Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia.

BACKGROUND: Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses. METHODS: In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment. RESULTS: Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up. CONCLUSIONS: Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits. IMPACT: Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.

Cerebral oxygen saturation and cerebrovascular instability in newborn infants with congenital heart disease compared to healthy controls.

OBJECTIVE: Infants with Congenital Heart Disease (CHD) are at risk for developmental delays, though the mechanisms of brain injury that impair development are unknown. Potential causes could include cerebral hypoxia and cerebrovascular instability. We hypothesized that we would detect significantly reduced cerebral oxygen saturation and greater cerebrovascular instability in CHD infants compared to the healthy controls. METHODS: We performed a secondary analysis on a sample of 43 term infants (28 CHD, 15 healthy controls) that assessed prospectively in temporal cross-section before or at 12 days of age. CHD infants were assessed prior to open-heart surgery. Cerebral oxygen saturation levels were estimated using Near-Infrared Spectroscopy, and cerebrovascular stability was assessed with the response of cerebral oxygen saturation after a postural change (supine to sitting). RESULTS: Cerebral oxygen saturation was 9 points lower in CHD than control infants in both postures (ß = -9.3; 95%CI = -17.68, -1.00; p = 0.028), even after controlling for differences in peripheral oxygen saturation. Cerebrovascular stability was significantly impaired in CHD compared to healthy infants (ß = -2.4; 95%CI = -4.12, -.61; p = 0.008), and in CHD infants with single ventricle compared with biventricular defects (ß = -1.5; 95%CI = -2.95, -0.05; p = 0.04). CONCLUSION: CHD infants had cerebral hypoxia and decreased cerebral oxygen saturation values following a postural change, suggesting cerebrovascular instability. Future longitudinal studies should assess the associations of cerebral hypoxia and cerebrovascular instability with long-term neurodevelopmental outcomes in CHD infants.

Functional connectivity of the reading network is associated with prenatal polybrominated diphenyl ether concentrations in a community sample of 5 year-old children: A preliminary study.

Genetic factors explain 60 percent of variance in reading disorder. Exposure to neurotoxicants, including polybrominated diphenyl ethers (PBDEs), may be overlooked risk factors for reading problems. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine associations between prenatal PBDE concentrations and functional connectivity of a reading-related network (RN) in a community sample of 5-year-old children (N = 33). Maternal serum PBDE concentrations (∑PBDE) were measured at 12.2 ±â€¯2.8 weeks gestation (mean ±â€¯SD). The RN was defined by 12 regions identified in prior task-based fMRI meta-analyses; global efficiency (GE) was used to measure network integration. Linear regression evaluated associations between ∑PBDE, word reading, and GE of the RN and the default mode network (DMN); the latter to establish specificity of findings. Weighted quantile sum regression analyses evaluated the contributions of specific PBDE congeners to observed associations. Greater RN efficiency was associated with better word reading in these novice readers. Children with higher ∑PBDE showed reduced GE of the RN; ∑PBDE was not associated with DMN efficiency, demonstrating specificity of our results. Consistent with prior findings, ∑PBDE was not associated word reading at 5-years-old. Altered efficiency and integration of the RN may underlie associations between ∑PBDE concentrations and reading problems observed previously in older children.

A preliminary study on prenatal polybrominated diphenyl ether serum concentrations and intrinsic functional network organization and executive functioning in childhood.

BACKGROUND: The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood. METHODS: In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using a graph-theoretical approach) in 5-year-old children (n = 34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent-report questionnaire (BRIEF-P) (n = 106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems. RESULTS: Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (ß's = .01, FDR-corrected p's ≤ .05); (b) more reported EF problems (ß's = .001, FDR-corrected p's ≤ .05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (ß's = .01, FDR-corrected p's < .05). CONCLUSIONS: Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher-order cognitive functions, such as EF, which could be explored in future studies.

Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior.

Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34-37 weeks gestation. Resting-state imaging data were acquired in the infants at 40-44 weeks postmenstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14 months PMA using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior.SIGNIFICANCE STATEMENT Preclinical studies in rodents and nonhuman primates and epidemiological studies in humans suggest that maternal immune activation (MIA) alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal third trimester interleukin-6 and C-reactive protein levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring.

Maternal prenatal iron status and tissue organization in the neonatal brain.

BACKGROUND: Children prenatally exposed to inadequate iron have poorer motor and neurocognitive development. No prior study to our knowledge has assessed the influence of maternal prenatal iron intake on newborn brain tissue organization in full-term infants. METHODS: Third trimester daily iron intake was obtained using the Automated Self-Administered 24-h Dietary Recall with n = 40 healthy pregnant adolescents (aged 14-19 y). Cord blood ferritin was collected in a subsample (n = 16). Newborn (mean = 39 gestational weeks at birth; range 37-41) magnetic resonance imaging scans were acquired on a 3.0 Tesla MR Scanner. Diffusion Tensor Imaging (DTI) slices were acquired to measure the directional diffusion of water indexed by fractional anisotropy (FA). RESULTS: Reported iron intake was inversely associated with newborn FA values (P ≤ 0.0001) predominantly in cortical gray matter. FA findings were similar using cord blood ferritin values. CONCLUSION: Higher maternal prenatal iron intake accentuates, and lower intake attenuates, the normal age-related decline in FA values in gray matter, perhaps representing increasing dendritic arborization and synapse formation with higher iron intake. These DTI results suggest that typical variation in maternal iron outside the scope of standard clinical surveillance exerts subtle effects on infant brain development.

Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.

Contextual control of audiovisual integration in low-level sensory cortices.

Potential sources of multisensory influences on low-level sensory cortices include direct projections from sensory cortices of different modalities, as well as more indirect feedback inputs from higher order multisensory cortical regions. These multiple architectures may be functionally complementary, but the exact roles and inter-relationships of the circuits are unknown. Using a fully balanced context manipulation, we tested the hypotheses that: (1) feedforward and lateral pathways subserve speed functions, such as detecting peripheral stimuli. Multisensory integration effects in this context are predicted in peripheral fields of low-level sensory cortices. (2) Slower feedback pathways underpin accuracy functions, such as object discrimination. Integration effects in this context are predicted in higher-order association cortices and central/foveal fields of low-level sensory cortex. We used functional magnetic resonance imaging to compare the effects of central versus peripheral stimulation on audiovisual integration, while varying speed and accuracy requirements for behavioral responses. We found that interactions of task demands and stimulus eccentricity in low-level sensory cortices are more complex than would be predicted by a simple dichotomy such as our hypothesized peripheral/speed and foveal/accuracy functions. Additionally, our findings point to individual differences in integration that may be related to skills and strategy. Overall, our findings suggest that instead of using fixed, specialized pathways, the exact circuits and mechanisms that are used for low-level multisensory integration are much more flexible and contingent upon both individual and contextual factors than previously assumed.

Brain anomalies in children exposed prenatally to a common organophosphate pesticide.

Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose-response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.

Decreased cortical complexity in methamphetamine abusers.

This study aimed to investigate if methamphetamine (MA) abusers exhibit alterations in complexity of the electroencephalogram (EEG) and to determine if these possible alterations are associated with their abuse patterns. EEGs were recorded from 48 former MA-dependent males and 20 age- and sex-matched healthy subjects. Approximate Entropy (ApEn), an information-theoretical measure of irregularity, of the EEGs was estimated to quantify the degree of cortical complexity. The ApEn values in MA abusers were significantly lower than those of healthy subjects in most of the cortical regions, indicating decreased cortical complexity of MA abusers, which may be associated with impairment in specialization and integration of cortical activities owing to MA abuse. Moreover, ApEn values exhibited significant correlations with the clinical factors including abuse patterns, symptoms of psychoses, and their concurrent drinking and smoking habits. These findings provide insights into abnormal information processing in MA abusers and suggest that ApEn of EEG recordings may be used as a potential supplementary tool for quantitative diagnosis of MA abuse. This is the first investigation to assess the "severity-dependent dynamical complexity" of EEG patterns in former MA abusers and their associations with the subjects' abuse patterns and other clinical measures.

Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD.

OBJECTIVE: Exposure to heavy maternal cigarette smoking in pregnancy and severe maternal psychosocial stress during pregnancy appear to be important risk factors for the development of ADHD. This study aimed to determine whether these perinatal risk factors were associated with neuropsychological deficits commonly seen in ADHD. METHOD: We examined the effect of these two risk factors on measures of attentional control, motor inhibition, visual-motor integration, and fine motor coordination in a group of 81 children with ADHD, aged from 8 to 18 years. The neuropsychological battery included the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test, the Beery Visual-Motor Integration Test, and the Purdue Pegboard Test. RESULTS: Heavy maternal smoking during pregnancy was associated with slower reaction times (p < .002), and reaction time variability (p < .007) on the CPT. CONCLUSIONS: This study suggests a persistent negative effect of heavy prenatal maternal smoking on attentional control in children with ADHD. Future studies should examine the neurobiological basis and determine the degree to which inherited genetic susceptibility factors contribute to this finding.

Severe psychosocial stress and heavy cigarette smoking during pregnancy: an examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome.

