A multi-site 99mTc-HMPAO SPECT study of cerebral blood flow in a community sample of patients with major depression.

Prior regional Cerebral Blood Flow (rCBF) studies in Major Depressive Disorder (MDD) have been limited by small, highly selective, non-representative samples that have yielded variable and poorly replicated findings. The aim of this study was to compare rCBF measures in a large, more representative community sample of adults with MDD and healthy control participants. This is a cross-sectional, retrospective multi-site cohort study in which clinical data from 338 patients 18-65 years of age with a primary diagnosis of MDD were retrieved from a central database for 8 privately owned, private-pay outpatient psychiatric centers across the United States. Two 99mTc-HMPAO SPECT brain scans, one at rest and one during performance of a continuous performance task, were acquired as a routine component of their initial clinical evaluation. In total, 103 healthy controls, 18-65 years old and recruited from the community were also assessed and scanned. Depressed patients had significantly higher rCBF in frontal, anterior cingulate, and association cortices, and in basal ganglia, thalamus, and cerebellum, after accounting for significantly higher overall CBF. Depression severity associated positively with rCBF in the basal ganglia, hippocampus, cerebellum, and posterior white matter. Elevated rCBF was especially prominent in women and older patients. Elevated rCBF likely represents pathogenic hypermetabolism in MDD, with its magnitude in direct proportion to depression severity. It is brain-wide, with disproportionate increases in cortical and subcortical attentional networks. Hypermetabolism may be a reasonable target for novel therapeutics in MDD.

Longitudinal, prospective study of head impacts in male high school football players.

INTRODUCTION: Repetitive, subconcussive events may adversely affect the brain and cognition during sensitive periods of development. Prevention of neurocognitive consequences of concussion in high school football is therefore an important public health priority. We aimed to identify the player positions and demographic, behavioral, cognitive, and impact characteristics that predict the frequency and acceleration of head impacts in high school football players. METHODS: In this prospective study, three cohorts of adolescent male athletes (N = 53, 28.3% Hispanic) were recruited over three successive seasons in a high school American football program. Demographic and cognitive functioning were assessed at baseline prior to participating in football. Helmet sensors recorded impact frequency and acceleration. Each head impact was captured on film from five different angles. Research staff verified and characterized on-field impacts. Player-level Poisson regressions and year-level and impact-level linear mixed-effect models were used to determine demographic, behavioral, cognitive, and impact characteristics as predictors of impact frequency and acceleration. RESULTS: 4,678 valid impacts were recorded. Impact frequency positively associated with baseline symptoms of hyperactivity-impulsivity [ß(SE) = 1.05 impacts per year per unit of symptom severity (1.00), p = 0.01] and inattentiveness [ß(SE) = 1.003 impacts per year per T-score unit (1.001), p = 0.01]. Compared to quarterbacks, the highest acceleration impacts were sustained by kickers/punters [ß(SE) = 21.5 g's higher (7.1), p = 0.002], kick/punt returners [ß(SE) = 9.3 g's higher (4.4), p = 0.03], and defensive backs [ß(SE) = 4.9 g's higher (2.5), p = 0.05]. Impacts were more frequent in the second [ß(SE) = 33.4 impacts (14.2), p = 0.02)] and third [ß(SE) = 50.9 impacts (20.1), p = 0.01] year of play. Acceleration was highest in top-of-the-head impacts [ß(SE) = 4.4 g's higher (0.8), p<0.001]. CONCLUSION: Including screening questions for Attention-Deficit/Hyperactivity Disorder in pre-participation evaluations can help identify a subset of prospective football players who may be at risk for increased head impacts. Position-specific strategies to modify kickoffs and correct tackling and blocking may also reduce impact burden.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Importance: Few translational human studies have assessed the association of prenatal maternal immune activation with altered brain development and psychiatric risk in newborn offspring. Objective: To identify the effects of maternal immune activation during the 2nd and 3rd trimesters of pregnancy on newborn brain metabolite concentrations, tissue microstructure, and longitudinal motor development. Design: Prospective longitudinal cohort study conducted from 2012 - 2017. Setting: Columbia University Irving Medical Center and Weill Cornell Medical College. Participants: 76 nulliparous pregnant women, aged 14 to 19 years, were recruited in their 2nd trimester, and their children were followed through 14 months of age. Exposure: Maternal immune activation indexed by maternal interleukin-6 and C-reactive protein in the 2nd and 3rd trimesters of pregnancy. Main Outcomes and Measures: The main outcomes included (1) newborn metabolite concentrations, measured as N-acetylaspartate, creatine, and choline using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity measured using Diffusion Tensor Imaging; and (3) indices of motor development assessed prenatally and postnatally at ages 4- and 14-months. Results: Maternal interleukin-6 and C-reactive protein levels in the 2nd or 3rd trimester were significantly positively associated with the N-acetylaspartate, creatine, and choline concentrations in the putamen, thalamus, insula, and anterior limb of the internal capsule. Maternal interleukin-6 was associated with fractional anisotropy in the putamen, insula, thalamus, precuneus, and caudate, and with mean diffusivity in the inferior parietal and middle temporal gyrus. C-reactive protein was associated with fractional anisotropy in the thalamus, insula, and putamen. Regional commonalities were found across imaging modalities, though the direction of the associations differed by immune marker. In addition, a significant positive association was observed between offspring motor development and both maternal interleukin-6 and C-reactive protein (in both trimesters) prenatally and 4- and 14-months of age. Conclusions and Relevance: Using a healthy sample, these findings demonstrate that levels of maternal immune activation in mid- to late pregnancy associate with tissue characteristics in newborn brain regions primarily supporting motor integration/coordination and behavioral regulation and may lead to alterations in motor development.

