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Attention-deficit hyperactivity disorder (ADHD) is a debilitating disorder with apparent roots in abnormal brain development. Here, we quantified the level of individual brain maturation in children with ADHD using structural neuroimaging and a recently developed machine learning algorithm. More specifically, we compared the BrainAGE index between three groups matched for chronological age (mean ± SD: 11.86 ± 3.25 years): 89 children diagnosed with ADHD, 34 asymptomatic siblings of those children with ADHD, and 21 unrelated healthy control children. Brains of children with ADHD were estimated significantly younger (-0.85 years) than brains of healthy controls (Cohen's d = -0.33; p = 0.028, one-tailed), while there were no significant differences between unaffected siblings and healthy controls. In addition, more severe ADHD symptoms were significantly associated with younger appearing brains. Altogether, these results are in line with the proposed delay of individual brain maturation in children with ADHD. However, given the relatively small sample size ( N = 144), the findings should be considered preliminary and need to be confirmed in future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kurth, Levitt, Gaser, Alger, Loo, Narr, O’Neill and Luders.)

We examined the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) of the right orbitofrontal cortex (OFC) in patients with refractory obsessive-compulsive disorder (OCD) and comorbid Major Depressive Disorder. All participants (n = 26) received excitatory stimulation of the left dorsolateral prefrontal cortex followed by inhibitory stimulation of bilateral supplementary motor area for 10 sessions. In 18 patients with poor early OCD response, treatment was augmented with OFC inhibitory stimulation after the tenth treatment session. Augmentation with OFC stimulation was well-tolerated, and associated with further alleviation of both OCD and depression symptoms, particularly in individuals with more severe illnesses., (Copyright © 2022 Elsevier B.V. All rights reserved.)

White matter alterations have been reported in children with prenatal alcohol exposure (PAE) and in children with attention deficit hyperactivity disorder (ADHD); however, as children with PAE often present with ADHD, covert PAE may have contributed to previous ADHD findings. Additionally, data regarding intracortical myelination in ADHD are lacking. Therefore, we evaluated intracortical myelination (assessed as the T1w/T2w ratio at 4 cortical ribbon levels) and myelin-related deep white matter features in children (aged 8-13 years) with ADHD with PAE (ADHD + PAE), children with familial ADHD without PAE (ADHD-PAE), and typically developing (TD) children. In widespread tracts, ADHD + PAE children showed higher mean and radial diffusivity than TD and ADHD-PAE children and lower fractional anisotropy than ADHD-PAE children; ADHD-PAE and TD children did not differ significantly. Compared to TD children, ADHD + PAE children had lower intracortical myelination only at the deepest cortical level (mainly in right insula and cingulate cortices), while ADHD-PAE children had lower intracortical myelination at multiple cortical levels (mainly in right insula, sensorimotor, and cingulate cortices); ADHD + PAE and ADHD-PAE children did not differ significantly in intracortical myelination. Considering the two ADHD groups jointly (via non-parametric combination) revealed common reductions in intracortical myelination, but no common deep white matter abnormalities. These results suggest the importance of considering PAE in ADHD studies of white matter pathology. ADHD + PAE may be associated with deeper, white matter abnormalities, while familial ADHD without PAE may be associated with more superficial, cortical abnormalities. This may be relevant to the different treatment response observed in these two ADHD etiologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Symptoms of major depressive disorder (MDD) are reported to change early in treatment with repetitive transcranial magnetic stimulation (rTMS). We evaluated early changes in sleep, anxiety, and mood as predictors of nonresponse to rTMS treatment., Methods: Three hundred twenty-nine subjects with nonpsychotic MDD completed a 6-week course of rTMS treatment. Subjects were stratified by the severity of their baseline depression, and had their overall depressive symptoms recorded every week of treatment. We evaluated lack of improvement in sleep, anxiety, and mood symptoms after 1 and 2 weeks as potential predictors of eventual nonresponse, defined as <50% improvement in compositive depressive symptoms after 6 weeks. This was measured as negative predictive value (NPV; the likelihood that lack of early symptom improvement accurately predicted eventual treatment nonresponse)., Results: Subjects with severe or very severe baseline depression achieving <20% improvement in mood at 1 week were correctly predicted as nonresponders with NPVs largely >90%. At 2 weeks, subjects with very severe baseline depression who failed to demonstrate any improvement in mood were all nonresponders. Lack of improvement in sleep at 2 weeks was also a significant predictor., Conclusions: Identifying a lack of early mood improvement is a practical and robust method to predict rTMS nonresponse. This suggests a treatment protocol change may be indicated in patients with more severe baseline depression showing minimal early mood improvement., (© 2022 Wiley Periodicals LLC.)

