Corpus callosum morphology and relationships to illness phenotypes in individuals with anorexia nervosa.

Anorexia nervosa is an often-severe psychiatric illness characterized by significantly low body weight, fear of gaining weight, and distorted body image. Multiple neuroimaging studies have shown abnormalities in cortical morphology, mostly associated with the starvation state. Investigations of white matter, while more limited in number, have suggested global and regional volume reductions, as well as abnormal diffusivity in multiple regions including the corpus callosum. Yet, no study has specifically examined thickness of the corpus callosum, a large white matter tract instrumental in the inter-hemispheric integration of sensory, motor, and cognitive information. We analyzed MRI data from 48 adolescents and adults with anorexia nervosa and 50 healthy controls, all girls/women, to compare corpus callosum thickness and examined relationships with body mass index (BMI), illness duration, and eating disorder symptoms (controlling for BMI). There were no significant group differences in corpus callosum thickness. In the anorexia nervosa group, severity of body shape concerns was significantly, positively correlated with callosal thickness in the rostrum, genu, rostral body, isthmus, and splenium. In addition, there were significant positive correlations between eating disorder-related obsessions and compulsions and thickness of the anterior midbody, rostral body, and splenium. There were no significant associations between callosal thickness and BMI or illness duration. In sum, those with AN with worse concerns about bodily appearance and worse eating disorder-related obsessive thought patterns and compulsive behaviours have regionally thicker corpus callosum, independent of current weight status. These findings provide important neurobiological links to key, specific eating disorder behavioural phenotypes.

Neural representations of anxiety in adolescents with anorexia nervosa: a multivariate approach.

Anorexia nervosa (AN) is characterized by low body weight, fear of gaining weight, and distorted body image. Anxiety may play a role in the formation and course of the illness, especially related to situations involving food, eating, weight, and body image. To understand distributed patterns and consistency of neural responses related to anxiety, we enrolled 25 female adolescents with AN and 22 non-clinical female adolescents with mild anxiety who underwent two fMRI sessions in which they saw personalized anxiety-provoking word stimuli and neutral words. Consistency in brain response patterns across trials was determined using a multivariate representational similarity analysis (RSA) approach within anxiety circuits and in a whole-brain voxel-wise searchlight analysis. In the AN group there was higher representational similarity for anxiety-provoking compared with neutral stimuli predominantly in prefrontal regions including the frontal pole, medial prefrontal cortex, dorsolateral prefrontal cortex, and medial orbitofrontal cortex, although no significant group differences. Severity of anxiety correlated with consistency of brain responses within anxiety circuits and in cortical and subcortical regions including the frontal pole, middle frontal gyrus, orbitofrontal cortex, thalamus, lateral occipital cortex, middle temporal gyrus, and cerebellum. Higher consistency of activation in those with more severe anxiety symptoms suggests the possibility of a greater degree of conditioned brain responses evoked by personally-relevant emotional stimuli. Anxiety elicited by disorder-related stimuli may activate stereotyped, previously-learned neural responses within- and outside of classical anxiety circuits. Results have implications for understanding consistent and automatic responding to environmental stimuli that may play a role in maintenance of AN.

Cytoarchitectonically Defined Volumes of Early Extrastriate Visual Cortex in Unmedicated Adults With Body Dysmorphic Disorder.

BACKGROUND: Individuals with body dysmorphic disorder (BDD) misperceive that they have prominent defects in their appearance, resulting in preoccupations, time-consuming rituals, and distress. Previous neuroimaging studies have found abnormal activation patterns in the extrastriate visual cortex, which may underlie experiences of distorted perception of appearance. Correspondingly, we investigated gray matter volumes in individuals with BDD in the early extrastriate visual cortex using cytoarchitectonically defined maps that were previously derived from postmortem brains. METHODS: We analyzed T1-weighted magnetic resonance imaging data from 133 unmedicated male and female participants (BDD: n = 65; healthy control subjects: n = 68). We used cytoarchitectonically defined probability maps for the early extrastriate cortex, consisting of areas corresponding to V2, V3d, V3v/VP, V3a, and V4v. Gray matter volumes were compared between groups, supplemented by testing associations with clinical symptoms. RESULTS: The BDD group exhibited significantly larger gray matter volumes in the left and right early extrastriate cortex. Region-specific follow-up analyses revealed multiple subregions showing larger volumes in BDD, significant in the left V4v. There were no significant associations after corrections for multiple comparisons between gray matter volumes in early extrastriate cortex and BDD symptoms, comorbid symptoms, or duration of illness. CONCLUSIONS: Greater volumes of the early extrastriate visual cortex were evident in those with BDD, which aligns with outcomes of prior studies revealing BDD-specific functional abnormalities in these regions. Enlarged volumes of the extrastriate cortex in BDD might manifest during neurodevelopment, which could predispose individuals to aberrant visual perception and contribute to the core phenotype of distortion of perception for appearance.

