Reduced Glx and GABA Inductions in the Anterior Cingulate Cortex and Caudate Nucleus Are Related to Impaired Control of Attention in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31-51 years) and 16 adults without ADHD (28-54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry.

Brain white matter structure and COMT gene are linked to second-language learning in adults.

Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects' grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype.

Some new angles on the magic angle: what MSK radiologists know and don't know about this phenomenon.

PURPOSE: Magic angle effects (MAE) are well-recognized in musculoskeletal (MSK) MRI. With short TE acquisitions, the signal intensity of tendons, ligaments, and menisci depend on their orientation relative to the main magnetic field (B0). An interactive resident physics teaching module simulating MR imaging of a tendon forced us to identify and correct several misconceptions we had about MAE. We suspected these misconceptions were shared by other MSK radiologists. MATERIALS AND METHODS: We surveyed members of the Society of Academic Bone Radiologists (SABR) regarding which pulse sequences, acquisition parameters, tissues and angles relative to B0 were most likely to produce MAE. RESULTS: Survey respondents knew that MAE strongly depend on TE and commonly appear on T1W, FSE and PD sequences, but were less aware that MAE may also appear on T2W, STIR and DWI sequences. They knew of MAE effects in tendons, ligaments and cartilage, but were less aware of those in entheses, peripheral nerves and intervertebral discs. Respondents underestimated the wide angular range (full-width at half-maximum ≈ 40∘) over which significant MAE can be seen with short TE. CONCLUSIONS: Collagen-containing tissues with parallel molecular alignment exhibit increased signal intensity when oriented at 55∘ relative to B0. Experienced MSK radiologists were found to underestimate the combinations of image parameters, pulse sequences, tissues and collagen orientations in which significant MAE may be seen. Our survey results highlight the need for ongoing MR physics education for practicing radiologists.

Neurochemical correlates of caudate atrophy in Huntington's disease.

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy ((1)H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous (1)H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two (1)H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized (1)H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N-acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches.

Transcranial Doppler-based assessment of cerebral autoregulation in critically ill children during diabetic ketoacidosis treatment.

OBJECTIVES: Impaired cerebral autoregulation may be associated with poor outcome in diabetic ketoacidosis. We examined change in cerebral autoregulation during diabetic ketoacidosis treatment. DESIGN: Prospective observational cohort study. SETTING: Tertiary care children's hospital. PATIENTS/SUBJECTS: Children admitted to the ICU with diabetic ketoacidosis (venous pH < 7.3, glucose > 300 mg/dL, HCO3 < 15 mEq/L, and ketonuria) constituted cases, and children with type I diabetes without diabetic ketoacidosis constituted controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between 2005 and 2009, 32 cases and 50 controls were enrolled. Transcranial Doppler ultrasonography was used to measure middle cerebral artery flow velocities, and cerebral autoregulation testing was achieved via tilt-table testing. Cases underwent two and controls underwent one cerebral autoregulation test. Cerebral autoregulation was quantified by the autoregulatory index (autoregulatory index < 0.4 = impaired and autoregulatory index 0.4-1.0 = intact autoregulation). The first autoregulation test was obtained early (time 1, 12-24 hr; median [interquartile range], 8 hr [5-18 hr]) during diabetic ketoacidosis treatment, and a second autoregulation test was obtained during recovery (time 2, 36-72 hr; median [ interquartile range], 46 hr [40-59 hr]) from time 0 (defined as time of insulin start). Cases had lower autoregulatory index at time 1 than time 2 (p < 0.001) as well lower autoregulatory index than control subjects (p < 0.001). Cerebral autoregulation was impaired in 40% (n = 13) of cases at time 1 and in 6% (n = 2) of cases at time 2. Five cases (17%) showed persistent impairment of cerebral autoregulation between times 1 and 2 of treatment. All control subjects had intact cerebral autoregulation. CONCLUSIONS: Impaired cerebral autoregulation was common early during diabetic ketoacidosis treatment. Although the majority improved during diabetic ketoacidosis treatment, 17% of subjects had impairment between 36 and 72 hours after start of insulin therapy. The observed impaired cerebral autoregulation appears specific to the diabetic ketoacidosis process in patients with type I diabetes.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia.