Aberrant hippocampus and amygdala morphology associated with cognitive deficits in schizophrenia.

Background: Working memory deficits are thought to be a primary disturbance in schizophrenia. We aimed to identify differences in morphology of the hippocampus and amygdala in patients with schizophrenia compared with healthy controls (HCs), and in patients who were either neuropsychologically near normal (NPNN) or neuropsychologically impaired (NPI). Morphological disturbances in the same subfields of the hippocampus and amygdala, but of greater magnitude in those with NPI, would strengthen evidence for the centrality of these limbic regions and working memory deficits in the pathogenesis of schizophrenia. Methods: We acquired anatomical MRIs in 69 patients with schizophrenia (18 NPNN, 46 NPI) and 63 age-matched HC participants. We compared groups in hippocampus and amygdala surface morphologies and correlated morphological measures with clinical symptoms and working memory scores. Results: Schizophrenia was associated with inward deformations of the head and tail of the hippocampus, protrusion of the hippocampal body, and widespread inward deformations of the amygdala. In the same regions where we detected the effects of schizophrenia, morphological measures correlated positively with the severity of symptoms and inversely with working memory performance. Patients with NPI displayed a similar pattern of anatomical abnormality compared to patients with NPNN. Conclusion: Our findings indicate that anatomical abnormalities of the hippocampus relate to working memory performance and clinical symptoms in persons with schizophrenia. Moreover, NPNN and NPI patients may lie on a continuum of severity, both in terms of working memory abilities and altered brain structure, with NPI patients being more severe than NPNN patients in both domains.

A randomized controlled trial of desvenlafaxine-induced structural brain changes in the treatment of persistent depressive disorder.

The anatomical changes that antidepressant medications induce in the brain and through which they exert their therapeutic effects remain largely unknown. We randomized 61 patients with Persistent Depressive Disorder (PDD) to receive either desvenlafaxine or placebo in a 12-week trial and acquired anatomical MRI scans in 42 of those patients at baseline before randomization and immediately at the end of the trial. We also acquired MRIs once in 39 age- and sex-matched healthy controls. We assessed whether the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, differentially changed cortical thickness during the trial compared with placebo. Patients relative to controls at baseline had thinner cortices across the brain. Although baseline thickness was not associated with symptom severity, thicker baseline cortices predicted greater reduction in symptom severity in those treated with desvenlafaxine but not placebo. We did not detect significant treatment-by-time effects on cortical thickness. These findings suggest that baseline thickness may serve as predictive biomarkers for treatment response to desvenlafaxine. The absence of treatment-by-time effects may be attributable either to use of insufficient desvenlafaxine dosing, a lack of desvenlafaxine efficacy in treating PDD, or the short trial duration.

Associations of Human Milk Oligosaccharides with Infant Brain Tissue Organization and Regional Blood Flow at 1 Month of Age.