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.

Effects of visual attention modulation on dynamic functional connectivity during own-face viewing in body dysmorphic disorder.

Body dysmorphic disorder (BDD) is characterized by preoccupations with misperceptions of one's physical appearance. Previous neuroimaging studies in BDD have yet to examine dynamic functional connectivity (FC) patterns between brain areas, necessary to capture changes in activity in response to stimuli and task conditions. We used Leading Eigenvector Dynamics Analysis to examine whole-brain dynamic FC from fMRI data during an own-face viewing task in 29 unmedicated adults with BDD with facial concerns and 30 healthy controls. The task involved two parts: (1) unconstrained, naturalistic viewing and (2) holding visual attention in the center of the image, to reduce scanning and fixation on perceived facial flaws. An FC state consisting of bilateral medial orbitofrontal cortex regions occurred significantly less often during the visual attention condition and afterward during the unconstrained face viewing in BDD participants, compared to the first unconstrained face viewing, a pattern that differed from controls. Moreover, the probability of this state during the second unconstrained face viewing was associated with severity of obsessions and compulsions and degree of poor insight in BDD, suggesting its clinical significance. These findings have implications for understanding the pathophysiology of own-face viewing in BDD and how it is affected by modification of viewing patterns, which may have implications for novel perceptual retraining treatment designs.

Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

Differential neuroimaging indices in prefrontal white matter in prenatal alcohol-associated ADHD versus idiopathic ADHD.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is common in fetal alcohol spectrum disorders (FASD) but also in patients without prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD may actually have ADHD and covert PAE, a treatment-relevant distinction. METHODS: We compared proton magnetic resonance spectroscopic imaging (MRSI; N = 44) and diffusion tensor imaging (DTI; N = 46) of the anterior corona radiata (ACR)-a key fiber tract in models of ADHD-at 1.5 T in children with ADHD with PAE (ADHD+PAE), children with ADHD without PAE (ADHD-PAE), children without ADHD with PAE (non-ADHD+PAE), and children with neither ADHD nor PAE (non-ADHD-PAE, i.e., typically developing controls). Levels of choline-compounds (Cho) were the main MRSI endpoint, given interest in dietary choline for FASD; the main DTI endpoint was fractional anisotropy (FA), as ACR FA may reflect ADHD-relevant executive control functions. RESULTS: For ACR Cho, there was an ADHD-by-PAE interaction (p = 0.038) whereby ACR Cho was 26.7% lower in ADHD+PAE than in ADHD-PAE children (p < 0.0005), but there was no significant ACR Cho difference between non-ADHD+PAE and non-ADHD-PAE children. Voxelwise false-discovery rate (FDR)-corrected analysis of DTI revealed significantly (q ≤ 0.0101-0.05) lower FA in ACR for subjects with PAE (ADHD+PAE or non-ADHD+PAE) than for subjects without PAE (ADHD-PAE or non-ADHD-PAE). There was no significant effect of ADHD on FA. Thus, in overlapping samples, effects of PAE on Cho and FA were observed in the same white-matter tract. CONCLUSIONS: These findings point to tract focal, white-matter pathology possibly specific for ADHD+PAE subjects. Low Cho may derive from abnormal choline metabolism; low FA suggests suboptimal white-matter integrity in PAE. More advanced MRSI and DTI-and neurocognitive assessments-may better distinguish ADHD+PAE from ADHD-PAE, helping identify covert cases of FASD.

