrogenesis in mice. The purified HSC-targeted IFNγ and mimIFNγ fusion proteins showed PDGFßR-specific binding and significantly reduced TGFß-induced collagen-I expression in human HSC (LX2 cells), while mouse IFNγ and mimIFNγ did not show any effect. Conversely, mouse IFNγ and BiPPB-IFNγ induced activation and dose-dependent nitric oxide release in mouse macrophages (express IFNγR while lack PDGFßR), which was not observed with mimIFNγ and BiPPB-mimIFNγ, due to the lack of IFNγR binding sites. In vivo, targeted BiPPB-IFNγ and BiPPB-mimIFNγ significantly activated intrahepatic IFNγ-signaling pathway compared to IFNγ and mimIFNγ suggesting increased liver accumulation. Furthermore, the targeted fusion proteins ameliorated liver fibrogenesis in mice by significantly reducing collagen and α-SMA expression and potentiating collagen degradation. IFNγ also induced reduction in fibrogenesis but showed significant decrease in platelet counts, which was restored with targeted proteins. These results suggest that these rationally designed proteins can be further developed as novel anti-fibrotic therapeutics.

Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.

Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFßR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFßR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases.

Neurocognitive consequences of a paediatric brain tumour and its treatment: a meta-analysis.

AIM: This meta-analysis provides a systematic review of studies into intellectual and attentional functioning of paediatric brain tumour survivors (PBTS) as assessed by two widely used measures: the Wechsler Intelligence Scale for Children (3rd edition; WISC-III) and the Conners' Continuous Performance Test (CPT). METHOD: Studies were located that reported on performance of PBTS (age range 6-16y). Meta-analytic effect sizes were calculated for Full-scale IQ, Performance IQ, and Verbal IQ as measured by the WISC-III, and mean hit reaction time, errors of omission, and errors of commission as measured by the CPT. Exploratory analyses investigated the possible impacts of treatment mode, tumour location, age at diagnosis, and time since diagnosis on intelligence. RESULTS: Twenty-nine studies were included: 22 reported on the WISC-III in 710 PBTS and seven on CPT results in 372 PBTS. PBTS performed below average (p(s) <0.001) on Full-scale IQ (Cohen's d=-0.79), Performance IQ (d=-0.90), and Verbal IQ (d=-0.54). PBTS committed more errors of omission than the norm (d=0.82, p<0.001); no differences were found for mean hit reaction time and errors of commission. Cranial radiotherapy, chemotherapy, and longer time since diagnosis were associated with lower WISC-III scores (p(s) <0.05). INTERPRETATION: PBTS have seriously impaired intellectual functioning and attentiveness. Being treated with cranial radiotherapy and/or chemotherapy as well as longer time since diagnosis leads to worse intellectual functioning.

Neurofeedback to improve neurocognitive functioning of children treated for a brain tumor: design of a randomized controlled double-blind trial.

BACKGROUND: Neurotoxicity caused by treatment for a brain tumor is a major cause of neurocognitive decline in survivors. Studies have shown that neurofeedback may enhance neurocognitive functioning. This paper describes the protocol of the PRISMA study, a randomized controlled trial to investigate the efficacy of neurofeedback to improve neurocognitive functioning in children treated for a brain tumor. METHODS/DESIGN: Efficacy of neurofeedback will be compared to placebo training in a randomized controlled double-blind trial. A total of 70 brain tumor survivors in the age range of 8 to 18 years will be recruited. Inclusion also requires caregiver-reported neurocognitive problems and being off treatment for more than two years. A group of 35 healthy siblings will be included as the control group. On the basis of a qEEG patients will be assigned to one of three treatment protocols. Thereafter patients will be randomized to receive either neurofeedback training (n=35) or placebo training (n=35). Neurocognitive tests, and questionnaires administered to the patient, caregivers, and teacher, will be used to evaluate pre- and post-intervention functioning, as well as at 6-month follow-up. Siblings will be administered the same tests and questionnaires once. DISCUSSION: If neurofeedback proves to be effective for pediatric brain tumor survivors, this can be a valuable addition to the scarce interventions available to improve neurocognitive and psychosocial functioning. TRIAL REGISTRATION: ClinicalTrials.gov NCT00961922.

Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection.

Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated. Confirming earlier work, we found that leptin produced comparable reductions of feeding and body weight when injected into the lateral ventricle or the fourth ventricle. We also found that lateral and fourth ventricle leptin injections produced comparable increases of STAT3 phosphorylation in both the hindbrain and the hypothalamus. Moreover, injection of 50 ng of leptin directly into the nucleus of the solitary tract also increased STAT3 phosphorylation in the hypothalamic arcuate and ventromedial nuclei. Increased hypothalamic STAT3 phosphorylation was not due to elevation of blood leptin concentrations and the pattern of STAT3 phosphorylation did not overlap distribution of the retrograde tracer, fluorogold, injected via the same cannula. Our observations indicate that even small leptin doses administered to the hindbrain can trigger leptin-related signaling in the forebrain, and raise the possibility that STAT3 phosphorylation in the hypothalamus may contribute to behavioral and metabolic changes observed after hindbrain leptin injections.

Pmch expression during early development is critical for normal energy homeostasis.

Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.

Hormones and the autonomic nervous system are involved in suprachiasmatic nucleus modulation of glucose homeostasis.

Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension.

Central nervous determination of food storage--a daily switch from conservation to expenditure: implications for the metabolic syndrome.

Here, we present a neuroendocrine concept to review the circularly interacting energy homeostasis system between brain and body. Body-brain interaction is circular because the brain immediately integrates an input to an output, and because part of this response may be that the brain modulates the sensitivity of this perception. First, we describe how the brain senses the body through neurons and blood-borne factors. Direct neuronal connections report the state of various organs. In addition, humoral factors are perceived by the blood-brain barrier and circumventricular organs. We describe how circulating energy carriers are sensed and what signals reach the brain during food intake, exercise and an immune response. We describe that the brain regulates the homeostatic process at two fundamentally different levels during the active and inactive states. The unbalanced output of the brain in the metabolic syndrome is discussed in relation with such circadian rhythms and with regional activity of the autonomic nervous system. In line with the above, we suggest a new approach for the diagnosis and therapy of the metabolic syndrome.

The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior.

Plasma glucose concentrations display a daily rhythm generated by the hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN). How the SCN orchestrates this rhythm is unknown. Because glucagon stimulates hepatic glucose production, we hypothesized that if glucagon has a daily rhythm, then it may be responsible for the glucose rhythm. From hourly blood samples, we determined daily glucagon concentrations for intact and SCN-lesioned rats. Intact ad libitum-fed rats showed a clear daily glucagon rhythm, and fasting resulted in an even more pronounced rhythm. It is interesting that a decrease in glucagon concentrations, instead of the expected increase, occurred already shortly after food removal. Toward the start of the active period, a peak in glucagon levels occurred, with concentrations similar to those measured in ad libitum-fed rats. SCN lesions abolished rhythmicity in plasma glucagon profiles. Scheduled-fed rats showed meal-induced glucagon peaks but also a daily rhythm in basal premeal glucagon concentrations. Plasma glucose concentrations of ad libitum-and scheduled-fed rats, however, were similar. In conclusion, feeding and the biological clock control 24-h plasma glucagon concentrations. In fed rats, glucagon is not responsible for the daily glucose rhythm. During fasting, however, glucagon may contribute to energy mobilization when the activity period starts.