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.

Emotional and Behavioral Correlates of Persisting Specific Learning Disabilities in Written Language during Middle Childhood and Early Adolescence.

Parents completed the Behavior Assessment System for Children-Second Edition Parent Report Scale (BASC2-PRS) while their children (94 boys, 61 girls; M=11 years-11 months) were given tests. Evidence-based profiles of multiple test scores and history (emergence and persistence) were used to assign to groups without specific learning disabilities in written language (SLDs-WL) (n= 42 control) or with SLDs-WL: (n=29 dysgraphia, n=65 dyslexia, or n=19 oral and written language learning disability [OWL LD]). Parent ratings fell in the clinical or at risk ranges for some individuals in all groups, but mean BASC2-PRS ratings showed nine significant main effects for group (n=4): Behavioral Symptoms Index, Internalizing Problems Composite, Adaptive Skills Composite, two Clinical Scales (Atypicality and Attention Problems), and four Adaptive Scales (Adaptability, Activities of Daily Living, Leadership, and Functional Communication). Each SLDs-WL group differed significantly from the control group on these nine ratings, except dysgraphia on Atypicality and dyslexia on Adaptive Composite, Adaptability, and Leadership; and each correlated with one or more hallmark impairments associated with a specific SLD-WL. In an fMRI study (without OWL LD), the dysgraphia and dyslexia groups, but not control group, showed connectivity with amygdala; BASC2 PRS Internalizing Problems Composite (internal stress) correlated with amygdala connectivity from two cortical regions involved in written word processing and production for all groups (N=40). Applications to assessing emotional and behavioral correlates of SLDs-WL for educational services and future research are discussed.

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.

Change in fractional anisotropy during treatment of diabetic ketoacidosis in children.

BACKGROUND: The pathophysiology resulting in cerebral edema in pediatric diabetic ketoacidosis (DKA) is unknown. To investigate the changes in white matter microstructure in this disease, we measured diffusion tensor imaging (DTI) parameters, including apparent diffusion coefficient (ADC), fractional anisotropy (FA), and radial and axial diffusivity in children with DKA at two time points during treatment. METHODS: A prospective observational study was conducted at Seattle Children's Hospital, Seattle, WA. Thirty-two children admitted with DKA (pH < 7.3, bicarbonate < 15 mEq/l, glucose > 300 mg/dl, and ketosis; 11.9 ± 3.2 y; and 47% male) were enrolled and underwent two serial paired diffusion magnetic resonance imaging (MRI) scans following hospital admission. Seventeen of the 32 participants had diffusion tensor images of adequate quality for tract-based spatial statistics (TBSS) analysis. RESULTS: TBSS mapping demonstrated main white matter tract areas with a significant increase in FA and areas with a significant decrease in ADC, from the first to the second MRI. Both radial and axial diffusivity terms showed change, with a diffuse pattern of involvement. CONCLUSION: Consistent DTI changes occurred during DKA treatment over a short time frame. These findings describe widespread water diffusion abnormalities in DKA, supporting an association between clinical illness and DTI markers of microstructural change in white matter.

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.

Distal ulna fractures.

In isolation, distal ulna fractures are rare. They are often found in conjunction with distal radius fractures, and the complexity of the interaction of the distal ulna with the radioulnar joint and triangular fibrocartilage complex makes understanding and treatment of distal ulna fractures challenging. Fixation of distal ulna fractures can be problematic owing to comminution making reduction challenging. A thin soft tissue can lead to hardware prominence and necessitate implant removal. In this Current Concepts article, we review the anatomy, pathology, and treatment of distal ulna fractures as well as potential complications and salvage procedures.

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.

A low-cost, computer-interfaced drawing pad for FMRI studies of dysgraphia and dyslexia.

We have developed a pen and writing tablet for use by subjects during fMRI scanning. The pen consists of two jacketed, multi-mode optical fibers routed to the tip of a hollowed-out ball-point pen. The pen has been further modified by addition of a plastic plate to maintain a perpendicular pen-tablet orientation. The tablet is simply a non-metallic frame holding a paper print of continuously varying color gradients. The optical fibers are routed out of the MRI bore to a light-tight box in an adjacent control room. Within the box, light from a high intensity LED is coupled into one of the fibers, while the other fiber abuts a color sensor. Light from the LED exits the pen tip, illuminating a small spot on the tablet, and the resulting reflected light is routed to the color sensor. Given a lookup table of position for each color on the tablet, the coordinates of the pen on the tablet may be displayed and digitized in real-time. While simple and inexpensive, the system achieves sufficient resolution to grade writing tasks testing dysgraphic and dyslexic phenomena.

