Seth D. Friedman

Brain structural abnormalities in young children with autism spectrum disorder

Objective To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. Methods Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. Results Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. Conclusions These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives.

Achieving progress in understanding the cause, nature, and treatment of autism requires an integration of concepts, approaches, and empirical findings from genetic, cognitive neuroscience, animal, and clinical studies. The need for such integration has been a fundamental tenet of the discipline of developmental psychopathology from its inception. It is likely that the discovery of autism susceptibility genes will depend on the development of dimensional measures of broader phenotype autism traits. It is argued that knowledge of the cognitive neuroscience of social and language behavior will provide a useful framework for defining such measures. In this article, the current state of knowledge of the cognitive neuroscience of social and language impairments in autism is reviewed. Following from this, six candidate broader phenotype autism traits are proposed: (a) face processing, including structural encoding of facial features and face movements, such as eye gaze; (b) social affiliation or sensitivity to social reward, pertaining to the social motivational impairments found in autism; (c) motor imitation ability, particularly imitation of body actions; (d) memory, specifically those aspects of memory mediated by the medial temporal lobe-prefrontal circuits; (e) executive function, especially planning and flexibility; and (f) Language ability, particularly those aspects of language that overlap with specific language impairment, namely, phonological processing.

Frontal lobe gray matter density decreases in bipolar I disorder.

BACKGROUND This study was conducted to explore differences in gray and white matter density between bipolar and healthy comparison groups using voxel-based morphometry (VBM). METHODS Brain magnetic resonance imaging was performed for 39 subjects with bipolar I disorder and 43 comparison subjects. Images were registered into a proportional stereotaxic space and segmented into gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping was used to calculate differences in gray and white matter density between groups. RESULTS Bipolar subjects had decreased gray matter density in left anterior cingulate gyrus (Brodmanns area [BA] 32, 7.3% decrease), an adjacent left medial frontal gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects. CONCLUSIONS The observation of a gray matter density decrease in the left anterior cingulate, which processes emotions, in bipolar subjects is consistent with prior reports that used region-of-interest analytic methods. Decreased gray matter density in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions, supports nondominant hemisphere dysfunction as a component of bipolar disorder.

Quantitative proton MRS predicts outcome after traumatic brain injury

Objective: To determine whether proton MRS (1H-MRS) neurochemical measurements predict neuropsychological outcome of patients with traumatic brain injury (TBI). Background: Although clinical indices and conventional imaging techniques provide critical information for TBI patient triage and acute care, none accurately predicts individual patient outcome. Methods: The authors studied 14 patients with TBI soon after injury (45 ± 21 days postinjury) and again at 6 months (172 ± 43 days) and 14 age-, sex-, and education-matched control subjects. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and gray matter using quantitative 1H-MRS. Outcome was assessed with the Glasgow Outcome Scale (GOS) and a battery of neuropsychological tests. A composite measure of neuropsychological function was calculated from individual test z-scores probing the major functional domains commonly impaired after head trauma. Results: Early NAA concentrations in gray matter predicted overall neuropsychological performance (r = 0.74, p = 0.01) and GOS (F = 11.93, p = 0.007). Other metabolite measures were not related to behavioral function at outcome. Conclusion: 1H-MRS provides a rapid, noninvasive tool to assess the extent of diffuse injury after head trauma, a component of injury that may be the most critical factor in evaluating resultant neuropsychological dysfunction. 1H-MRS can be added to conventional MR examinations with minimal additional time, and may prove useful in assessing injury severity, guiding patient care, and predicting patient outcome.

Metabolic and Cognitive Response to Human Traumatic Brain Injury: A Quantitative Proton Magnetic Resonance Study

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique insight into brain cellular metabolism following traumatic brain injury (TBI). The aim of the present study was to assess change in neurometabolite markers of brain injury during the recovery period following TBI. We studied 19 TBI patients at 1.5, 3, and 6 months postinjury and 28 controls. We used 1H-MRS to quantify N-acetylaspartate (NAA), creatine (Cre), choline (Cho), and myoinositol (mIns) in occipitoparietal gray matter (GM) and white matter (WM) remote from the primary injury focus. Neuropsychological testing quantified cognitive impairment and recovery. At 1.5 months, we found cognitive impairment (mean z score = -1.36 vs. 0.18,p < 0.01), lower NAA (GM: 12.42 mM vs. 13.03, p = 0.01; WM: 11.75 vs. 12.81, p < 0.01), and elevated Cho (GM: 1.51 vs. 1.25, p < 0.01; WM: 1.98 vs. 1.79, p < 0.01) in TBI patients compared with controls. GM NAA at 1.5 months predicted cognitive function at outcome (6 months postinjury; r = 0.63, p = 0.04). GM NAA continued to fall by 0.46 mM between 1.5 and 3 months (p = 0.02) indicating continuing neuronal loss, metabolic dysfunction, or both. Between 3 and 6 months, WM NAA increased by 0.55 mM (p = 0.06) suggesting metabolic recovery. Patients with poorer outcomes had elevated mean GM Cho at 3 months postinjury, suggesting active inflammation, as compared to patients with better outcomes (p = 0.002). 1H-MRS offers a noninvasive approach to assessing neuronal injury and inflammation following TBI, and may provide unique data for patient management and assessment of therapeutic efficacy.

