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.

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.

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.

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.

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.

Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.

Domoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (˜0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA exposure on reproductive and neurobehavioral endpoints in a preclinical nonhuman primate model. To this end, we initiated a long-term study using adult, female Macaca fascicularis monkeys exposed to daily, oral doses of 0.075 or 0.15 mg/kg of DA for a range of 321-381, and 346-554 days, respectively. This time period included a pre-pregnancy, pregnancy, and postpartum period. Throughout these times, trained data collectors observed intentional tremors in some exposed animals during biweekly clinical examinations. The present study explores the basis of this neurobehavioral finding with in vivo imaging techniques, including diffusion tensor magnetic resonance imaging and spectroscopy. Diffusion tensor analyses revealed that, while DA exposed macaques did not significantly differ from controls, increases in DA-related tremors were negatively correlated with fractional anisotropy, a measure of structural integrity, in the internal capsule, fornix, pons, and corpus callosum. Brain concentrations of lactate, a neurochemical closely linked with astrocytes, were also weakly, but positively associated with tremors. These findings are the first documented results suggesting that chronic oral exposure to DA at concentrations near the current human regulatory limit are related to structural and chemical changes in the adult primate brain.

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.

Strength of Ventral Tegmental Area Connections With Left Caudate Nucleus Is Related to Conflict Monitoring.

Successful learning requires the control of attention to monitor performance and compare actual versus expected outcomes. Neural activity in the ventral tegmental area (VTA) has been linked to attention control in animals. However, it is unknown whether the strength of VTA connections is related to conflict monitoring in humans. To study the relationship between VTA connections and conflict monitoring, we acquired diffusion tensor imaging (DTI) data on 50 second language learners who we have previously studied. We performed probabilistic tractography to document VTA connections with the dorsal striatum and the anterior cingulate cortex (ACC), and administered the Flanker task in which subjects were required to monitor and report conflicts in visual stimuli. Reaction times (RTs) indexed students' conflict monitoring. Probabilistic tractography revealed distinct neural connections between the VTA and the dorsal striatum and ACC. Correlational analyses between tractography and flanker RTs revealed that the strength of VTA connections with the left caudate nucleus was negatively correlated with RTs recorded in the presence of conflicts. This provides the first evidence to suggest that VTA connections with the left caudate nucleus are related to conflict monitoring in humans.

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.

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.

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.

ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) "A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)", was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

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.

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 and Behavioral Assessment of Executive Functions for Self-Regulating Levels of Language in Reading Brain.

This brief research report examines brain-behavioral relationships specific to levels of language in the complex reading brain. The first specific aim was to examine prior findings for significant fMRI connectivity from four seeds (left precuneus, left occipital temporal, left supramarginal, left inferior frontal) for each of four levels of language-subword, word (word-specific spelling or affixed words), syntax (with and without homonym foils or affix foils), and multi-sentence text to identify significant fMRI connectivity (a) unique to the lower level of language when compared to the immediately higher adjacent level of language across subword-word, word-syntax, and syntax-text comparisons; and (b) involving a brain region associated with executive functions. The second specific aim was to correlate the magnitude of that connectivity with standard scores on tests of Focused Attention (D-K EFS Color Word Form Inhibition) and Switching Attention (Wolf & Denckla Rapid Automatic Switching). Seven correlations were significant. Focused Attention was significantly correlated with the word level (word-specific spellings of real words) fMRI task in left cingulum from left inferior frontal seed. Switching Attention was significantly correlated with the (a) subword level (grapheme-phoneme correspondence) fMRI task in left and right Cerebellum V from left supramarginal seed; (b) the word level (word-specific spelling) fMRI task in right Cerebellum V from left precuneus seed; (c) the syntax level (with and without homonym foils) fMRI task in right Cerebellum V from left precuneus seed and from left supramarginal seed; and (d) syntax level (with and without affix foils) fMRI task in right Cerebellum V from left precuneus seed. Results are discussed in reference to neuropsychological assessment of supervisory attention (focused and switching) for specific levels of language related to reading acquisition in students with and without language-related specific learning disabilities and self-regulation of the complex reading brain.

The Neurobiological Mechanism of Chemical Aversion (Emetic) Therapy for Alcohol Use Disorder: An fMRI Study.

A recent NIH epidemiology study found the lifetime prevalence of alcohol use disorder in the United States to be 29%. Alcohol drinking behavior is strongly "learned" via pleasure center activation/reinforcement. Alcohol craving is a powerful desire to drink alcoholic beverages. Craving was added as one of the defining criteria for alcohol use disorder in DSM5, and craving reduction is becoming an increasingly important treatment goal. In the current study, patients with alcohol use disorder received 10 days of inpatient multi-modal treatments at Schick Shadel Hospital (SSH) of Seattle. The treatments included five chemical aversion conditioning sessions that associated alcohol cues (and alcohol) with nausea and emesis. All patients met DSM4 criteria for alcohol use disorder, were heavy drinkers, and reported craving alcohol pre-treatment. Craving reduction was one of the primary treatment goals. This is the first fMRI study to measure the effects of chemical aversion therapy on alcohol craving-related brain activity. Patients were recruited as subjects for the University of Washington (UW) brain scan study following SSH admission but before treatment onset. Prior to treatment, patients reported craving/desire for alcohol. After treatment (after four SSH chemical aversion treatments, again after five SSH chemical treatments, 30 and 90-days post-discharge), these same patients reported avoidance/aversion to alcohol. Most of the participants (69%) reported being still sober 12 months post-treatment. Consistent with a craving reduction mechanism of how chemical aversion therapy facilitates sobriety, results of the UW fMRI brain scans showed significant pre- to post-treatment reductions in craving-related brain activity in the occipital cortex. Additional fMRI brain scan studies are needed to further explore the neurobiological mechanism of chemical aversion therapy treatment for alcohol use disorder, and other substance use disorders for which chemical aversion therapy is used (e.g., opioid dependence and cocaine dependence). Substance use disorders are estimated to affect well over one billion people worldwide.