Background: An improved understanding of the neurodevelopmental differences between attention deficit hyperactivity disorder with and without prenatal alcohol exposure (ADHD + PAE and ADHD-PAE, respectively) is needed. Herein, we evaluated gyrification (cortical folding) in children with ADHD + PAE compared to that in children with familial ADHD-PAE and typically developing (TD) children., Methods: ADHD + PAE (n = 37), ADHD-PAE (n = 25), and TD children (n = 27), aged 8-13 years, were compared on facial morphological, neurobehavioral, and neuroimaging assessments. Local gyrification index (LGI) maps were compared between groups using general linear modelling. Relationships between LGI and clincobehavioral parameters in children with ADHD ± PAE were evaluated using multivariate partial least squares., Results: ADHD + PAE and ADHD-PAE groups showed significantly lower LGI (relative to TD) in numerous regions, overlapping in medial prefrontal, parietal, and temporo-occipital cortices (p < 0.001). However, LGI in left mid-dorsolateral prefrontal cortex was uniquely lower in the ADHD + PAE group (p < 0.001). Partial least squares analysis identified one significant latent variable (accounting for 59.3 % of the crossblock correlation, p < 0.001), reflecting a significant relationship between a profile of lower LGI in prefrontal (including left mid-dorsolateral), insular, cingulate, temporal, and parietal cortices and a clinicobehavioral profile of PAE, including a flat philtrum and upper vermillion border, lower IQ, poorer behavioral regulation scores, and greater hyperactivity/impulsivity., Conclusions: Children with ADHD + PAE uniquely demonstrate lower mid-dorsolateral LGI, with widespread lower LGI related to more severe facial dysmorphia and neurobehavioral impairments. These findings add insight into the brain bases of PAE symptoms, potentially informing more targeted ADHD treatments based on an objective differential diagnosis of ADHD + PAE vs. ADHD-PAE., (Copyright © 2021. Published by Elsevier B.V.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Intermittent theta-burst stimulation priming (iTBS-P) can improve clinical outcome of patients with Major Depressive Disorder (MDD) who do not show early benefit from 10 Hz stimulation of left dorsolateral prefrontal cortex (DLPFC), also known as high-frequency left-sided (HFL) stimulation. The intensity and pulse number for iTBS-P needed to induce clinical benefit have not been systematically examined., Objective: To study the effect of intensity and pulse number on the clinical efficacy of iTBS-P., Methods: We conducted a retrospective review of 71 participants who received at least five sessions of HFL with limited clinical benefit and received iTBS-P augmentation for between 5 and 25 sessions. Intensity of iTBS-P priming stimuli ranged from 75 to 120% of motor threshold (MT) and pulse number ranged from 600 to 1800. Associations among intensity, pulse number, and clinical outcome were analyzed using a mixed methods linear model with change in IDS-SR as the primary outcome variable, priming stimulation intensity (subthreshold or suprathreshold), pulse number (<1200 or >1200 pulses), and gender as fixed factors, and number of iTBS-P treatments and age as continuous covariates., Results: Subjects who received subthreshold intensity iTBS-P experienced greater reduction in depressive symptoms than those who received suprathreshold iTBS-P (p = 0.011) with no effect of pulse number after controlling for stimulus intensity., Conclusions: Subthreshold intensity iTBS-P was associated with greater clinical improvement than suprathreshold stimulation. This finding is consistent with iTBS-P acting through homeostatic plasticity mechanisms., Competing Interests: Declaration of competing interest Drs. Corlier, Tadayonnejad, Marder, Krantz, Wilke, Levitt, and Ginder, along with Ms. Doan Ngo have no disclosures, Andrew Wilson has served as a consultant to HeartCloud, Inc within the past 36 months. Dr. Leuchter discloses that within the past 36 months he has received research support from the National Institutes of Health, Neuronetics, Department of Defense, CHDI Foundation, and NeuroSigma, Inc. He has served as a consultant to NeoSync, Inc., Ionis Pharmaceuticals, Inc., and ElMindA. He is Chief Scientific Officer of Brain Biomarker Analytics LLC (BBA). Dr. Leuchter has equity interest in BBA. Jonathan Lee has received in-kind equipment support from Magventure Inc. The authors report no other conflicts of interest in this work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective intervention for treatment-resistant Major Depressive Disorder (MDD). Early improvement during high-frequency left-sided (HFL) stimulation of the dorsolateral prefrontal cortex (DLPFC) is an important predictor of longer-term outcome, but most patients benefit later in their treatment course. We examined patients without early improvement with HFL to determine whether augmentation with additional stimulation approaches improved treatment outcome., Methods: 139 participants received HFL in a measurement-based care paradigm. Participants who achieved < 20% improvement by treatment 10 could continue with HFL (N = 17) or receive one of two augmentation strategies: bilateral stimulation (BL; HFL followed by low-frequency stimulation of right DLPFC) (N = 69) or intermittent theta-burst priming of left DLPFC (iTBS-P) (N = 17) for their remaining treatment sessions. The primary outcome was the percent reduction in depressive symptoms at treatment 30., Results: Participants who achieved < 20% improvement by treatment 10 and continued with HFL showed limited benefit. iTBS-P participants had significantly greater improvement, while those receiving BL trended toward improved outcomes. Ten sessions of either augmentation strategy appeared necessary to determine the likelihood of benefit., Conclusions: Augmentation of early non-response to HFL appears to improve rTMS outcomes, with a novel iTBS-P strategy surpassing both continued HFL or BL treatment in participants with < 20% improvement after 10 treatments. These findings suggest that measurement-based care with addition of augmented stimulation for those not showing early improvement may yield superior rTMS treatment outcomes., (Published by Elsevier B.V.)

