Brain age prediction and deviations from normative trajectories in the neonatal connectome.

Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brain's maturity relative to normative data. The difference between the individual's predicted and chronological age-or brain age gap (BAG)-represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We used resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predicted PMA for term and preterm infants. Predicted ages from each modality were correlated. At the network level, nearly all canonical brain networks-even putatively later developing ones-generated accurate PMA prediction. Additionally, BAGs were associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period.

Utilizing maternal prenatal cognition as a predictor of newborn brain measures of intellectual development.

Identifying reliable indicators of cognitive functioning prior to age five has been challenging. Prior studies have shown that maternal cognition, as indexed by intellectual quotient (IQ) and years of education, predict child intelligence at school age. We examined whether maternal full scale IQ, education, and inhibitory control (index of executive function) are associated with newborn brain measures and toddler language outcomes to assess potential indicators of early cognition. We hypothesized that maternal indices of cognition would be associated with brain areas implicated in intelligence in school-age children and adults in the newborn period. Thirty-seven pregnant women and their newborns underwent an MRI scan. T2-weighted images and surface-based morphometric analysis were used to compute local brain volumes in newborn infants. Maternal cognition indices were associated with local brain volumes for infants in the anterior and posterior cingulate, occipital lobe, and pre/postcentral gyrus - regions associated with IQ, executive function, or sensori-motor functions in children and adults. Maternal education and executive function, but not maternal intelligence, were associated with toddler language scores at 12 and 24 months. Newborn brain volumes did not predict language scores. Overall, the pre/postcentral gyrus and occipital lobe may be unique indicators of early intellectual development in the newborn period. Given that maternal executive function as measured by inhibitory control has robust associations with the newborn brain and is objective, brief, and easy to administer, it may be a useful predictor of early developmental and cognitive capacity for young children.

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.

Putamen Structure and Function in Familial Risk for Depression: A Multimodal Imaging Study.

BACKGROUND: The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression. METHODS: The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively. RESULTS: After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, ß-left = -0.17, ß-right = -0.15, ps = .002), N-acetylaspartate/creatine ratio (ß-left= -0.40, ß-right= -0.37, ps < .0001), and activation modulated by valence (ß-left = -0.22, ß-right = -0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (ß-left = -0.72, p = .013; ß-right = -0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33). CONCLUSIONS: Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them.

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.

Measuring variability of local brain volume using improved volume preserved warping.

Measuring local brain volume is clinically important in neuroimaging studies. Voxel preserved warping (VPW) and Jacobian determinant are effective methods for studying local brain volume changes and variations (LBVCV) across multiple brains. However, these LBVCV methods typically depend on the local deformation without using the global deformation, while both deformations are needed in co-registering the brains under examination so that the brains can be compared on a common and fair basis. However, instead of employing a uniformed strategy, different co-registration methods have developed their own unique strategy in performing global and local transformation of the co-registration of the brains, and how the global and local transformations may combine to achieve the final goal of co-registration is not their concern, as long as the final registration may accomplish the co-registering job satisfactorily. The aforementioned inconsistency thus makes the LBVCV measurement that relies on the registration methods for studying local brain volumes totally unstable and actually unreliable. To address the uncertainty in measuring local brain volume variability caused by the un-uniqueness of performing global and local deformations during co-registration, the present study proposes new VPW approaches (VPWα and VPWß), which no longer require the separation of the global and local transformation components but employ only the general deformation concatenating both components, as long as the general registration may achieve the task of co-registering brain images. The new VPW methods are validated in theory and in practice, using both simulated and real-world imaging data, respectively, based on two registration methods popularly in use by the neuroimaging research community, i.e., the Automatic Registration Toolbox (ART) and Symmetric Image Normalization Method (SyN) registration methods. Experiments using simulated data demonstrated that the proposed new VPW methods may reliably measure local brain volume changes and variability. In contrast, traditional methods typically may result in LBVCV maps containing significantly inconsistent even false findings. In the experiments using real neuroimaging datasets from a schizophrenia study, the results based on the proposed new VPW methods were highly consistent, no matter which registration method was employed. Otherwise, the LBVCV results based on traditional approaches would show significant difference, depending on the individual registration method that the analysis employed. LBVCV assessments based on traditional methods appear to be unreliable. The proposed new VPW methods for measuring local volume changes is independent of registration methods, and therefore can serve as alternative approaches for assessing LBVCV reliably.