BACKGROUND: Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat: 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury and promotes glial cell survival and angiogenesis. We hypothesized that HT and concurrent Epo will be safe and effective, improve survival, and reduce moderate-severe cerebral palsy (CP) in a term nonhuman primate model of perinatal asphyxia. METHODOLOGY: Thirty-five Macaca nemestrina were delivered after 15-18 min of umbilical cord occlusion (UCO) and randomized to saline (n = 14), HT only (n = 9), or HT+Epo (n = 12). There were 12 unasphyxiated controls. Epo (3,500 U/kg × 1 dose followed by 3 doses of 2,500 U/kg, or Epo 1,000 U/kg/day × 4 doses) was given on days 1, 2, 3, and 7. Timed blood samples were collected to measure plasma Epo concentrations. Animals underwent MRI/MRS and diffusion tensor imaging (DTI) at <72 h of age and again at 9 months. A battery of weekly developmental assessments was performed. RESULTS: UCO resulted in death or moderate-severe CP in 43% of saline-, 44% of HT-, and 0% of HT+Epo-treated animals. Compared to non-UCO control animals, UCO animals exhibit poor weight gain, behavioral impairment, poor cerebellar growth, and abnormal brain DTI. Compared to UCO saline, UCO HT+Epo improved motor and cognitive responses, cerebellar growth, and DTI measures and produced a death/disability relative risk reduction of 0.911 (95% CI -0.429 to 0.994), an absolute risk reduction of 0.395 (95% CI 0.072-0.635), and a number needed to treat of 2 (95% CI 2-14). The effects of HT+Epo on DTI included an improved mode of anisotropy, fractional anisotropy, relative anisotropy, and volume ratio as compared to UCO saline-treated infants. No adverse drug reactions were noted in animals receiving Epo, and there were no hematology, liver, or kidney laboratory effects. CONCLUSIONS/SIGNIFICANCE: HT+Epo treatment improved outcomes in nonhuman primates exposed to UCO. Adjunctive use of Epo combined with HT may improve the outcomes of term human infants with HIE, and clinical trials are warranted.

Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects.

Non-alcoholic fatty liver disease is associated with insulin resistance and dyslipidaemia and can progress to steatohepatitis and cirrhosis. We sought to determine whether dietary fat and saturated fat content alter liver fat in the absence of weight change in an older population. Liver fat was quantified by magnetic resonance spectroscopy before and after 4 weeks on an isoenergetic low-fat/low-saturated fat/low-glycaemic index (LGI) (LSAT: 23 % fat/7 % saturated fat/GI < 55) or a high-fat/high-saturated fat/high-GI (HSAT: 43 % fat/24 % saturated fat/GI>70) diet in older subjects. In the present study, twenty subjects (seven males/thirteen females; age 69.3 (SEM 1.6) years, BMI 26.9 (SEM 0.8) kg/m2) were randomised to the LSAT diet and fifteen subjects (six males/nine females; age 68.6 (SEM 1.8) years, BMI 28.1 (SEM 0.9) kg/m2) to the HSAT diet. Weight remained stable. Liver fat decreased significantly on the LSAT diet (median 2.2 (interquartile range (IQR) 3.1) to 1.7 (IQR 1.8) %, P= 0.002) but did not change on the HSAT diet (median 1.2 (IQR 4.1) to 1.6 (IQR 3.9) %). The LSAT diet lowered fasting glucose and total cholesterol, HDL-cholesterol and LDL-cholesterol and raised TAG (P< 0.05), while the HSAT diet had no effect on glucose or HDL-cholesterol but increased total cholesterol and LDL-cholesterol (P< 0.05). Fasting insulin and homeostasis model of insulin resistance did not change significantly on either diet, but the Matsuda index of insulin sensitivity improved on the LSAT diet (P< 0.05). Assignment to the LSAT v. HSAT diet was a predictor of changes in lipid parameters but not liver fat. We conclude that diet composition may be an important factor in the accumulation of liver fat, with a low-fat/low-saturated fat/LGI diet being beneficial.