Animal studies have shown that human milk oligosaccharides (HMOs) are important in early brain development, yet their roles have not been assessed in humans. The purpose of this study was to determine the associations of HMOs with MRI indices of tissue microstructure and regional cerebral blood flow (rCBF) in infants. Mother-infant pairs (N = 20) were recruited at 1 month postpartum. Milk was assayed for the concentrations of the HMOs 2'-fucosyllactose (2'FL), 3-fucosyllactose (3FL), 3'-sialyllactose (3'SL), and 6'-sialyllactose (6'SL). Diffusion and arterial spin labeling measures were acquired using a 3.0-Tesla MRI scanner. Multiple linear regression was used to assess the voxel-wise associations of HMOs with fractional anisotropy (FA), mean diffusivity (MD), and rCBF values across the brain. After adjusting for pre-pregnancy BMI, sex, birthweight, and postmenstrual age at time of scan, a higher 2'FL concentration was associated with reduced FA, increased MD, and reduced rCBF in similar locations within the cortical mantle. Higher 3FL and 3'SL concentrations were associated with increased FA, reduced MD, and increased rCBF in similar regions within the developing white matter. The concentration of 6'SL was not associated with MRI indices. Our data reveal that fucosylated and sialylated HMOs differentially associate with indices of tissue microstructure and rCBF, suggesting specific roles for 2'FL, 3FL, and 3'SL in early brain maturation.

Morphological Biomarkers in the Amygdala and Hippocampus of Children and Adults at High Familial Risk for Depression.

Major Depressive Disorder (MDD) is highly familial, and the hippocampus and amygdala are important in the pathophysiology of MDD. Whether morphological markers of risk for familial depression are present in the hippocampus or amygdala is unknown. We imaged the brains of 148 individuals, aged 6 to 54 years, who were members of a three-generation family cohort study and who were at either high or low familial risk for MDD. We compared surface morphological features of the hippocampus and amygdala across risk groups and assessed their associations with depression severity. High- compared with low-risk individuals had inward deformations of the head of both hippocampi and the medial surface of the left amygdala. The hippocampus findings persisted in analyses that included only those participants who had never had MDD, suggesting that these are true endophenotypic biomarkers for familial MDD. Posterior extension of the inward deformations was associated with more severe depressive symptoms, suggesting that a greater spatial extent of this biomarker may contribute to the transition from risk to the overt expression of symptoms. Significant associations of these biomarkers with corresponding biomarkers for cortical thickness suggest that these markers are components of a distributed cortico-limbic network of familial vulnerability to MDD.

Prenatal exposure to air pollution is associated with altered brain structure, function, and metabolism in childhood.

BACKGROUND: Prenatal exposure to air pollution disrupts cognitive, emotional, and behavioral development. The brain disturbances associated with prenatal air pollution are largely unknown. METHODS: In this prospective cohort study, we estimated prenatal exposures to fine particulate matter (PM2.5 ) and polycyclic aromatic hydrocarbons (PAH), and then assessed their associations with measures of brain anatomy, tissue microstructure, neurometabolites, and blood flow in 332 youth, 6-14 years old. We then assessed how those brain disturbances were associated with measures of intelligence, ADHD and anxiety symptoms, and socialization. RESULTS: Both exposures were associated with thinning of dorsal parietal cortices and thickening of postero-inferior and mesial wall cortices. They were associated with smaller white matter volumes, reduced organization in white matter of the internal capsule and frontal lobe, higher metabolite concentrations in frontal cortex, reduced cortical blood flow, and greater microstructural organization in subcortical gray matter nuclei. Associations were stronger for PM2.5 in boys and PAH in girls. Youth with low exposure accounted for most significant associations of ADHD, anxiety, socialization, and intelligence measures with cortical thickness and white matter volumes, whereas it appears that high exposures generally disrupted these neurotypical brain-behavior associations, likely because strong exposure-related effects increased the variances of these brain measures. CONCLUSIONS: The commonality of effects across exposures suggests PM2.5 and PAH disrupt brain development through one or more common molecular pathways, such as inflammation or oxidative stress. Progressively higher exposures were associated with greater disruptions in local volumes, tissue organization, metabolite concentrations, and blood flow throughout cortical and subcortical brain regions and the white matter pathways interconnecting them. Together these affected regions comprise cortico-striato-thalamo-cortical circuits, which support the regulation of thought, emotion, and behavior.

Using tissue microstructure and multimodal MRI to parse the phenotypic heterogeneity and cellular basis of autism spectrum disorder.