Background: Trichotillomania (TTM) is a chronic and impairing psychiatric disorder with suspected dysfunctional cortico-striato-thalamo-cortical (CSTC) circuit activity reflecting excitatory/inhibitory signaling imbalance. TTM neurochemistry is understudied, with no prior research using magnetic resonance spectroscopy (MRS). This pilot investigation examined associations between TTM diagnosis, symptom severity, and response to behavioral treatment with MRS neurometabolites glutamate (Glu) and γ-aminobutyric acid (GABA) in CSTC structures., Methods: Proton echo-planar spectroscopic imaging (PEPSI) MRS was acquired from bilateral pregenual anterior cingulate cortex (pACC), caudate, putamen, globus pallidus, thalamus, and proximal white matter in 10 unmedicated girls with TTM, ages 9-17 years, before and after treatment, and from 13 age- and sex-matched healthy controls., Results: Nine of 10 TTM patients were treatment responders. Pretreatment mean Glu and GABA did not differ significantly between participants and controls. Pretreatment TTM symptoms were correlated with Glu in (left + right) pACC (r = 0.88, p = 0.02) and thalamus (r = 0.82, p = 0.012), and were negatively correlated with pACC GABA (r = -0.84, p = 0.034). Mean GABA in putamen increased 69% (baseline to post-treatment) (p = 0.027). Higher pretreatment Glu in caudate, putamen, globus pallidus, and thalamus predicted greater symptom decreases with treatment (all r < -0.6, p < 0.05); higher caudate GABA predicted less treatment-related symptom decline (r = 0.86, p = 0.014)., Limitations: Small sample, GABA quantified with spectral fitting rather than editing., Conclusion: Consistent with other neuroimaging, MRS reveals discrete CSTC chemical changes with effective behavior therapy, and possibly with TTM etiology. TTM symptoms relate to excess excitatory versus inhibitory signaling in pACC and thalamus; symptom improvement may reflect reduced excitatory drive of the CSTC direct-pathway activity., Competing Interests: Declaration of Competing Interest Dr. Peris receives funding from the National Institutes of Mental Health (NIMH) and the TLC Foundation for Body Focused Repetitive Behavior and royalties from Oxford University Press. Dr. McCracken reports receiving consultant income from Roche, Octapharma, and GW Biosciences; research clinical trial contracts from Roche, Think Now, Inc, and NICHD; and payment for expert witness participation for Lannett Pharmaceuticals. Dr. Piacentini has received grant or research support from NIMH, the TLC Foundation for Body-focused Repetitive Behaviors, the Tourette Association of America, and Pfizer Pharmaceuticals through the Duke University Clinical Research Institute Network. He receives publication royalties from Guilford Press and Oxford University Press. He receives speaking honoraria and/or travel support from the Tourette Association of America, the International Obsessive Compulsive Disorder Foundation, and the TLC Foundation for Body-focused Repetitive Behaviors., (Copyright © 2020. Published by Elsevier B.V.)