Toward a better understanding of the savant brain.

OBJECTIVE: The objectives of this study are to investigate the neuroanatomy, regional brain connectivity, and neurochemistry of a prodigious artistic savant; to place these findings within the context of existing neuroimaging literature of savant syndrome; and to discuss the utility of newer imaging modalities to extend our current understanding of mechanisms underlying savant skills. METHODS: High-resolution magnetic resonance (MR) imaging, J-resolved MR spectroscopy, and diffusion tensor imaging data were acquired during a single scanning session for a 63-year-old male autistic savant with prodigious artistic skills. Regional and compartmental brain volumes, N-acetyl aspartate, choline, creatine, glutamate and γ-aminobutyric acid concentrations, fractional anisotropy values, and white matter bundle volumes as well as axial, radial, and mean diffusivities were calculated. RESULTS: No gross anatomical differences were observed. By morphological assessment, cerebral volume (1362 mL) was larger than normative literature values for adult males. The corpus callosum was intact and did not exhibit abnormal structural features. The right cerebral hemisphere was 1.9% larger than the left hemisphere; the right amygdala and right caudate nuclei were 24% and 9.9% larger, respectively, compared with the left side. In contrast, the putamen was 8.3% larger on the left side. Fractional anisotropy was increased on the right side as compared with the left for 4 of the 5 bilateral regions studied (the amygdala, caudate, frontal lobe, and hippocampus). Fiber tract bundle volumes were larger on the right side for the amygdala, hippocampus, frontal lobe, and occipital lobe. Both the left and the right hippocampi had substantially increased axial and mean diffusivities as compared with those of a comparison sample of nonsavant adult males. The corpus callosum and left amygdala also exhibited high axial, radial, and mean diffusivities. MR spectroscopy revealed markedly decreased γ-aminobutyric acid and glutamate in the parietal lobe. CONCLUSIONS: Although examination of brain gross morphometry demonstrated no clinically remarkable abnormalities, utilization of conventional as well as newer MR imaging technologies revealed several atypical structural and chemical features that may be involved in the special skills of this prodigious savant. The multimodal imaging approach presented in this study is suitable for the evaluation of larger samples of savants with a diverse range of talents to investigate common brain features that may underlie the exceptional cognitive capabilities characteristic of savant syndrome. Given the high co-occurrence of the two syndromes, elucidating the underlying neurophysiologic basis of savant syndrome may also lead to a better understanding of autism spectrum disorder.

Perinatal asphyxia in a nonhuman primate model.

Perinatal asphyxia is a leading cause of brain injury in neonates, occurring in 2-4 per 1,000 live births, and there are limited treatment options. Because of their similarity to humans, nonhuman primates are ideal for performing preclinical tests of safety and efficacy for neurotherapeutic interventions. We previously developed a primate model of acute perinatal asphyxia using 12-15 min of umbilical cord occlusion. Continuing this research, we have increased cord occlusion time from 15 to 18 min and extended neurodevelopmental follow-up to 9 months. The purpose of this report is to evaluate the increase in morbidity associated with 18 min of asphyxia by comparing indices obtained from colony controls, nonasphyxiated controls and asphyxiated animals. Pigtail macaques were delivered by hysterotomy after 0, 15 or 18 min of cord occlusion, then resuscitated. Over the ensuing 9 months, for each biochemical and physiologic parameters, behavioral and developmental evaluations, and structural and spectroscopic MRI were recorded. At birth, all asphyxiated animals required resuscitation with positive pressure ventilation and exhibited biochemical and clinical characteristics diagnostic of hypoxic-ischemic encephalopathy, including metabolic acidosis and attenuated brain activity. Compared with controls, asphyxiated animals developed long-term physical and cognitive deficits. This preliminary report characterizes the acute and chronic consequences of perinatal asphyxia in a nonhuman primate model, and describes diagnostic imaging tools for quantifying correlates of neonatal brain injury as well as neurodevelopmental tests for evaluating early motor and cognitive outcomes.