Relationships between Eye Movements during Sentence Reading Comprehension, Word Spelling and Reading, and DTI and fmri Connectivity In Students with and without Dysgraphia or Dyslexia.

While eye movements were recorded and brains scanned, 29 children with and without specific learning disabilities (SLDs) decided if sentences they read (half with only correctly spelled words and half with homonym foils) were meaningful. Significant main effects were found for diagnostic groups (non-SLD control, dysgraphia control, and dyslexia) in total fixation (dwell) time, total number of fixations, and total regressions in during saccades; the dyslexia group had longer and more fixations and made more regressions in during saccades than either control group. The dyslexia group also differed from both control groups in (a) fractional anisotropy in left optic radiation and (b) silent word reading fluency on a task in which surrounding letters can be distracting, consistent with Rayner's selective attention dyslexia model. Different profiles for non-SLD control, dysgraphia, and dyslexia groups were identified in correlations between total fixation time, total number of fixations, regressions in during saccades, magnitude of gray matter connectivity during the fMRI sentence reading comprehension from left occipital temporal cortex seed with right BA44 and from left inferior frontal gyrus with right inferior frontoccipital fasciculus, and normed word-specific spelling and silent word reading fluency measures. The dysgraphia group was more likely than the non-SLD control or dyslexia groups to show negative correlations between eye movement outcomes and sentences containing incorrect homonym foils. Findings are discussed in reference to a systems approach in future sentence reading comprehension research that integrates eye movement, brain, and literacy measures.

Changes in DTI Diffusivity and fMRI Connectivity Cluster Coefficients for Students with and without Specific Learning Disabilities In Written Language: Brain's Response to Writing Instruction.

Before and after computerized writing instruction, participants completed assessment with normed measures and DTI and fMRI connectivity scanning. Evidence-based differential diagnosis was used at time 1 to assign them to diagnostic groups: typical oral and written language (n=6), dysgraphia (impaired handwriting, n=10), dyslexia (impaired word spelling and reading, n=20), and OWL LD (impaired syntax construction, n=6). The instruction was aimed at subword letter writing, word spelling, and syntax composing. With p <.001 to control for multiple comparisons, the following significant findings were observed in academic achievement, DTI (radial diffusivity RD, axial diffusivity AD, and mean diffusivity MD), and graph cluster coefficients for fMRI connectivity. A time effect (pre-post intervention increase) in handwriting and oral construction of sentence syntax was significant; but diagnostic group effects were significant for dictated spelling and creation of word-specific spellings, with the dyslexia and OWL LD groups scoring lower than the typical control or dysgraphia groups. For RD a time effect occurred in anterior corona radiata and superior frontal. For AD a time effect occurred in superior corona radiata, superior frontal region, middle frontal gyrus, and superior longitudinal fasciculus. For MD a time effect occurred in the same regions as AD and also anterior coronal radiata. A diagnostic group effect occurred for graph cluster coefficients in fMRI connectivity while writing the next letter in alphabet from memory; but the diagnostic group × time interaction was not significant. The only significant time × treatment interaction occurred in right inferior frontal gyrus associated with orthographic coding. Compared to time 1, cluster coefficients increased at time 2 in all groups except in the dysgraphia group in which they decreased. Implications of results are discussed for response to instruction (RTI) versus evidence-based differential diagnosis for identifying students with SLDs in writing which may be best understood at both the behavioral and brain levels of analysis.

ERPs While Judging Meaningfulness of Sentences With and Without Homonym or Morpheme Spelling Foils: Comparing 4th to 9th Graders With and Without Spelling Disabilities.

Thirteen students with and twelve students without spelling disabilities judged whether sentences (1/3 all correct spellings, 1/3 with homonym foil, 1/3 with morpheme foil) were meaningful while event-related potentials (ERPs) were measured with EGI Geodesic EEG System 300 (128-channel hydro-cell nets). For N400, Rapid Automatic Switching (RAS) correlated with comprehending sentences with homonym foils in control group but with morpheme foils in SLD group. For P600, dictated spelling correlated with comprehending sentences with morpheme foils in the control group but solving anagrams with homonym foils in the SLD group. Educational significance and neuropsychological significance of these contrasting results are discussed.

Patterns of biomarkers for three phenotype profiles of persisting specific learning disabilities during middle childhood and early adolescence: A preliminary study.

Students without specific learning disabilities [SLDs] [n=18] and with one of three persisting SLDs in written language despite early and current specialized instruction-Dysgraphia [n=21], Dyslexia [n=40], or oral and written language learning disability OWL LD [n=14]- in grades 4 to 9 [N=56 boys, 38 girls] completed behavioral phenotyping assessment and gave a small blood or saliva sample. Molecular analyses informed by current cross-site research on gene candidates for learning disabilities identified associations between molecular genetic markers and the two defining behavioral phenotypes for each SLDs-WL; dysgraphia [impaired writing alphabet from memory for rs3743204 and sentence copying in best handwriting for rs79382 both in DYX1C1], dyslexia [impaired silent word reading/decoding rate for rs4535189 in DCDC2 and impaired spelling/encoding for rs374205 in DYX1C1], and OWL LD [impaired aural syntax comprehension for rs807701 and oral syntax construction for rs807701 both in DYX1C1]. Implications of these identified associations between molecular markers for alleles for different sites within two gene candidates [and mostly one] and hallmark phenotypes are discussed for translation science [application to practice] and neuroimaging that has identified contrasting brain bases for each of the three SLDs.