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC)., Methods: In 26 adults with TRD, we used Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents., Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment., Limitations: This study had an open-label design in a population receiving naturalistic treatment., Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression., Competing Interests: I. Cook reports a grant from NeoSync and earns equity interest from Los Angeles TMS Institute Inc., Neuro-Sigma Inc., HeartCloud Inc., and BrainCloud Corporation, outside the submitted work. A. Leuchter reports grants from the National Institutes from Health, Neuronetics, NeuroSigma Inc., the US Department of Defense, and the CHDI Foundation. He is a consultant and stockholder of NeoSync Inc., a consultant with Ionis Pharmaceuticals and EIMindA, and earns equity from Brain Biomarker Analytics LCC. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

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., (© 2019 Wiley Periodicals, Inc.)

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS., Methods: Medications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks., Results: Use of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02)., Conclusions: Concomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

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.

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: fMRI graph theory reveals resting-state brain networks, but has never been used in pediatric OCD., Methods: Whole-brain resting-state fMRI was acquired at 3T from 21 children with OCD and 20 age-matched healthy controls. BOLD connectivity was analyzed yielding global and local graph-theory metrics across 100 child-based functional nodes. We also compared local metrics between groups in frontopolar, supplementary motor, and sensorimotor cortices, regions implicated in recent neuroimaging and/or brain stimulation treatment studies in OCD., Results: As in adults, the global metric small-worldness was significantly (P<0.05) lower in patients than controls, by 13.5% (%mean difference=100%X(OCD mean - control mean)/control mean). This suggests less efficient information transfer in patients. In addition, modularity was lower in OCD (15.1%, P<0.01), suggesting less granular - or differently organized - functional brain parcellation. Higher clustering coefficients (23.9-32.4%, P<0.05) were observed in patients in frontopolar, supplementary motor, sensorimotor, and cortices with lower betweenness centrality (-63.6%, P<0.01) at one frontopolar site. These findings are consistent with more locally intensive connectivity or less interaction with other brain regions at these sites., Limitations: Relatively large node size; relatively small sample size, comorbidities in some patients., Conclusions: Pediatric OCD patients demonstrate aberrant global and local resting-state network connectivity topologies compared to healthy children. Local results accord with recent views of OCD as a disorder with sensorimotor component., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Obesity and overweight are often defined by the body mass index (BMI), which associates with metabolic and cardiovascular disease, and possibly with dementia as well as variations in brain volume. However, body fat distribution and abdominal obesity (as measured by waist circumference) is more strongly correlated with cardiovascular and metabolic risk than is BMI. While prior studies have revealed negative associations between gray matter tissue volumes and BMI, the relationship with respect to waist circumference remains largely unexplored. We therefore investigated the effects of both BMI and waist circumference on local gray matter volumes in a group of 115 healthy subjects screened to exclude physical or mental disorders that might affect the central nervous system. Results revealed significant negative correlations for both BMI and waist circumference where regional gray matter effects were largest within the hypothalamus and further encompassed prefrontal, anterior temporal and inferior parietal cortices, and the cerebellum. However, associations were more widespread and pronounced for waist circumference than BMI. Follow-up analyses showed that these relationships differed significantly across gender. While associations were similar for both BMI and waist circumference for males, females showed more extensive correlations for waist circumference. Our observations suggest that waist circumference is a more sensitive indicator than BMI, particularly in females, for potentially determining the adverse effects of obesity and overweight on the brain and associated risks to health., (Copyright © 2012 Wiley Periodicals, Inc.)

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., (Copyright © 2013 American Academy of Child & Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