BACKGROUND: Identifying the brain bases for phenotypic heterogeneity in Autism Spectrum Disorder (ASD) will advance understanding of its pathogenesis and improve its clinical management. METHODS: We compared Diffusion Tensor Imaging (DTI) indices and connectome measures between 77 ASD and 88 Typically Developing (TD) control participants. We also assessed voxel-wise associations of DTI indices with measures of regional cerebral blood flow (rCBF) and N-acetylaspartate (NAA) to understand how tissue microstructure associates with cellular metabolism and neuronal density, respectively. RESULTS: Autism Spectrum Disorder participants had significantly lower fractional anisotropy (FA) and higher diffusivity values in deep white matter tracts, likely representing ether reduced myelination by oligodendrocytes or a reduced density of myelinated axons. Greater abnormalities in these measures and regions were associated with higher ASD symptom scores. Participant age, sex and IQ significantly moderated these group differences. Path analyses showed that reduced NAA levels accounted significantly for higher diffusivity and higher rCBF values in ASD compared with TD participants. CONCLUSIONS: Reduced neuronal density (reduced NAA) likely underlies abnormalities in DTI indices of white matter microstructure in ASD, which in turn are major determinants of elevated blood flow. Together, these findings suggest the presence of reduced axonal density and axonal pathology in ASD white matter. Greater pathology in turn accounts for more severe symptoms, lower intellectual ability, and reduced global efficiency for measures of white matter connectivity in ASD.

Association of Prenatal Sugar Consumption with Newborn Brain Tissue Organization.

Animal studies have shown that exposure to excess sugar during the prenatal and postnatal periods may alter early brain structure in rat pups. However, evidence in humans is lacking. The aim of this study was to determine associations of maternal total and added sugar intake in pregnancy with early brain tissue organization in infants. Adolescent mothers (n = 41) were recruited during pregnancy and completed 24 h dietary recalls during the second trimester. Diffusion tensor imaging was performed on infants using a 3.0 Tesla Magnetic Resonance Imaging Scanner at 3 weeks. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were constructed. A multiple linear regression was used to examine voxel-wise associations across the brain. Adjusting for postmenstrual age, sex, birth weight, and total energy intake revealed that maternal total and added sugar consumption were associated inversely and diffusely with infant MD values, not FA values. Inverse associations were distributed throughout all of the cortical mantle, including the posterior periphery (Bs = -6.78 to -0.57, Ps < 0.001) and frontal lobe (Bs = -4.72 to -0.77, Ps ≤ 0.002). Our findings suggest that maternal total and added sugar intake during the second trimester are significantly associated with features of brain tissue organization in infants, the foundation for future functional outcomes.

Neonatal brain metabolite concentrations: Associations with age, sex, and developmental outcomes.

Age and sex differences in brain metabolite concentrations in early life are not well understood. We examined the associations of age and sex with brain metabolite levels in healthy neonates, and investigated the associations between neonatal brain metabolite concentrations and developmental outcomes. Forty-one infants (36-42 gestational weeks at birth; 39% female) of predominantly Hispanic/Latina mothers (mean 18 years of age) underwent MRI scanning approximately two weeks after birth. Multiplanar chemical shift imaging was used to obtain voxel-wise maps of N-acetylaspartate (NAA), creatine, and choline concentrations across the brain. The Bayley Scales of Infant and Toddler Development, a measure of cognitive, language, and motor skills, and mobile conjugate reinforcement paradigm, a measure of learning and memory, were administered at 4 months of age. Findings indicated that postmenstrual age correlated positively with NAA concentrations in multiple subcortical and white matter regions. Creatine and choline concentrations showed similar but less pronounced age related increases. Females compared with males had higher metabolite levels in white matter and subcortical gray matter. Neonatal NAA concentrations were positively associated with learning and negatively associated with memory at 4 months. Age-related increases in NAA, creatine, and choline suggest rapid development of neuronal viability, cellular energy metabolism, and cell membrane turnover, respectively, during early life. Females may undergo earlier and more rapid regional developmental increases in the density of viable neurons compared to males.

Associations of Maternal Prenatal Drug Abuse With Measures of Newborn Brain Structure, Tissue Organization, and Metabolite Concentrations.