Virtual reality as an adjunctive non-pharmacologic analgesic for acute burn pain during medical procedures.

INTRODUCTION: Excessive pain during medical procedures is a widespread problem but is especially problematic during daily wound care of patients with severe burn injuries. METHODS: Burn patients report 35-50% reductions in procedural pain while in a distracting immersive virtual reality, and fMRI brain scans show associated reductions in pain-related brain activity during VR. VR distraction appears to be most effective for patients with the highest pain intensity levels. VR is thought to reduce pain by directing patients' attention into the virtual world, leaving less attention available to process incoming neural signals from pain receptors. CONCLUSIONS: We review evidence from clinical and laboratory research studies exploring Virtual Reality analgesia, concentrating primarily on the work ongoing within our group. We briefly describe how VR pain distraction systems have been tailored to the unique needs of burn patients to date, and speculate about how VR systems could be tailored to the needs of other patient populations in the future.

Change in mean transit time, apparent diffusion coefficient, and cerebral blood volume during pediatric diabetic ketoacidosis treatment.

OBJECTIVES: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We examined measures describing potential causes of whole brain and regional brain edema (mean transit time, apparent diffusion coefficient, and relative cerebral blood volume) during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Regional children's hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After Institutional Review Board approval, children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis) underwent two serial paired contrast-enhanced (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional (frontal lobe, occipital lobe, and basal ganglia) mean transit time, apparent diffusion coefficient, and relative cerebral blood volume between the two time periods (12-24 hrs) and (36-72 hrs) after start of insulin treatment (time 0) were determined. Thirteen children (median age, 10.3 ± 1.1 yrs; 7 female) with diabetic ketoacidosis were examined. Overall, whole brain and regional mean transit time decreased from time 1 (first magnetic resonance imaging after time 0) to time 2 (second magnetic resonance imaging after time 0) by 51% ± 59% (p = .01), without differences between the brain regions examined. Whole brain apparent diffusion coefficient increased by 4.7% ± 3.4% (p = .001), without differences between the brain regions examined. There was no change in relative cerebral blood volume for the whole brain and for the three brain regions examined. CONCLUSIONS: In this study, whole brain mean transit time decreased and apparent diffusion coefficient increased, suggesting a vasogenic process between the two study periods during diabetic ketoacidosis treatment.

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24-25 weeks vs. 26-27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.

Improving 1H MRSI measurement of cerebral lactate for clinical applications.

Accurate measurement of cerebral lactate is critical to the understanding of brain function for psychiatric disorders such as panic disorder and bipolar disorder as well as mitochondrial dysfunction. Proton magnetic spectroscopic imaging (MRSI) techniques can be used to study lactate in vivo; however, accurate measurement of cerebral lactate, which is normally at low basal abundance, can be challenging. In this study, regional lactate measurements obtained with two different MRSI analytic approaches were evaluated using proton echo-planar spectroscopic imaging (PEPSI) data from 18 healthy adults participating in an in vivo sodium lactate infusion study. The results demonstrate that averaging data within a region of interest (ROI) before spectral fitting with LCModel results in significantly improved lactate measurement as compared to averaging chemical concentrations derived from the fitting of individual voxels in the ROI. Simulation results that confirm this finding are also presented. This study additionally outlines an atlas-based approach for the systematic computation of regional distributions of chemical concentrations in large MRSI data sets.

Change in blood-brain barrier permeability during pediatric diabetic ketoacidosis treatment.