Pregenual Anterior Cingulate Dysfunction Associated with Depression in OCD: An Integrated Multimodal fMRI/1H MRS Study.

Depression is a commonly occurring symptom in obsessive-compulsive disorder (OCD), and is associated with worse functional impairment, poorer quality of life, and poorer treatment response. Understanding the underlying neurochemical and connectivity-based brain mechanisms of this important symptom domain in OCD is necessary for development of novel, more globally effective treatments. To investigate biopsychological mechanisms of comorbid depression in OCD, we examined effective connectivity and neurochemical signatures in the pregenual anterior cingulate cortex (pACC), a structure known to be involved in both OCD and depression. Resting-state functional magnetic resonance imaging (fMRI) and 1H magnetic resonance spectroscopy (MRS) data were obtained from participants with OCD (n=49) and healthy individuals of equivalent age and sex (n=25). Granger causality-based effective (directed) connectivity was used to define causal networks involving the right and left pACC. The interplay between fMRI connectivity, 1H MRS and clinical data was explored by applying moderation and mediation analyses. We found that the causal influence of the right dorsal anterior midcingulate cortex (daMCC) on the right pACC was significantly lower in the OCD group and showed significant correlation with depressive symptom severity in the OCD group. Lower and moderate levels of glutamate (Glu) in the right pACC significantly moderated the interaction between right daMCC-pACC connectivity and depression severity. Our results suggest a biochemical-connectivity-psychological model of pACC dysfunction contributing to depression in OCD, particularly involving intracingulate connectivity and glutamate levels in the pACC. These findings have implications for potential molecular and network targets for treatment of this multi-faceted psychiatric condition.

Glutamate in Pediatric Obsessive-Compulsive Disorder and Response to Cognitive-Behavioral Therapy: Randomized Clinical Trial.

Cognitive-behavioral therapy (CBT) is effective for pediatric obsessive-compulsive disorder (OCD), but non-response is common. Brain glutamate (Glu) signaling may contribute to OCD pathophysiology and moderate CBT outcomes. We assessed whether Glu measured with magnetic resonance spectroscopy (MRS) was associated with OCD and/or CBT response. Youths aged 7-17 years with DSM-IV OCD and typically developing controls underwent 3 T proton echo-planar spectroscopic imaging (PEPSI) MRS scans of pregenual anterior cingulate cortex (pACC) and ventral posterior cingulate cortex (vPCC)-regions possibly affected by OCD-at baseline. Controls returned for re-scan after 8 weeks. OCD youth-in a randomized rater-blinded trial-were re-scanned after 12-14 weeks of CBT or after 8 weeks of minimal-contact waitlist; waitlist participants underwent a third scan after crossover to 12-14 weeks of CBT. Forty-nine children with OCD (mean age 12.2±2.9 years) and 29 controls (13.2±2.2 years) provided at least one MRS scan. At baseline, Glu did not differ significantly between OCD and controls in pACC or vPCC. Within controls, Glu was stable from scan-to-scan. Within OCD subjects, a treatment-by-scan interaction (p=0.034) was observed, driven by pACC Glu dropping 19.5% from scan-to-scan for patients randomized to CBT, with minor increases (3.8%) for waitlist participants. The combined OCD participants (CBT-only plus waitlist-CBT) also showed a 16.2% (p=0.004) post-CBT decrease in pACC Glu. In the combined OCD group, within vPCC, lower pre-CBT Glu predicted greater post-CBT improvement in symptoms (CY-BOCS; r=0.81, p=0.00025). Glu may be involved in the pathophysiology of OCD and may moderate response to CBT.

Cingulate and thalamic metabolites in obsessive-compulsive disorder.

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity.

Neurobehavioral comorbidities of pediatric epilepsies are linked to thalamic structural abnormalities.

PURPOSE: Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomic underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the comorbidities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes. METHODS: We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N = 21), CAE (N = 20), and HC (N = 27). Study subjects underwent structural magnetic resonance imaging (MRI), intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, intelligence quotient (IQ), language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC. KEY FINDINGS: Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction. SIGNIFICANCE: Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.