The neurophysiological bases of cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) are incompletely understood. Previous studies, though sparse, implicate metabolic changes in pregenual anterior cingulate cortex (pACC) and anterior middle cingulate cortex (aMCC) as neural correlates of response to CBT. The goal of this pilot study was to determine the relationship between levels of the neurochemically interlinked metabolites glutamate + glutamine (Glx) and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) in pACC and aMCC to pretreatment OCD diagnostic status and OCD response to CBT. Proton magnetic resonance spectroscopic imaging ((1)H MRSI) was acquired from pACC and aMCC in 10 OCD patients at baseline, 8 of whom had a repeat scan after 4 weeks of intensive CBT. pACC was also scanned (baseline only) in 8 age-matched healthy controls. OCD symptoms improved markedly in 8/8 patients after CBT. In right pACC, tNAA was significantly lower in OCD patients than controls at baseline and then increased significantly after CBT. Baseline tNAA also correlated with post-CBT change in OCD symptom severity. In left aMCC, Glx decreased significantly after intensive CBT. These findings add to evidence implicating the pACC and aMCC as loci of the metabolic effects of CBT in OCD, particularly effects on glutamatergic and N-acetyl compounds. Moreover, these metabolic responses occurred after just 4 weeks of intensive CBT, compared to 3 months for standard weekly CBT. Baseline levels of tNAA in the pACC may be associated with response to CBT for OCD. Lateralization of metabolite effects of CBT, previously observed in subcortical nuclei and white matter, may also occur in cingulate cortex. Tentative mechanisms for these effects are discussed. Comorbid depressive symptoms in OCD patients may have contributed to metabolite effects, although baseline and post-CBT change in depression ratings varied with choline-compounds and myo-inositol rather than Glx or tNAA., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: The brain mechanisms of cognitive-behavioral therapy (CBT), a highly effective treatment for pediatric obsessive-compulsive disorder (OCD), are unknown. Neuroimaging in adult OCD indicates that CBT is associated with metabolic changes in striatum, thalamus, and anterior cingulate cortex. We therefore probed putative metabolic effects of CBT on these brain structures in pediatric OCD using proton magnetic resonance spectroscopic imaging (1H MRSI)., Method: Five unmedicated OCD patients (4 ♀, 13.5±2.8) and 9 healthy controls (7 ♀, 13.0±2.5) underwent MRSI (1.5 T, repetition-time/echo-time=1500/30 ms) of bilateral putamen, thalamus and pregenual anterior cingulate cortex (pACC). Patients were rescanned after 12 weeks of exposure-based CBT. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) of OCD symptoms was administered before and after CBT., Results: Four of 5 patients responded to CBT (mean 32.8% CY-BOCS reduction). Multiple metabolite effects emerged. Pre-CBT, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (tNAA) in left pregenual anterior cingulate cortex (pACC) was 55.5% higher in patients than controls. Post-CBT, tNAA (15.0%) and Cr (23.9%) in left pACC decreased and choline compounds (Cho) in right thalamus increased (10.6%) in all 5 patients. In left thalamus, lower pre-CBT tNAA, glutamate+glutamine (Glx), and myo-inositol (mI) predicted greater post-CBT drop in CY-BOCS (r=0.98) and CY-BOCS decrease correlated with increased Cho., Conclusions: Interpretations are offered in terms of the Glutamatergic Hypothesis of Pediatric OCD. Similar to 18FDG-PET in adults, objectively measurable regional MRSI metabolites may indicate pediatric OCD and predict its response to CBT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

Background: Subjects with autism suffer from impairments of social interaction, deviations in language usage, as well as restricted and stereotyped patterns of behavior. These characteristics are found irrespective of age, IQ, and gender of affected subjects. However, brain changes due to age, IQ, and gender might pose potential confounds in autism neuroimaging analyses., Methods: To investigate gray matter differences in autism that are not related to these potential confounds, we performed a voxel-based morphometry analysis in 52 affected children and adolescents and 52 matched control subjects., Results: We observed diminished gray matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin., Conclusions: This finding provides support for further investigations of the theory of abnormal functioning of this hormonal system in autism and potentially for experimental therapeutic approaches with oxytocin and related neuropeptides., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This cross-sectional study sought to confirm the presence and regional profile of previously reported changes in laminar cortical thickness in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) compared with typically developing control subjects., Method: High-resolution magnetic resonance images were obtained from 22 (19 male and 3 female subjects; mean age 11.7 years) children and adolescents with ADHD and 22 age- and sex-matched control subjects (mean age 11.7 years). Brain tissue volumes were estimated for each subject. Cortical pattern matching methods were used to sample measures of laminar thickness at high spatial frequency across homologous regions of the cortex. Volume and thickness measures were compared across diagnostic groups with and without controlling for general intelligence. False discovery rate correction confirmed regional results., Results: The subjects with ADHD exhibited significant reductions in overall brain volume, gray matter volume, and mean cortical thickness compared with the controls, whereas white matter volumes were significantly increased in ADHD. Highly significant cortical thinning (false discovery rate-corrected p < .0006) was observed over large areas of the frontal, temporal, parietal, and occipital association cortices and aspects of motor cortex but not within the primary sensory regions., Conclusions: Cortical thickness reductions present a robust neuroanatomical marker for child and adolescent ADHD. Observations of widespread cortical thinning expand on earlier cross-sectional findings and provide further evidence to support that the neurobiological underpinnings of ADHD extend beyond prefrontal and subcortical circuits.