Importance: Increasing rates of illicit drug use during pregnancy may be associated with risk for long-term health problems in prenatally exposed children. Objective: To identify the associations of prenatal exposure to illicit drugs with organization of the newborn brain. Design, Setting, and Participants: For this cohort study, a volunteer sample of 210 illicit drug-using and nonusing mothers and their newborns was enrolled from prenatal clinics and drug abuse treatment programs in New York, New York. Enrollment, scanning, and long-term follow-up occurred from September 2004 through February 2012, and image processing and statistical analyses continued through fall 2018. In addition to 26 participants with incomplete data, a total of 64 mothers were lost to follow-up during pregnancy, and 13 newborns were lost to follow-up at birth because of perinatal complications. Exposures: Newborns were assigned to 1 of 4 primary exposure groups based on the history of most frequent maternal drug use: marijuana, cocaine, methadone maintenance, and/or heroin. Unexposed newborns were controls. Main Outcomes and Measures: Unsedated magnetic resonance imaging (MRI) of newborn brains was performed shortly after birth. Infant neurodevelopmental outcomes were assessed at age 12 months. MRI modalities included anatomical imaging, diffusion tensor imaging, T2 relaxometry, and magnetic resonance spectroscopic imaging. Infant neurodevelopmental outcomes included Bayley scales of infant development-III and Vineland Adaptive Behavior Scales. Statistical analyses were performed with results represented on the brain images. Results: Of 118 mothers, 42 (35%) were in the control group (mean [SD] age, 25.9 [6.1] years), 29 (25%) were in the cocaine group (mean [SD] age, 29.0 [6.1] years), 29 (25%) were in the marijuana group (mean [SD] age, 24.3 [5.5] years), and 18 (15%) were in the methadone and/or heroin group (mean [SD] age, 30.9 [5.7] years). Not all newborns could be scanned successfully; therefore, usable MRIs were acquired for 118 newborns from predominantly minority groups and with economically disadvantaged mothers. Anatomic abnormalities were detected in similar locations across all 3 drug exposures and included smaller volumes in the dorsal, medial, and ventral surfaces of the frontal lobe and dose-related increases in volumes in the lateral temporal lobe, dorsal parietal lobe, and superior frontal gyrus. Dose-related increases in diffusion tensor measures of tissue organization, decreases in T2 relaxometry times, and increases in spectroscopy metabolite concentrations were similar across exposures. These associations of exposures with brain measures were similar to the associations of newborn age with brain measures. The anatomic and diffusion tensor imaging measures suppressively mediated the associations of prenatal exposure with poorer 12-month infant outcomes. Conclusions and Relevance: The findings suggest that prenatal drug exposure is associated with measures of newborn brain tissue in patterns that may indicate that exposures accelerated normal fetal brain maturation, which in turn mediated the associations with poorer 12-month infant outcomes.

Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder.

BACKGROUND: Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ. METHODS: We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ. RESULTS: Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas. CONCLUSIONS: Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

Maturation of Brain Microstructure and Metabolism Associates with Increased Capacity for Self-Regulation during the Transition from Childhood to Adolescence.

Children ages 9-12 years face increasing social and academic expectations that require mastery of their thoughts, emotions, and behavior. Little is known about the development of neural pathways integral to these improving capacities during the transition from childhood to adolescence. Among 234 healthy, inner-city male and female youth (species Homo sapiens) 9-12 years of age followed by the Columbia Center for Children's Environmental Health, we acquired diffusion tensor imaging, multiplanar chemical shift imaging, and cognitive measures requiring self-regulation. We found that increasing age was associated with increased fractional anisotropy and decreased apparent diffusion coefficient, most prominently in the frontal and cingulate cortices, striatum, thalamus, deep white matter, and cerebellum. Additionally, we found increasing age was associated with increased N-acetyl-l-aspartate (NAA) in the anterior cingulate and insular cortices, and decreased NAA in posterior cingulate and parietal cortices. Age-associated changes in microstructure and neurometabolite concentrations partially mediated age-related improvements in performance on executive function tests. Together, these findings suggest that maturation of key regions within cortico-striatal-thalamo-cortical circuits subserve the emergence of improved self-regulatory capacities during the transition from childhood to adolescence.SIGNIFICANCE STATEMENT Few imaging studies of normal brain development have focused on a population of inner-city, racial/ethnic minority youth during the transition from childhood to adolescence, a period when self-regulatory capacities rapidly improve. We used DTI and MPCSI to provide unique windows into brain maturation during this developmental epoch, assessing its mediating influences on age-related improvement in performance on self-regulatory tasks. Our findings suggest that rapid maturation of cortico-striato-thalamo-cortical circuits, represented as progressive white-matter maturation (increasing FA and increasing NAA, Ch, Cr concentrations accompanying advancing age) in frontal regions and related subcortical projections and synaptic pruning (decreasing NAA, Ch, Cr, Glx) in posterior regions, support age-related improvements in executive functioning and self-regulatory capacities in youth 9-12 years of age.

