Jenifer Juranek

Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication

Two autistic children with a chromosome 15q11‐q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Ann Neurol 2003;53:801–804

Predicting Functional Gains in a Stroke Trial

Background and Purpose— A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment. Methods— Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains. Results— Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment. Conclusions— Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention.

Association between amygdala volume and anxiety level : Magnetic resonance imaging (MRI) study in autistic children

Our objective was to evaluate brain-behavior relationships between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in a well-characterized population of autistic children. Volumes for the amygdala, hippocampus, and whole brain were obtained from three-dimensional magnetic resonance images (MRIs) captured from 42 children who met the criteria for autistic disorder. Anxious/depressed symptoms were assessed in these children by the Anxious/Depressed subscale of the Child Behavior Checklist. To investigate the association between anxious/depressed scores on the Child Behavior Checklist and amygdala volume, data were analyzed using linear regression methods with Pearson correlation coefficients. A multivariate model was used to adjust for potential covariates associated with amygdala volume, including age at MRI and total brain size. We found that anxious/depressed symptoms were significantly correlated with increased total amygdala volume (r = .386, P = .012) and right amygdala volume (r = .469, P = .002). The correlation between anxious/depressed symptoms and left amygdala volume did not reach statistical significance (r = .249, P = .112). Child Behavior Checklist anxious/depressed scores were found to be a significant predictor of amygdala total (P = .014) and right amygdala (P = .002) volumes. In conclusion, we have identified a significant brain-behavior relationship between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in our autistic cohort. This specific relationship has not been reported in autism. However, the existing literature on human psychiatry and behavior supports our reported evidence for a neurobiologic relationship between symptoms of anxiety and depression with amygdala structure and function. Our results highlight the importance of characterizing comorbid psychiatric symptomatology in autism. The abundance of inconsistent findings in the published literature on autism might reflect differences between study populations regarding age at MRI, level of impairment within autistic subjects, and underlying anxiety level in the selected study groups.

Development and organization of the human brain tissue compartments across the lifespan using diffusion tensor imaging.

We used a diffusion tensor imaging-based whole-brain tissue segmentation to characterize age-related changes in (a) whole-brain grey matter, white matter, and cerebrospinal fluid relative to intracranial volume and (b) the corresponding brain tissue microstructure using measures of diffusion tensor anisotropy and mean diffusivity. The sample, a healthy cohort of 119 right-handed males and females aged 7–68 years. Our results demonstrate that white matter and grey matter volumes and their corresponding diffusion tensor anisotropy and mean diffusivity follow nonlinear trajectories with advancing age. In contrast, cerebrospinal fluid volume increases linearly with age.

Vulnerability of the frontal-temporal connections in temporal lobe epilepsy

OBJECTIVE In temporal lobe epilepsy (TLE), frontal-temporal connections are integral parts of the epileptogenic network. Although frontal-temporal gray matter abnormalities have been consistently demonstrated in TLE, white matter connections between these two lobes require further study in this disease setting. We therefore investigated the integrity of two major frontal-temporal white matter association tracts, uncinate fasciculus (UF) and arcuate fasciculus (AF), and their clinical correlates. METHODS Using diffusion tensor imaging (DTI) tractography, integrity of the UF and AF was examined in 22 individuals (12 subjects with TLE and 10 age-matched healthy controls). DTI indices of these tracts were compared between the two subject groups and correlates examined with clinical variables that included age of seizure onset, duration of epilepsy, history of febrile seizure and antiepileptic medication exposure. RESULTS In subjects with TLE, the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of UF and AF ipsilateral to the side of seizure onset were abnormal when compared to healthy controls. Furthermore, lower UF FA correlated with earlier age of seizure onset. CONCLUSION TLE is associated with abnormal integrity of frontal-temporal white matter tracts, but only on the side of seizure onset. This suggests that frontal-temporal white matter tracts are vulnerable to recurrent seizures and/or the factors precipitating the epilepsy.

ANOMALOUS DEVELOPMENT OF BRAIN STRUCTURE AND FUNCTION IN SPINA BIFIDA MYELOMENINGOCELE

Spina bifida myelomeningocele (SBM) is a specific type of neural tube defect whereby the open neural tube at the level of the spinal cord alters brain development during early stages of gestation. Some structural anomalies are virtually unique to individuals with SBM, including a complex pattern of cerebellar dysplasia known as the Chiari II malformation. Other structural anomalies are not necessarily unique to SBM, including altered development of the corpus callosum and posterior fossa. Within SBM, tremendous heterogeneity is reflected in the degree to which brain structures are atypical in qualitative appearance and quantitative measures of morphometry. Hallmark structural features of SBM include overall reductions in posterior fossa and cerebellum size and volume. Studies of the corpus callosum have shown complex patterns of agenesis or hypoplasia along its rostral-caudal axis, with rostrum and splenium regions particularly susceptible to agenesis. Studies of cortical regions have demonstrated complex patterns of thickening, thinning, and gyrification. Diffusion tensor imaging studies have reported compromised integrity of some specific white matter pathways. Given equally complex ocular motor, motor, and cognitive phenotypes consisting of relative strengths and weaknesses that seem to align with altered structural development, studies of SBM provide new insights to our current understanding of brain structure-function associations.