Previous magnetic resonance imaging (MRI)-based volumetric studies have shown age-related increases in the volume of total white matter and decreases in the volume of total gray matter of normal children. Recent adaptations of image analysis strategies enable the detection of human brain growth with improved spatial resolution. In this article, we further explore the spatio-temporal complexity of adolescent brain maturation with tensor-based morphometry. By utilizing a novel non-linear elastic intensity-based registration algorithm on the serial structural MRI scans of 13 healthy children, individual Jacobian growth maps are generated and then registered to a common anatomical space. Statistical analyses reveal significant tissue growth in cerebral white matter, contrasted with gray matter loss in parietal, temporal, and occipital lobe. In addition, a linear regression with age and gender suggests a slowing down of the growth rate in regions with the greatest white matter growth. We demonstrate that a tensor-based Jacobian map is a sensitive and reliable method to detect regional tissue changes during development., ((c) 2007 Wiley-Liss, Inc.)

Background: Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have revealed structural abnormalities in the brains of affected individuals. One of the most replicated alterations is a significantly smaller corpus callosum (CC), for which conflicting reports exist with respect to the affected callosal segments., Methods: We applied novel surface-based geometrical modeling methods to establish the presence, direction, and exact location of callosal alterations in ADHD at high spatial resolution. For this purpose, we calculated the thickness of the CC at 100 equidistant midsagittal points in an age-matched male sample of 19 individuals with ADHD and 19 typically developing control subjects., Results: In close agreement with many prior observations, the CC was shown to be significantly thinner in ADHD subjects in anterior and, particularly, posterior callosal sections. Covarying for intelligence did not significantly alter the observed ADHD effects. However, group differences were no longer present in anterior sections when covarying for brain volume and after excluding ADHD subjects comorbid for oppositional defiant disorder., Conclusions: Decreased callosal thickness may be associated with fewer fibers or a decrease in the myelination of fibers connecting the parietal and prefrontal cortices. This might affect interhemispheric communication channels that are necessary to sustain attention or motor control, thus contributing to symptoms of hyperactivity and impulsivity, or inattention, observed in ADHD. Future studies are necessary to determine whether callosal abnormalities reflect maturational delays or persist into adulthood.

We used diffusion tensor imaging to investigate fractional anisotropy (FA), a measure of fiber tract integrity, in attention-deficit hyperactivity disorder (ADHD). Using a tract-based atlasing approach on six-direction diffusion tensor imaging data, we examined FA within the cingulum, corpus callosum, corticospinal tract, fornix, optic radiations, superior longitudinal fasciculus, uncinate fasciculus, and the superior and inferior occipitofrontal fasciculi in an all-male sample of 17 children and adolescents with ADHD and 16 age-matched controls. ADHD patients had significantly lower FA in the corticospinal tract (P=0.02) and the superior longitudinal fasciculus (P=0.017) compared with controls. Results support that disruptions in motor and attentional networks may contribute toward ADHD pathophysiology. Future research may clarify how ADHD subtype and psychiatric comorbidities affect diffusion measures.

The anterior cingulate is a key component of neural networks subserving attention and emotion regulation, functions often impaired in patients with psychosis. The study aimed to examine anterior cingulate volumes and sulcal morphology in a group of patients with childhood-onset schizophrenia (COS) compared with controls. Brain magnetic resonance imaging (MRI) scans were obtained in 13 COS and 18 matched control children, ages 6-17 years. Volume measures for the anterior cingulate gyrus (ACG) were obtained through manual labeling. A determination of cingulate sulcal pattern (single or double) was made for each hemisphere. The COS group had a reduced leftward skew of the double cingulate sulcal pattern, and absence of the normal left>right ACG volume asymmetry. The right ACG was larger in the COS than in controls. The schizophrenic children showed decreases in all ACG volumes with age, while the controls showed increases or no change. The data suggest that significant cingulate abnormalities may result from deviations in progressive neurodevelopmental processes, beginning before birth and continuing through childhood and adolescence, in persons who develop schizophrenia. These structural differences may relate to the well-described cognitive deficits these children display, and to the cardinal symptoms of schizophrenia.