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.

Altruism and "love of neighbor" offer neuroanatomical protection against depression.

We prospectively investigate protective benefits against depression of cortical thickness across nine regions of a Ventral Frontotemporal Network (VFTN), previously associated with spiritual experience. Seventy-two participants at high and low risk for depression (Mean age 41 years; 22-63 years; 40 high risk, 32 low risk) were drawn from a three-generation, thirty-eight year study. FreeSurfer estimated cortical thickness over anatomical MRIs of the brain (Year 30) for each of the nine ROIs. Depression (MDD with SAD-L; symptoms with PHQ; Years 30 and 38) and spirituality (self-report on five phenotypes; Year 35), respectively, were associated with the weighted average of nine regions of interest. VFTN thickness was: 1) positively associated (p<0.01) with two of five spiritual phenotypes, altruism and love of neighbor, interconnectedness at a trend level, but neither commitment nor practice, 2) inversely associated with a diagnosis of MDD (SADS-L Year 30, for any MDD in the past ten years), and 3) prospectively neuroanatomically protective against depressive symptoms (PHQ-9 Year 38) for those at high familial risk.

Depression Risk Is Associated With Weakened Synchrony Between the Amygdala and Experienced Emotion.

BACKGROUND: Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism. METHODS: Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study. RESULTS: Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation. CONCLUSIONS: Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants' parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally.

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.

Prenatal socioeconomic status and social support are associated with neonatal brain morphology, toddler language and psychiatric symptoms.

Few studies have assessed the association of parental socioeconomic status (SES) with brain measures in neonates, at a time when exposure to the postnatal environment is minimal. Social support may buffer the adverse consequences of SES, and has been associated with better cognitive - emotional development in children. We studied the association of prenatal SES and social support with neonatal brain structure, and toddler cognition, and psychiatric symptoms. In a sample of 37 healthy neonates, we correlated a measure of SES and marital/partner status (an index of social support) with morphological features of the cerebral surface measured on high-resolution MRI scans between the 1st - 6th weeks of postnatal life. We then assessed how SES relates to cognitive and behavioral outcomes at age 24-months. We found that neonates born to mothers with lower SES had greater local volumes at the surface of the right occipital lobe, left temporal pole, and left inferior frontal and anterior cingulate regions. Partner status moderated the associations of SES on neonatal brain morphology. Lower SES was associated with poorer language scores and less severe ADHD and ODD symptoms. In summary, SES was associated with neonatal brain structure and language and behavioral outcomes at toddler age. Future studies with a greater sample size and longitudinal MRI scans will help to determine whether prenatal SES continues to relate to early brain development in the same or different brain regions.

Social motivational processing and interpersonal function in aging cocaine smokers.

Illicit drug use among aging cohorts is increasing, yet little is known about functional impairments in older drug users. Given the importance of social integration for aging and documented social decrements in cocaine users, we examined social function and its neurocognitive substrates in aging cocaine users relative to carefully matched non-cocaine users. Regular (≥twice/week), long-term (≥15 years) cocaine smokers 50-60 years old (COCs; n = 22; four women) and controls (CTRLs; n = 19; four women) underwent standardized probes of social reward and threat processing during functional magnetic resonance imaging and a behavioral facial affect recognition task. Self-report and peer-report of daily interpersonal function were also collected. COCs, and CTRLs reporting current marijuana or alcohol use, were tested after four drug-free inpatient days. COCs had pronounced problems in daily social function relative to CTRLs indicated by both their own and their peers' reports. Compared with CTRLs, COCs had stronger amygdala responses to social threat versus control stimuli, with no other differences in social processing or cognition. Aging cocaine users appear to have marked, generalized difficulties in 'real-world' interpersonal function but largely intact social processing on laboratory-based measures when compared with appropriately matched controls and tested under well-controlled conditions. Daily social difficulties may be related to transient factors such as acute/residual drug effects or cocaine-related changes in health behaviors (e.g. disrupted sleep and poor diet). These data suggest that interpersonal function may be a valid intervention target for aging cocaine users and warrants further study in older drug users.

Stability of Cortical Thinning in Persons at Increased Familial Risk for Major Depressive Disorder Across 8 Years.