OBJECTIVE: Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We aimed to examine blood-brain barrier permeability during treatment of diabetic ketoacidosis in children. DESIGN: Prospective observational study. SETTING: Seattle Children's Hospital, Seattle, WA. PATIENTS: Children admitted with diabetic ketoacidosis (pH <7.3, HCO3 <15 mEq/L, glucose >300 mg/dL, and ketosis). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Subjects underwent two serial paired contrast-enhanced perfusion (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional blood-brain barrier permeability (permeability ratio*100 and % permeability ratio change) between illness and recovery were determined. Time 0 reflects start of insulin treatment. Thirteen children (median age 10.0 +/- 1.1 yrs; seven female) with diabetic ketoacidosis were enrolled. Permeability ratio increased from time 1 (first magnetic resonance image after time 0) to time 2 (second magnetic resonance image after time 0) in the frontal cortex (ten of 13 subjects), occipital cortex (ten of 13 subjects), and basal ganglia (nine of 13). Whole brain permeability ratio increased from time 1 to time 2 (160%) and regional increase in permeability ratio was greatest in the frontal cortex (148%) compared with the occipital cortex (128%) and basal ganglia (112%). CONCLUSIONS: Overall, whole brain and regional blood-brain barrier permeability increased in most subjects during diabetic ketoacidosis treatment. The frontal region had more blood-brain barrier permeability than other brain regions examined.

Behavioral and brain evidence for language by ear, mouth, eye, and hand and motor skills in literacy learning.

Two studies were conducted of students with and without persisting Specific Learning Disabilities (SLDs-WL) in Grades 4 to 9 (M = 11 years, 11 months) that supported the hypotheses that CELF 4 parent ratings for listening (language by ear), speaking (language by mouth), reading (language by eye), and writing (language by hand) were correlated with both (a) normed, standardized behavioral measures of listening, speaking, reading, and writing achievement (Study 1, 94 boys and 61 girls); and (b) fMRI connectivity or DTI white matter integrity involving brain regions for primary motor functions or motor planning and control, or motor timing in a subsample of right handers who did not wear metal (Study 2, 28 boys and 16 girls). Results of these assessment studies, which have implications for planning instruction for three SLDs-WL (dysgraphia, dyslexia, and oral and written language learning disability [OWL LD]), show that more than multisensory instruction is relevant. Language by ear, by mouth, by eye, and by hand, as well as motor planning, control, and output skills and motor timing should also be considered. Research is also reviewed that supports other processes beyond multisensory input alone that should also be considered for students with SLDs-WL.

Paclitaxel Reduces Brain Injury from Repeated Head Trauma in Mice.

Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubule-stabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in a spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel-treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury.

Abnormal fMRI Connectivity in Children with Dyslexia During a Phoneme Task: Before But Not After Treatment .

Brains of 18 children with dyslexia (5 girls, 13 boys) and 21 and without dyslexia (8 girls, 13 boys) were scanned before and after the children with dyslexia received instructional treatment. Both at Time 1 and Time 2 all children performed an fMRI phoneme mapping task during brain scanning-deciding whether letter(s) in pair of pronounceable nonwords could stand for the same sound. Results were analyzed with a seed point correlational method for functional connectivity from four seed points based on prior studies: inferior frontal gyrus, middle frontal gyrus, the occipital region, and cerebellum. At Time 1 before treatment, a significant difference in fMRI connectivity occurred between children with dyslexia and normal reading controls in the left inferior frontal gyrus and its correlations with right and left middle frontal gyrus, right and left supplemental motor area, left precentral gyrus, and right superior frontal gyrus. There were no significant differences for the seed regions placed in the middle frontal gyrus, occipital gyrus or cerebellum. Children with dyslexia had greater functional connectivity from the left inferior frontal gyrus seed point to the right inferior frontal gyrus than did the children without dyslexia. Compared to adults with and without dyslexia who differed in bilateral connectivity from left inferior frontal gyrus on the same task, the children with and without dyslexia differed in left side connectivity from left inferior frontal gyrus. At Time 2 after treatment, the children with dyslexia, who had participated in a three-week instructional program that provided explicit instruction in linguistic awareness, alphabetic principle (taught in a way to maximize temporal contiguity of grapheme-phoneme associations), decoding and spelling, and a writers' workshop, did not differ from the children without dyslexia in any of the clusters in the group difference map identifying differences between dyslexics and good readers, showing that functional connectivity (and not just regions of interest) may normalize following instructional treatment.