Regional brain chemical alterations in young children with autism spectrum disorder

Objective: The authors evaluated regional brain chemistry for evidence of increased neuronal packing density in autism. Methods: Forty-five 3- to 4-year-old children with autism spectrum disorder (ASD), 13 children with typical development (TD), and 15 children with delayed development (DD) were studied using dual-echo proton echoplanar spectroscopic imaging (32 × 32 matrix-1 cm3 voxels) to measure brain chemical concentrations and relaxation times. Chemical quantification was corrected for tissue partial volume and relative measures of chemical relaxation (T2r) were calculated from the paired echoes. Measures from averaged and individual regions were compared using analysis of variance corrected for multiple comparisons. Results: ASD subjects demonstrated reduced N-acetylaspartate (NAA) (−10%), creatine (Cre) (−8%), and myo-inositol (−13%) concentrations compared to TD controls and prolonged NAA T2r relative to TD (7%) and DD (9%) groups. Compared to DD subjects, children with ASD also demonstrated prolonged T2r for choline (10%) and Cre (9%). Regional analyses demonstrated subtle patterns of chemical alterations in ASD compared to the TD and DD groups. Conclusions: Brain chemical abnormalities are present in ASD at 3 to 4 years of age. However, the direction and widespread distribution of these abnormalities do not support hypothesis of diffuse increased neuronal packing density in ASD.

Magnetic Resonance Spectroscopy in Traumatic Brain Injury

Magnetic resonance spectroscopy (MRS) offers a unique non-invasive approach for assessing the metabolic status of the brain in vivo and is particularly suited to studying traumatic brain injury (TBI). In particular, MRS provides a noninvasive means for quantifying such neurochemicals as N-acetylaspartate (NAA), creatine, phosphocreatine, choline, lactate, myo-inositol, glutamine, glutamate, adenosine triphosphate (ATP), and inorganic phosphate in humans following TBI and in animal models. Many of these chemicals have been shown to be perturbed following TBI. NAA, a marker of neuronal integrity, has been shown to be reduced following TBI, reflecting diffuse axonal injury or metabolic depression, and concentrations of NAA predict cognitive outcome. Elevation of choline-containing compounds indicates membrane breakdown or inflammation or both. MRS can also detect alterations in high energy phosphates reflecting the energetic abnormalities seen after TBI. Accordingly, MRS may be useful to monitor cellular response to therapeutic interventions in TBI.

Neuroimaging of Mitochondrial Disease

Mitochondrial disease represents a heterogeneous group of genetic disorders that require a variety of diagnostic tests for proper determination. Neuroimaging may play a significant role in diagnosis. The various modalities of nuclear magnetic resonance imaging (MRI) allow for multiple independent detection procedures that can give important anatomical and metabolic clues for diagnosis. The non-invasive nature of neuroimaging also allows for longitudinal studies. To date, no pathonmonic correlation between specific genetic defect and neuroimaging findings have been described. However, certain neuroimaging results can give important clues that a patient may have a mitochondrial disease. Conventional MRI may show deep gray structural abnormalities or stroke-like lesions that do not respect vascular territories. Chemical techniques such as proton magnetic resonance spectroscopy (MRS) may demonstrate high levels of lactate or succinate. When found, these results are suggestive of a mitochondrial disease. MRI and MRS studies may also show non-specific findings such as delayed myelination or non-specific leukodystrophy picture. However, in the context of other biochemical, structural, and clinical findings, even non-specific findings may support further diagnostic testing for potential mitochondrial disease. Once a diagnosis has been established, these non-invasive tools can also aid in following disease progression and evaluate the effects of therapeutic interventions.

Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-Induced neurotoxicity

Squads of rats were assayed at three intervals following MA-induced neurotoxicity to investigate the persistence of monoamine deficits, the potential for monoamine recovery, and spatial task abilities. At 48, 139, and 237 days postinjection, MA animals showed significant monoamine depletions compared with controls. Investigating percent depletions (MA/control) across time showed monoamine recovery in some structures. Initially, 5-HT within medial prefrontal cortex (MPFC), caudate (CdN), and hippocampus (HPC) was reduced to 30% of control levels. By 237 days, MPFC and CdN levels were elevated to 70%. Similarly, initial CdN DA reductions (30% of control levels) showed recovery to 80% by 237 days. These findings support neurochemical recovery following MA neurotoxicity. However, the persistent depression of HPC 5-HT suggests that not all structures recover equally. The HPC did show elevated turnover (metabolite/neurotransmitter) over time, suggesting a unique compensatory response. MA treatment also produced an impairment in the Morris water-maze place task at 65 days postinjection. No impairments were observed in water-maze moving platform or place task at 79 and 165 days postinjection, respectively, or in T-maze alternation. The possibility that partial recovery in tissue monamine levels underlies the sparing of function and behavioral improvement is discussed.

Reproducibility of 1H‐MRS in vivo

The current study sought to investigate the reproducibility of a quantitative spectroscopic examination, using rigorous positioning guidelines and automated spectral fitting for measuring the cerebral metabolites N‐acetylaspartate (NAA), creatine (Cre), choline (Cho), and myo‐inositol (ml). Ten subjects were studied in three sessions to determine the variability associated with measurement of metabolites in normal‐appearing occipitoparietal white matter, using short echo STEAM spectroscopy. A careful relocalization protocol based on local landmarks identified on thin‐slice images was used. No changes in mean metabolite concentrations for each subject between sessions were found, confirming relocalization. Mean coefficients of variation in measurement of NAA, Cre, Cho, and ml were 3.30, 4.33, 5.30, and 8.10, respectively. These data suggest that changes in metabolite concentrations as small as 12% can be confidently discerned in an individual subject over time. The implication of these results to study design is discussed. Magn Reson Med 41:193‐197, 1999.