Behavioral and neurophysiologic response to therapy for chronic aphasia.

UNLABELLED Breier JI, Juranek J, Maher LM, Schmadeke S, Men D, Papanicolaou AC. Behavioral and neurophysiologic response to therapy for chronic aphasia. OBJECTIVE To characterize the relationship between neurophysiologic changes in the brain and behavioral response to constraint-induced language therapy (CILT) by using magnetoencephalography (MEG). DESIGN Case series. SETTING Medical school. PARTICIPANTS Patients (N=23) with chronic aphasia after first-time unilateral stroke in the left hemisphere. INTERVENTIONS Constraint-induced language therapy administered for 3 hours 4 times per week for 3 weeks. Language testing and functional imaging during a language comprehension task using MEG before, immediately after, and 3 months after CILT with a subgroup of patients undergoing additional MEG scanning and language testing 3 weeks before CILT. MAIN OUTCOME MEASURES The percent of correct information units and the number of late dipoles normalized to total activation. RESULTS Three patterns of behavioral and neurophysiologic response to CILT were identified. Patients with significant improvement in language immediately after CILT who lost these gains at follow-up had greater right hemisphere activation than other patients at all MEG scanning sessions. Patients with significant improvement in language immediately after CILT who maintained these gains at follow-up exhibited an increase in left temporal activation after CILT, whereas patients who did not exhibit significant improvement in language after CILT exhibited comparably greater activation in left parietal areas. CONCLUSIONS Results suggest that although the right hemisphere may support recovery of language function in response to therapy, this recovery may not be stable, and some participation of perilesional areas of the left hemisphere may be necessary for a stable behavioral response.

Activity in the Peri-Infarct Rim in Relation to Recovery From Stroke

Background and Purpose— In the rim of tissue surrounding a cortical infarct, animal studies have described an increase in a number of growth-related processes that likely contribute to behavioral recovery. The current study hypothesized that in patients with good outcome after stroke, brain activation in peri-infarct tissue would be greater than normal. Methods— In 15 patients with good recovery chronically after ischemic cortical stroke, activation within peri-infarct brain tissue was directly compared with activation within the same brain tissue of 13 control subjects. Results— Although most patients did show activation within peri-infarct tissues, their activation compared with controls was reduced rather than increased. Evaluation of the T2*-weighted images underlying functional MRI mapping disclosed a significant gradient of increased T2* signal in peri-infarct tissues, likely attributable to tissue changes such as gliosis. Conclusions— Among well-recovered stroke patients, cortical activation is present in the area surrounding a cortical infarct but is smaller than normal. A baseline derangement of the T2*-weighted signal underlying functional MRI (fMRI) is also present in this area, which might influence interpretation of fMRI findings. The relationship between increased tissue T2* signal and fMRI activation is not known and requires further study.

Brain Volumes in Adolescents With Very Low Birth Weight: Effects on Brain Structure and Associations With Neuropsychological Outcomes

The aims of this study were to examine abnormalities in brain structure in adolescents and young adults with very low birth weight (VLBW, <1,500 g) and associations of these abnormalities with neuropsychological outcomes. The sample of 108 participants from 14 to 19 years of age included 37 participants with <750 g birth weight, 35 with 750–1,499 g birth weight, and 36 normal birth weight (NBW) controls. One or both of the VLBW groups had smaller brain volumes, larger lateral ventricles, and a small surface area of the corpus callosum than the NBW controls. Group differences in white matter (WM) structures, subcortical gray matter (GM), and the cerebellum were found even when controlling for whole brain volume (WBV), and were most pronounced in the <750 g group. WM reductions in the two VLBW groups relative to NBW controls were associated with more pervasive cognitive deficits than were reductions in subcortical GM. Associations of cognitive outcomes with structural abnormalities remained when controlling for WBV or neonatal risks. The results are consistent with previous findings of residual brain abnormalities in adolescents and young adults with VLBW and provide new information on their cognitive correlates.

Rightward hemispheric asymmetries in auditory language cortex in children with autistic disorder: An MRI investigation

Purpose: determine if language disorder in children with autistic disorder (AD) corresponds to abnormalities in hemispheric asymmetries in auditory language cortex. Methods: MRI morphometric study in children with AD (n = 50) to assess hemispheric asymmetries in auditory language cortex. A key region of interest was the planum temporale (PT), which is larger in the left hemisphere in most healthy individuals. Results: (i) Heschl’s gyrus and planum polare showed typical hemisphere asymmetry patterns; (ii) posterior Superior Temporal Gyrus (pSTG) showed significant rightward asymmetry; and (iii) PT showed a trend for rightward asymmetry that was significant when constrained to right-handed boys (n = 30). For right-handed boys, symmetry indices for pSTG were significantly positively correlated with those for PT. PT asymmetry was age dependent, with greater rightward asymmetry with age. Conclusions: results provide evidence for rightward asymmetry in auditory association areas (pSTG and PT) known to subserve language processing. Cumulatively, our data provide evidence for a differing maturational path for PT for lower functioning children with AD, with both pre- and post-natal experience likely playing a role in PT asymmetry.