The posterior superior temporal gyrus (STG) is the approximate site of Wernicke's area, a language region, which in previous studies has been reported to be abnormal in adults with schizophrenia. The present study assesses volumetric differences in the superior temporal gyrus of subjects with childhood-onset schizophrenia (COS). MRI scans of 18 subjects diagnosed with childhood-onset schizophrenia and 16 age- and sex-matched normals were analyzed to assess possible volume differences. The COS subjects displayed significant enlargement of the right posterior superior temporal gyrus, showing white matter increases bilaterally in this region. Our findings are consistent with studies that have found increased volumes in temporal lobe regions in COS and may provide a possible neural correlate for the language impairment observed in COS patients.

This study examined frontal lobe subregions in 46 normal children and adolescents (25 females, mean age: 11.08, SD: 3.07; and 21 males, mean age: 10.76, SD: 2.61) to assess the effects of age and gender on volumetric measures as well as hemispheric asymmetries. Superior, middle, inferior, and orbito-frontal gray, white, and cerebrospinal (CSF) volumes were manually delineated in high-resolution magnetic resonance imaging (MRI) data to assess possible morphological changes. We report a significant age-related increase in the white matter of the left inferior frontal gyrus (IFG) in boys (P = 0.007). Additionally, the left IFG was significantly larger in boys compared to girls (P = 0.004). Boys showed increased gray matter volume relative to girls even after correcting for total cerebral volume. Also, boys were found to have significant Right > Left asymmetry patterns with greater right hemispheric volumes for total cerebral volume, total cerebral white matter, MFG white matter, and SFG white matter (P < 0.001). Girls showed significant Right > Left asymmetry patterns in total cerebral and SFG white matter (P < 0.001). These findings suggest continued modification of the IFG during normal development in boys, and significant gender differences in IFG gray matter between boys and girls that may be possibly linked to gender differences in speech development and lateralization of language.

Thought disorder has been described as a hallmark feature in both adult and childhood-onset schizophrenia. The nucleus accumbens (NAc) has been repeatedly proposed as a critical station for modulating gating of information flow and processing of information within the thalamocortical circuitry. The aim of the present study was to investigate the relationship of thought disorder measures, which were administered to 12 children with schizophrenia and 15 healthy age-matched controls, and NAc volumes obtained from high-resolution volumetric magnetic resonance imaging analyses. The propensity for specific thought disorder features was significantly related to NAc volumes, despite no statistically significant differences in the NAc volumes of children with schizophrenia and normal children. Smaller left NAc volumes were significantly related to poor on-line revision of linguistic errors in word choice, syntax and reference. On the other hand, underuse of on-line repair of errors in planning and organizing thinking was significantly associated with decreased right NAc volumes. The results of this pilot study suggest that the NAc is implicated in specific thought patterns of childhood. They also suggest that subcortical function in the NAc might reflect hemispheric specialization patterns with left lateralization for revision of linguistic errors and right lateralization for repair strategies involved in the organization of thinking.

Background: Autism is a developmental disorder of unknown neurologic basis. Based on prior work, we used proton magnetic resonance spectroscopic imaging ((1)H- MRSI) to investigate brain structures, including cingulate and caudate, that we hypothesized would reveal metabolic abnormalities in subjects with autism., Methods: In 22 children with autism, 5 to 16 years old, and 20 age-matched healthy control subjects, (1)H-MRSI assessed levels of N-acetyl compounds (NAA), choline compounds (Cho), and creatine plus phosphocreatine (Cr) at 272 msec echo-time and 1.5 T., Results: In subjects with autism compared with control subjects, Cho was 27.2% lower in left inferior anterior cingulate and 19.1% higher in the head of the right caudate nucleus; Cr was 21.1% higher in the head of the right caudate nucleus, but lower in the body of the left caudate nucleus (17.9%) and right occipital cortex (16.6%)., Conclusions: Results are consistent with altered membrane metabolism, altered energetic metabolism, or both in the left anterior cingulate gyrus, both caudate nuclei, and right occipital cortex in subjects with autism compared with control subjects.