Attention-deficit/hyperactivity disorder (ADHD) is frequently diagnosed in children with Tourette syndrome (TS). The basis for this co-occurrence is uncertain. This study aimed to determine if specific pre- and perinatal risk factors, including heavy maternal smoking and severe psychosocial stress during pregnancy, were associated with one or both disorders, or neither. We compared maternal report data on pre- and perinatal risk factors on 222 children between the ages of 7 and 18 years including 45 individuals with TS alone, 52 individuals with ADHD alone, 60 individuals with condition of comorbid TS + ADHD, and 65 unaffected control children. Pre- and perinatal histories as well as psychiatric assessments were performed using standardized questionnaires and semi-structured interviews with the mothers and children. Logistic regression was used to determine the odds ratio for each variable of interest. Compared to the mothers of unaffected control children, the mothers of children with ADHD alone reported higher rates of heavy smoking (>10 cigarettes per day) during pregnancy and higher levels of severe psychosocial stress during pregnancy (OR = 13.5, p < 0.01 and OR = 6.8, p < 0.002, respectively). The TS + ADHD and the TS alone patients also had higher rates heavy maternal smoking and high levels of psychosocial stress compared to the control children, but these differences failed to reach statistical significance (heavy smoking: OR = 8.5, p < 0.052, OR = 4.6, p < 0.19, respectively; severe psychosocial stress: OR = 3.1, p < 0.07, OR = 2.6, p < 0.11, respectively). Heavy maternal smoking and severe levels psychosocial stress during pregnancy were independently associated with a diagnosis of ADHD. TS patients also had higher rates of these risk factors, but the ORs failed to reach statistical significance. Efforts are needed to reduce the frequency of these risk factors in high-risk populations. Future studies, using genetically sensitive designs, are also needed to sort out the causal pathways.

A Tc-99m SPECT study of regional cerebral blood flow in patients with transient global amnesia.

OBJECTIVES: This study aimed to determine whether regional cerebral blood flow (rCBF) is abnormal in patients who have Transient Global Amnesia (TGA). METHODS: We obtained noninvasive rCBF measurements using Tc-99m-ethyl cysteinate diamer Single Photon Emission Computed Tomography (SPECT) in 7 patients diagnosed with TGA within 4 days of onset of the amnestic episode while the patients were still symptomatic and in 17 age-matched healthy control subjects. We assessed memory functioning using the Hopkins's Verbal Learning Test (HVLT) and Statistical Parametric Mapping to compare rCBF across diagnostic groups. RESULTS: The patients with TGA were significantly impaired in their performance on the 20-minute delayed recall of the HVLT. They also exhibited significantly decreased rCBF on their SPECT scans in the inferior and middle frontal gyrus bilaterally, with more prominent left-sided reductions in the superior temporal, precentral, and postcentral gyri, as well as increased rCBF primarily in the right hemisphere within the middle temporal, superior temporal, and inferior frontal gyri, cerebellum, and thalamus, compared with the normal control group. CONCLUSION: These findings suggest that lateralized abnormalities in brain functioning are an important component of the pathophysiology of TGA. Lateralized abnormalities may disrupt functions that are relatively specific to the left hemisphere, including receptive language, symbolic representation, and the processing of local features in the environment, while preserving anterograde memory processes. Increased flow to the right hemisphere centered on regions that subserve the functions of expressive language and visuospatial processing, and may represent processes that compensate for flow reductions to the left hemisphere.

Increased fasting plasma ghrelin levels during alcohol abstinence.

AIMS: Ghrelin is a peptide hormone that antagonizes the action of leptin and is thereby thought to regulate feeding behaviour. The actions of ghrelin and leptin appear to be mediated by the neuropeptide Y (NPY) and Agouti-related protein (AGRP) system. Recent studies have suggested that leptin and NPY play significant roles in the pathophysiology of alcoholism. The aim of this study was to determine whether ghrelin is associated with the state and duration of abstinence in individuals with alcohol dependence. METHODS: Fasting plasma ghrelin levels were compared between 47 individuals with chronic alcoholism during a period of abstinence and 50 control subjects. RESULTS: Fasting plasma ghrelin levels were higher in alcohol abstainers than those in controls. Furthermore, a positive correlation was observed between ghrelin levels and the duration of abstinence. In addition, daily alcohol intake prior to abstinence was inversely related to ghrelin levels. CONCLUSIONS: These findings suggest that ghrelin plays a role in the pathogenesis of alcohol dependence, particularly during the abstinence period, in individuals with chronic alcoholism.

Replication of a premenstrual decrease in right-ear advantage on language-related dichotic listening tests of cerebral laterality.

Five fused dichotic word tasks measured perceptual asymmetry in 30 women at 4 weekly intervals. The five tasks varied according to whether the stimuli presented were word-word pairs or nonsense word-pairs, or whether they consisted of neutral words paired with positive emotion-evoking words (e.g. hug-tug), neutral words paired with negative emotion-evoking words (e.g. till-kill), or neutral words paired with neutral words (e.g. bean-dean). Overall right-ear advantage (REA) decreased in the premenstrual week relative to the postmenstrual week, replicating previous results using identical measures. In addition, REA scores were similar at menstrual, postmenstrual and midcycle weeks. Additional data from 12 men suggests sex differences in task performance were small or non-existent. In both women and men, there were no effects of repeated testing on REA, but emotional proclivity indices, defined as the tendency to recall words of positive or negative affective tone, increased across the four test sessions. As found previously, there was a trend for women to hear fewer positive words during the premenstrual week. These data are consistent with other research suggesting that a progesterone-mediated decrease in functional asymmetry occurs in the luteal phase. Future research manipulating task demands (e.g. memory load) or the affective valence of the stimuli may be useful in understanding the observed changes in hemispheric advantage.