Relationships between GABA, glutamate, and GABA/glutamate and social and olfactory processing in children with autism spectrum disorder.

Theories of altered inhibitory/excitatory signaling in autism spectrum disorder (ASD) suggest that gamma amino butyric acid (GABA) and glutamate (Glu) abnormalities may underlie social and sensory challenges in ASD. Magnetic resonance spectroscopy was used to measure Glu and GABA+ levels in the amygdala-hippocampus region and cerebellum in autistic children (n = 30), a clinical control group with sensory abnormalities (SA) but not ASD (n = 30), and children with typical development (n = 37). All participants were clinically assessed using the Autism Diagnostic Interview-Revised, the Autism Diagnostic Observation Scale-2, and the Child Sensory Profile-2. The Social Responsiveness Scale-2, Sniffin Sticks Threshold Test, and the University of Pennsylvania Smell Identification Test were administered to assess social impairment and olfactory processing. Overall, autistic children showed increased cerebellar Glu levels compared to TYP children. Evidence for altered excitatory/inhibitory signaling in the cerebellum was more clear-cut when analyses were restricted to male participants. Further, lower cerebellar GABA+/Glu ratios were correlated to more severe social impairment in both autistic and SA males, suggesting that the cerebellum may play a transdiagnostic role in social impairment. Future studies of inhibitory/excitatory neural markers, powered to investigate the role of sex, may aid in parsing out disorder-specific neurochemical profiles.

Phase-adjusted echo time (PATE)-averaging 1 H MRS: application for improved glutamine quantification at 2.89 T.

(1) H MRS investigations have reported altered glutamatergic neurotransmission in a variety of psychiatric disorders. The unraveling of glutamate from glutamine resonances is crucial for the interpretation of these observations, although this remains a challenge at clinical static magnetic field strengths. Glutamate resolution can be improved through an approach known as echo time (TE) averaging, which involves the acquisition and subsequent averaging of multiple TE steps. The process of TE averaging retains the central component of the glutamate methylene multiplet at 2.35 ppm, with the simultaneous attenuation of overlapping phase-modulated coupled resonances of glutamine and N-acetylaspartate. We have developed a novel post-processing approach, termed phase-adjusted echo time (PATE) averaging, for the retrieval of glutamine signals from a TE-averaged (1) H MRS dataset. The method works by the application of an optimal TE-specific phase term, which is derived from spectral simulation, prior to averaging over TE space. The simulation procedures and preliminary in vivo spectra acquired from the human frontal lobe at 2.89 T are presented. Three metabolite normalization schemes were developed to evaluate the frontal lobe test-retest reliability for glutamine measurement in six subjects, and the resulting values were comparable with previous reports for within-subject (9-14%) and inter-subject (14-20%) measures. Using the acquisition parameters and TE range described, glutamine quantification is possible in approximately 10 min. The post-processing methods described can also be applied retrospectively to extract glutamine and glutamate levels from previously acquired TE-averaged (1) H MRS datasets.

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.

Prolonged, Low-Level Exposure to the Marine Toxin, Domoic Acid, and Measures of Neurotoxicity in Nonhuman Primates.