Effects of the antidepressant medication duloxetine on brain metabolites in persistent depressive disorder: A randomized, controlled trial.

BACKGROUND: To assess whether patients with Persistent Depressive Disorder (PDD) have abnormal levels of N-acetyl-aspartate (NAA) and whether those levels normalize following treatment with the antidepressant medication duloxetine. Furthermore, we conducted post hoc analyses of other important brain metabolites to understand better the cellular and physiological determinants for changes in NAA levels. METHODS: We acquired proton (1H) magnetic resonance spectroscopic imaging (MRSI) data on a 3 Tesla (3T), GE Magnetic Resonance Imaging (MRI) scanner in 41 patients (39.9±10.4 years, 22 males) with PDD at two time points: before the start and at the end of a 10-week, placebo-controlled, double-blind, randomized controlled trial (RCT) of the antidepressant medication duloxetine. Patients were randomized such that 21 patients received the active medication and 20 patients received placebo during the 10 week period of the trial. In addition, we acquire 1H MRSI data once in 29 healthy controls (37.7±11.2 years, 17 males). FINDINGS: Patients had significantly higher baseline concentrations of NAA across white matter (WM) pathways and subcortical gray matter, and in direct proportion to the severity of depressive symptoms. NAA concentrations declined in duloxetine-treated patients over the duration of the trial in the direction toward healthy values, whereas concentrations increased in placebo-treated patients, deviating even further away from healthy values. Changes in NAA concentration did not mediate medication effects on reducing symptom severity, however; instead, changes in symptom severity partially mediated the effects of medication on NAA concentration, especially in the caudate and putamen. INTERPRETATION: These findings, taken together, suggest that PDD is not a direct consequence of elevated NAA concentrations, but that a more fundamental pathophysiological process likely causes PDD and determines the severity of its symptoms. The findings also suggest that although duloxetine normalized NAA concentrations in patients, it did so by modulating the severity of depressive symptoms. Medication presumably reduced depressive symptoms through other, as yet unidentified, brain processes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00360724.

Hyperperfusion of Frontal White and Subcortical Gray Matter in Autism Spectrum Disorder.

BACKGROUND: Our aim was to assess resting cerebral blood flow (rCBF) in children and adults with autism spectrum disorder (ASD). METHODS: We acquired pulsed arterial spin labeling magnetic resonance imaging data in 44 generally high-functioning participants with ASD simplex and 66 typically developing control subjects with comparable mean full-scale IQs. We compared rCBF values voxelwise across diagnostic groups and assessed correlations with symptom scores. We also assessed the moderating influences of participant age, sex, and IQ on our findings and the correlations of rCBF with N-acetylaspartate metabolite levels. RESULTS: We detected significantly higher rCBF values throughout frontal white matter and subcortical gray matter in participants with ASD. rCBF correlated positively with socialization deficits in participants with ASD in regions where hyperperfusion was greatest. rCBF declined with increasing IQ in the typically developing group, a correlation that was absent in participants with ASD, whose rCBF values were elevated across all IQ levels. rCBF in the ASD group correlated inversely with N-acetylaspartate metabolite levels throughout the frontal white matter, with greater rCBF accompanying lower and increasingly abnormal N-acetylaspartate levels relative to those of typically developing control subjects. CONCLUSIONS: These findings taken together suggest the presence of altered metabolism, likely of mitochondrial origin, and dysfunctional maintenance processes that support axonal functioning in ASD. These disturbances in turn likely reduce neural efficiency for cognitive and social functioning and trigger compensatory responses from supporting glial cells, which subsequently increase rCBF to affected white matter. These findings, if confirmed, suggest cellular and molecular targets for novel therapeutics that address axonal pathology and bolster glial compensatory responses in ASD.

Characterization of the central sulcus in the brain in early childhood.

Characterization of the developing brain during early childhood is of interest for both neuroscience and medicine, and in particular, is key to understanding what goes wrong in neurodevelopmental disorders. In particular, the cortex grows rapidly in the first 3 years of life, and creating a normative atlas can provide a comparison tool to diagnose disorders at an early stage, thereby empowering early interventional therapies. Zooming in on specific sulci may provide additional targeted information, and notably, an understanding of central sulcus growth can provide important insight on the development of laterality. However, there currently do not exist any atlases of specific changes in sulci as the brain grows. In this pilot study, we explore regional differences in the depth of the central sulcus between two and three year old infants using brain magnetic resonance images.