BACKGROUND: A biological marker of vulnerability should precede onset of illness and be independent of disease course. We previously reported that cortical thinning may serve as a potential biomarker for risk for familial depression. We now test stability of the cortical thinning across 8 years, and whether thinning mediates associations between familial risk and depressive traits. METHOD: Participants were from a 3-generation family study of depression, where 2nd and 3rd generation offspring were characterized as being at high- or low-risk for depression based on the presence/absence of major depression in the 1st generation. The analysis includes 82 offspring with anatomical MRI scans across two assessment waves, 7.8 (S.D.1.3, range: 5.2-10.9) years apart. RESULTS: High-risk offspring had thinner bilateral superior and middle frontal gyri, and left inferior parietal lobule, at both time-points. High intra-subject correlation (0.60

Prospective Study of Stereotactic Body Radiation Therapy for Thymoma and Thymic Carcinoma: Therapeutic Effect and Toxicity Assessment.

Stereotactic body radiation therapy (SBRT) is an important modality in treatment of tumors. We hypothesized that SBRT can achieve excellent local control with limited toxicity in patients with thymic tumors. A single-institution prospective study was performed with 32 patients who underwent SBRT of thymoma and thymic carcinoma between 2005 and 2014. Thirty-two patients including 39 target lesions were analyses in this study. Almost half of the patients (46.9%) were type C by histopathology and more than half (56.3%) were classified into stage IVA or IVB. The median dose of SBRT for gross tumor volume (GTV) was 56 Gy (range 49-70 Gy). Results showed that the response rate was 96.9% after SBRT and the median tumor shrinkage rate was 62.2% (range 3.8-100%). For the patients with both stage II-III and type A-B (n = 6), the median PFS was 28 months. In-field failure was only observed in 4 patients, and outside-field failure was seen in 2 patients. The local control rate was 81.25%. Patients treated with SBRT had an excellent local control with mild toxicities, which suggests that SBRT is feasible for the patients with thymic tumors who are unable to undergo either surgery or conventionally fractionated radiation therapy.

Neuroanatomical correlates of familial risk-for-depression and religiosity/spirituality.

OBJECTIVE: To examine potential neural substrates that underlie the interplay between religiosity/spirituality and risk-for-depression. A new wave of data from a longitudinal, three generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. MEASURES PARTICIPANTS AND METHODS: Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. Religiosity/spirituality measures were collected at the same time as the MRI scans and comprised self-report ratings of personal religious/spiritual (R/S) importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of religiosity/spirituality and risk-for-depression were examined on measures of cortical thickness and cortical surface area. RESULTS: A high degree of belief in the importance of religion/spirituality was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. CONCLUSIONS AND RELEVANCE: The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to religious/spiritual individuals at high risk for depression.

Segmenting and validating brain tissue definitions in the presence of varying tissue contrast.

We propose a method for segmenting brain tissue as either gray matter or white matter in the presence of varying tissue contrast, which can derive from either differential changes in tissue water content or increasing myelin content of white matter. Our method models the spatial distribution of intensities as a Markov Random Field (MRF) and estimates the parameters for the MRF model using a maximum likelihood approach. Although previously described methods have used similar models to segment brain tissue, accurate model of the conditional probabilities of tissue intensities and adaptive estimates of tissue properties to local intensities generates tissue definitions that are accurate and robust to variations in tissue contrast with age and across illnesses. Robustness to variations in tissue contrast is important to understand normal brain development and to identify the brain bases of neurological and psychiatric illnesses. We used simulated brains of varying tissue contrast to compare both visually and quantitatively the performance of our method with the performance of prior methods. We assessed validity of the cortical definitions by associating cortical thickness with various demographic features, clinical measures, and medication use in our three large cohorts of participants who were either healthy or who had Bipolar Disorder (BD), Autism Spectrum Disorder (ASD), or familial risk for Major Depressive Disorder (MDD). We assessed validity of the tissue definitions using synthetic brains and data for three large cohort of individuals with various neuropsychiatric disorders. Visual inspection and quantitative analyses showed that our method accurately and robustly defined the cortical mantle in brain images with varying contrast. Furthermore, associating the thickness with various demographic and clinical measures generated findings that were novel and supported by histological analyses or were supported by previous MRI studies, thereby validating the cortical definitions generated by the proposed method: (1) Although cortical thickness decreased with age in adolescents, in adults cortical thickness did not correlate significantly with age. Our synthetic data showed that the previously reported thinning of cortex in adults is likely due to decease in tissue contrast, thereby suggesting that the method generated cortical definitions in adults that were invariant to tissue contrast. In adolescents, cortical thinning with age was preserved likely due to widespread dendritic and synaptic pruning, even though the effects of decreasing tissue contrast were minimized. (3) The method generated novel finding of both localized increases and decreases in thickness of males compared to females after controlling for the differing brain sizes, which are supported by the histological analyses of brain tissue in males and females. (4) The proposed method, unlike prior methods, defined thicker cortex in BD individuals using lithium. The novel finding is supported by the studies that showed lithium treatment increased dendritic arborization and neurogenesis, thereby leading to thickening of cortex. (5) In both BD and ASD participants, associations of more severe symptoms with thinner cortex showed that correcting for the effects of tissue contrast preserved the biological consequences of illnesses. Therefore, consistency of the findings across the three large cohorts of participants, in images acquired on either 1.5T or 3T MRI scanners, and with findings from prior histological analyses provides strong evidence that the proposed method generated valid and accurate definitions of the cortex while controlling for the effects of tissue contrast.