BACKGROUND: The excitotoxic molecule, domoic acid (DA), is a marine algal toxin known to induce overt hippocampal neurotoxicity. Recent experimental and epidemiological studies suggest adverse neurological effects at exposure levels near the current regulatory limit (20 ppm, ∼0.075-0.1mg/kg). At these levels, cognitive effects occur in the absence of acute symptoms or evidence of neuronal death. OBJECTIVES: This study aimed to identify adverse effects on the nervous system from prolonged, dietary DA exposure in adult, female Macaca fascicularis monkeys. METHODS: Monkeys were orally exposed to 0, 0.075, and 0.15mg/kg per day for an average of 14 months. Clinical blood counts, chemistry, and cytokine levels were analyzed in the blood. In-life magnetic resonance (MR) imaging assessed volumetric and tractography differences in and between the hippocampus and thalamus. Histology of neurons and glia in the fornix, fimbria, internal capsule, thalamus, and hippocampus was evaluated. Hippocampal RNA sequencing was used to identify differentially expressed genes. Enrichment of gene networks for neuronal health, excitotoxicity, inflammation/glia, and myelin were assessed with Gene Set Enrichment Analysis. RESULTS: Clinical blood counts, chemistry, and cytokine levels were not altered with DA exposure in nonhuman primates. Transcriptome analysis of the hippocampus yielded 748 differentially expressed genes (fold change≥1.5; p≤0.05), reflecting differences in a broad molecular profile of intermediate early genes (e.g., FOS, EGR) and genes related to myelin networks in DA animals. Between exposed and control animals, MR imaging showed comparable connectivity of the hippocampus and thalamus and histology showed no evidence of hypomyelination. Histological examination of the thalamus showed a larger microglia soma size and an extension of cell processes, but suggestions of a GFAP+astrocyte response showed no indication of astrocyte hypertrophy. DISCUSSION: In the absence of overt hippocampal excitotoxicity, chronic exposure of Macaca fascicularis monkeys to environmentally relevant levels of DA suggested a subtle shift in the molecular profile of the hippocampus and the microglia phenotype in the thalamus that was possibly reflective of an adaptive response due to prolonged DA exposure. https://doi.org/10.1289/EHP10923.

fMRI evidence of neural abnormalities in the subcortical face processing system in ASD.

Recent evidence suggests that a rapid, automatic face detection system is supported by subcortical structures including the amygdala, pulvinar, and superior colliculus. Early-emerging abnormalities in these structures may be related to reduced social orienting in children with autism, and subsequently, to aberrant development of cortical circuits involved in face processing. Our objective was to determine whether functional abnormalities in the subcortical face processing system are present in adults with autism spectrum disorders (ASD) during supraliminal fearful face processing. Participants included twenty-eight individuals with ASD and 25 controls group-matched on age, IQ, and behavioral performance. The ASD group met diagnostic criteria on the ADI-R, ADOS-G, and DSM-IV. Both the ASD and control groups showed significant activation in bilateral fusiform gyri. The control group exhibited additional significant responses in the right amygdala, right pulvinar, and bilateral superior colliculi. In the direct group comparison, the controls showed significantly greater activation in the left amygdala, bilateral fusiform gyrus, right pulvinar, and bilateral superior colliculi. No brain region showed significantly greater activation in the ASD group compared to the controls. Thus, basic rapid face identification mechanisms appear to be functional in ASD. However, individuals with ASD failed to engage the subcortical brain regions involved in face detection and automatic emotional face processing, suggesting a core mechanism for impaired socioemotional processing in ASD. Neural abnormalities in this system may contribute to early-emerging deficits in social orienting and attention, the putative precursors to abnormalities in social cognition and cortical face processing specialization.

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.

Hypertension despite dehydration during severe pediatric diabetic ketoacidosis.

OBJECTIVE: Diabetic ketoacidosis (DKA) may result in both dehydration and cerebral edema but these processes may have opposing effects on blood pressure. We examined the relationship between dehydration and blood pressure in pediatric DKA. DESIGN: A retrospective review was performed at Seattle Children's Hospital, Seattle, WA. Participants were hospitalized children less than 18 yr. Intervention(s) or main exposure was to patients with DKA (venous pH < 7.3, glucose > 300 mg/dL, HCO(3) < 15 mEq/L, and urinary ketosis). Dehydration was calculated as percent body weight lost at admission compared to discharge. Hypertension (systolic and/or diastolic blood pressure (DBP) percentile > 95%) was defined based on National Heart, Lung, and Blood Institute (NHLBI, 2004) nomograms and hypotension was defined as systolic blood pressure (SBP) <70 + 2 [age]. RESULTS: Thirty-three patients (median 10.9 yr; range 10 months to 17 yr) were included. Fifty-eight percent of patients (19/33) had hypertension on admission before treatment and 82% had hypertension during the first 6 h of admission. None had admission hypotension. Hypertension 48 h after treatment and weeks after discharge was common (28 and 19%, respectively). Based on weight gained by discharge, 27% of patients had mild, 61% had moderate, and 12% presented with severe dehydration. CONCLUSION: Despite dehydration, most children admitted with severe DKA had hypertension.