Right Forceps Minor and Anterior Thalamic Radiation Predict Executive Function Skills in Young Bilingual Adults.

Executive function (EF) skills enhance learning across domains, and are particularly linked to the acquisition of a second language. Previous studies have shown that bilingual individuals show enhanced EF skills in cognitive tasks where they attended a targeted dimension of a stimulus while inhibiting other competing cues. Brain imaging revealed that bilingual young adults' performances in the Stroop color-naming task were related to the volume of anterior cingulate cortex (ACC) and inferior frontal lobe. Subjects who had greater white-matter in the frontal cortex showed enhanced performances in the same task, suggesting that brain fiber pathways connecting ACC to the frontal region may be related to the Stroop color-naming task. No studies to date have examined the tissue properties of brain fiber pathways connecting these brain regions and their association with subjects' EF performances. Importantly, there are no data establishing whether bilingual subjects exhibit different reaction times when words are presented in their first versus second language. To study these questions, we used behavioral and unbiased whole-brain analyses, recruiting 21 Chinese students. Using the Stroop color-naming task, we measured subjects' reaction times (RTs) in which color names were displayed using fonts that matched the named color (congruent task) or mismatched the color (incongruent task). Students performed the task twice, first in English, the subjects' second language, then in Chinese, the subjects' primary language. Results from whole-brain analysis showed that students' RTs in both the English and Chinese tasks were significantly correlated with the mode of anisotropy (MO) in a brain cluster containing the forceps minor and anterior thalamic radiation in the right hemisphere. We also found that fractional anisotropy (FA) significantly predicted students' RTs, with higher FA predicting shorter RT. Taken together, our findings demonstrate that right forceps minor and anterior thalamic radiation predict EF skills, suggesting that this brain feature may be important for young bilingual adults using their first and second languages to direct their attention when conflicting cues are present.

Brain's functional network clustering coefficient changes in response to instruction (RTI) in students with and without reading disabilities: Multi-leveled reading brain's RTI.

In students in grades 4 to 9 (22 males, 20 females), two reading disability groups-dyslexia (n = 20) or oral and written language learning disability (OWL LD) (n = 6)-were compared to each other and two kinds of control groups-typical readers (n = 6) or dysgraphia (n = 10) on word reading/spelling skills and fMRI imaging before and after completing 18 computerized reading lessons. Mixed ANOVAs showed significant time effects on repeated measures within participants and between groups effects on three behavioral markers of reading disabilities-word reading/spelling: All groups improved on the three behavioral measures, but those without disabilities remained higher than those with reading disabilities. On fMRI reading tasks, analyzed for graph theory derived clustering coefficients within a neural network involved in cognitive control functions, on a word level task the time × group interaction was significant in right medial cingulate; on a syntax level task the time × group interaction was significant in left superior frontal and left inferior frontal gyri; and on a multi-sentence text level task the time × group interaction was significant in right middle frontal gyrus. Three white matter-gray matter correlations became significant only after reading instruction: axial diffusivity in left superior frontal region with right inferior frontal gyrus during word reading judgments; mean diffusivity in left superior corona radiata with left middle frontal gyrus during sentence reading judgments; and mean diffusivity in left anterior corona radiata with right middle frontal gyrus during multi-sentence reading judgments. Significance of results for behavioral and brain response to reading instruction (RTI) is discussed.