White matter microstructure in subjects with attention-deficit/hyperactivity disorder and their siblings.

OBJECTIVE: Previous voxel-based and regions-of-interest (ROI)-based diffusion tensor imaging (DTI) studies have found above-normal mean diffusivity (MD) and below-normal fractional anisotropy (FA) in subjects with attention-deficit/hyperactivity disorder (ADHD). However, findings remain mixed, and few studies have examined the contribution of ADHD familial liability to white matter microstructure. METHOD: We used refined DTI tractography methods to examine MD, FA, axial diffusivity (AD), and radial diffusivity (RD) of the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major, forceps minor, superior longitudinal fasciculus, and uncinate fasciculus in children and adolescents with ADHD (n = 56), unaffected siblings of ADHD probands (n = 31), and healthy controls (n = 17). RESULTS: Subjects with ADHD showed significantly higher MD than controls in the anterior thalamic radiation, forceps minor, and superior longitudinal fasciculus. Unaffected siblings of subjects with ADHD displayed similar differences in MD as subjects with ADHD. Although none of the tested tracts showed a significant effect of FA, the tracts with elevated MD likewise displayed elevated AD both in subjects with ADHD and in unaffected siblings. Differences in RD between subjects with ADHD, unaffected siblings, and controls were not as widespread as differences in MD and AD. CONCLUSION: Our findings suggest that disruptions in white matter microstructure occur in several large white matter pathways in association with ADHD and indicate a familial liability for the disorder. Furthermore, MD may reflect these abnormalities more sensitively than FA.

1H MRSI of middle frontal gyrus in pediatric ADHD.

Neuroimaging studies in multiple modalities have implicated the left or right dorsolateral prefrontal cortex (here, middle frontal gyrus) in attentional functions, in ADHD, and in dopamine agonist treatment of ADHD. The far lateral location of this cortex in the brain, however, has made it difficult to study with magnetic resonance spectroscopy (MRS). We used the smaller voxel sizes of the magnetic resonance spectroscopic imaging (MRSI) variant of MRS, acquired at a steep coronal-oblique angle to sample bilateral middle frontal gyrus in 13 children and adolescents with ADHD and 13 age- and sex-matched healthy controls. Within a subsample of the ADHD patients, aspects of attention were also assessed with the Trail Making Task. In right middle frontal gyrus only, mean levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA), creatine + phosphocreatine (Cr), choline-compounds (Cho), and myo-inositol (mI) were significantly lower in the ADHD than in the control sample. In the ADHD patients, lower right middle frontal Cr was associated with worse performance on Trails A and B (focused attention, concentration, set-shifting), while the opposite relationship held true for the control group on Trails B. These findings add to evidence implicating right middle frontal cortex in ADHD. Lower levels of these multiple species may reflect osmotic adjustment to elevated prefrontal cortical perfusion in ADHD and/or a previously hypothesized defect in astrocytic production of lactate in ADHD resulting in decelerated energetic metabolism (Cr), membrane synthesis (Cho, mI), and acetyl-CoA substrate for NAA synthesis. Lower Cr levels may indicate attentional or executive impairments.

Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.

Amygdala volumes in childhood absence epilepsy.

Abnormal amygdala volumes in pediatric mood-anxiety disorders and attention deficit hyperactivity disorder (ADHD), as well as high rates of these diagnoses in childhood absence epilepsy (CAE), prompted this study of amygdala volume in CAE. Twenty-six children with CAE and 23 normal children, aged 6.6-15.8 years, underwent MRI at 1.5 T. The tissue imaged with MRI was segmented, and amygdala volumes were obtained by manual tracings. There were no significant amygdala volume differences between the CAE and normal groups. Within the CAE group, however, the children with ADHD had significantly smaller amygdala volumes than the subjects with CAE with no psychopathology and those with mood/anxiety diagnoses. There was also a significant relationship between higher seizure frequency and greater amygdala asymmetry in the epilepsy group. Given ongoing development of the amygdala during late childhood and adolescence, despite the lack of significant group differences in amygdala volumes, the association of amygdala volume abnormalities with ADHD and seizure frequency implies a possible impact of the disorder on amygdala development and CAE-associated comorbidities, such as ADHD.