Proton Chemical Shift Imaging of the Brain in Pediatric and Adult Developmental Stuttering.

IMPORTANCE: Developmental stuttering is a neuropsychiatric condition of incompletely understood brain origin. Our recent functional magnetic resonance imaging study indicates a possible partial basis of stuttering in circuits enacting self-regulation of motor activity, attention, and emotion. OBJECTIVE: To further characterize the neurophysiology of stuttering through in vivo assay of neurometabolites in suspect brain regions. DESIGN, SETTING, AND PARTICIPANTS: Proton chemical shift imaging of the brain was performed in a case-control study of children and adults with and without stuttering. Recruitment, assessment, and magnetic resonance imaging were performed in an academic research setting. MAIN OUTCOMES AND MEASURES: Ratios of N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NAA) to creatine (Cr) and choline compounds (Cho) to Cr in widespread cerebral cortical, white matter, and subcortical regions were analyzed using region of interest and data-driven voxel-based approaches. RESULTS: Forty-seven children and adolescents aged 5 to 17 years (22 with stuttering and 25 without) and 47 adults aged 21 to 51 years (20 with stuttering and 27 without) were recruited between June 2008 and March 2013. The mean (SD) ages of those in the stuttering and control groups were 12.2 (4.2) years and 13.4 (3.2) years, respectively, for the pediatric cohort and 31.4 (7.5) years and 30.5 (9.9) years, respectively, for the adult cohort. Region of interest-based findings included lower group mean NAA:Cr ratio in stuttering than nonstuttering participants in the right inferior frontal cortex (-7.3%; P = .02), inferior frontal white matter (-11.4%; P < .001), and caudate (-10.6%; P = .04), while the Cho:Cr ratio was higher in the bilateral superior temporal cortex (left: +10.0%; P = .03 and right: +10.8%; P = .01), superior temporal white matter (left: +14.6%; P = .003 and right: +9.5%; P = .02), and thalamus (left: +11.6%; P = .002 and right: +11.1%; P = .001). False discovery rate-corrected voxel-based findings were highly consistent with region of interest findings. Additional voxel-based findings in the stuttering sample included higher NAA:Cr and Cho:Cr ratios (regression coefficient, 197.4-275; P < .001) in the posterior cingulate, lateral parietal, hippocampal, and parahippocampal cortices and amygdala, as well as lower NAA:Cr and Cho:Cr ratios (regression coefficient, 119.8-275; P < .001) in the superior frontal and frontal polar cortices. Affected regions comprised nodes of the Bohland speech-production (motor activity regulation), default-mode (attention regulation), and emotional-memory (emotion regulation) networks. Regional correlations were also observed between local metabolites and stuttering severity (r = 0.40-0.52; P = .001-.02). CONCLUSIONS AND RELEVANCE: This spectroscopy study of stuttering demonstrates brainwide neurometabolite alterations, including several regions implicated by other neuroimaging modalities. Prior ascription of a role in stuttering to inferior frontal and superior temporal gyri, caudate, and other structures is affirmed. Consistent with prior functional magnetic resonance imaging findings, these results further intimate neurometabolic aberrations in stuttering in brain circuits subserving self-regulation of speech production, attention, and emotion.

Serotonin signaling modulates the effects of familial risk for depression on cortical thickness.

Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The "s" allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.

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

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