This study presents the first three-dimensional mapping of cortical sulcal patterns in autism, a pervasive developmental disorder, the underlying neurobiology of which remains unknown. High-resolution T(1)-weighted MRI scans were acquired in 21 autistic (age 10.7 +/- 3.1 years) and 20 normal control (age 11.3 +/- 2.9) children and adolescents. Using parametric mesh-based analytic techniques, we created three-dimensional models of the cerebral cortex and detailed maps of 22 major sulci in stereotaxic space. These average maps revealed anatomic shifting of major sulci primarily in frontal and temporal areas. Specifically, we found anterior and superior shifting of the superior frontal sulci bilaterally (P < or = 0.0003), anterior shifting of the right Sylvian fissure (P = 0.0002), the superior temporal sulcus (P = 0.0006 right, P = 0.02 left) and the left inferior frontal sulcus (P < or = 0.002) in the autistic group relative to the normal group. Less significant sulcal shifts occurred in the intraparietal and collateral sulci. These findings may indicate delayed maturation in autistic subjects in these brain regions involved in functions including working memory, emotion processing, language and eye gaze.

The majority of anatomic and neuroimaging studies in adult-onset schizophrenia demonstrate decreased volumes of the medial temporal lobe when compared with findings in normal individuals. The goal of this study was to investigate the hypothesis that subjects with childhood-onset schizophrenia would show decreased volumes of the medial temporal lobe when compared to normal children. Thirteen children meeting DSM-III-R criteria for schizophrenia (mean age 14.2+/-3.8 years) and 20 normal children (mean age 12.0+/-2.8 years) were investigated. MRI scans were performed on a 1.5-T GE Signa MR scanner using a coronal plane SPGR at 1.4-mm slice thickness. Volumes were assessed by manually tracing bilateral hippocampus, amygdala and temporal lobes. After adjustment for age and total brain volume, the amygdala was significantly larger in the schizophrenics than in the control subjects, and this volume increase was more pronounced on the left side. Hippocampus volumes did not differ significantly across groups. There was a nearly significant left-greater-than-right asymmetry of the amygdala in the schizophrenic group but not in the normal group. A nearly significant right-greater-than-left asymmetry was found in the anterior hippocampus for both schizophrenic and control groups. These findings are consistent with previous reports of at least initial sparing of temporal lobe regions in childhood-onset schizophrenia.

This study reports the first comprehensive three-dimensional (3D) maps of cortical patterns in children. Using a novel parametric mesh-based analytic technique applied to high-resolution T1-weighted MRI scans, we examined age (6-16 years) and gender differences in cortical complexity (the fractal dimension or complexity of sulcal/gyral convolutions) and asymmetry of 24 primary cortical sulci in normally developing children (N=24). Three-dimensional models of the cerebral cortex were extracted and major sulci mapped in stereotaxic space. Given the documented age-related changes in frontal lobe functions and several neuroimaging studies that have reported accompanying volumetric changes in these regions, we hypothesized that, with age, we would find continued modifications of the cerebrum in frontal cortex. We also predicted that phylogenetically older regions of the cerebrum, such as olfactory cortex, would be less variable in anatomic location across subjects and with age. Age-related increases in cortical complexity were found in both left and right inferior frontal and left superior frontal regions, possibly indicating an increase in secondary branching with age in these regions. Moreover, a significant increase in the length of the left inferior frontal sulcus and a posterior shifting of the left pre-central sulcus was associated with age. Three-dimensional asymmetry and anatomic variability maps revealed a significant left-greater-than-right asymmetry of the Sylvian fissures and superior temporal sulci, and increased variance in dorsolateral frontal and perisylvian areas relative to ventral regions of the cortex. These results suggest increases in cortical complexity and subtle modifications of sulcal topography of frontal lobe regions, likely reflecting ongoing processes such as myelination and synaptic remodeling that continue into the second decade of life. More studies in a larger sample set and/or longitudinal design are needed to address the issues of normal individual variation and sulcal development.

1. The aim was to investigate cerebellar vermis cross-sectional area in a group of high-functioning autistic children and normal control children. 2. Cerebellar vermis area measurements were completed on MRI scans from 8 autistic children (mean age 12.5 +/- 2.2, mean IQ 83.3 +/- 11.9) and 21 normal children (mean age 12.0 +/- 2.8, mean IQ 115 +/- 11). 3. The area of cerebellar vermis lobules VIII-X was significantly smaller in the autistic children than in the normal control subjects. ANCOVA demonstrated a confounding effect of IQ on these results. 4. Larger studies of autistic and normal subjects will be needed to assess the relationship between cerebellar abnormalities, autistic symptoms and IQ.