Mira Raman

Functional MRI of the rodent somatosensory pathway using multislice echo planar imaging

A multislice EPI sequence was used to obtain functional MR images of the entire rat brain with BOLD contrast at 11.7 T. Ten to 11 slices covering the rat brain, with an in‐plane resolution of 300 μm, provided enough sensitivity to detect activation in brain regions known to be involved in the somatosensory pathway during stimulation of the forelimbs. These regions were identified by warping a digitized rat brain atlas to each set of images. Data analysis was constrained to four major areas of the somatosensory pathway: primary and secondary somatosensory cortices, thalamus, and cerebellum. Incidence maps were generated. Electrical stimulation at 3 Hz led to significant activation in the primary sensory cortex in all rats. Activation in the secondary sensory cortex and cerebellum was observed in 70% of the studies, while thalamic activation was observed in 40%. The amplitude of activation was measured for each area, and average response time courses were calculated. Finally, the frequency dependence of the response to forepaw stimulation was measured in each of the activated areas. Optimal activation occurred in all areas at 3 Hz. These results demonstrate that whole‐brain fMRI can be performed on rodents at 11.7 T to probe a well‐defined neural network. Magn Reson Med 52:89–99, 2004. Published 2004 Wiley‐Liss, Inc.

Alterations in White Matter Structure in Young Children With Type 1 Diabetes

OBJECTIVE To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children. RESEARCH DESIGN AND METHODS Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition. RESULTS Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects. CONCLUSIONS These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

BOLD and CBV‐weighted functional magnetic resonance imaging of the rat somatosensory system

A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran‐10 contrast agent for CBV fMRI. CBV‐weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran‐10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30‐mg Fe/kg dose. Incidence of activation followed a similar trend. Magn Reson Med, 2006. Published 2005 Wiley‐Liss, Inc.

Topological properties of large-scale structural brain networks in children with familial risk for reading difficulties.

Developmental dyslexia is a neurobiological deficit characterized by persistent difficulty in learning to read in children and adults who otherwise possess normal intelligence. Functional and structural connectivity data suggest that developmental dyslexia could be a disconnection syndrome. However, whether abnormalities in connectivity exist in beginning readers at-risk for reading difficulties is unknown. Using graph-theoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 42 beginning readers with (FH+) and without (FH-) familial risk for reading difficulties. We constructed separate structural correlation networks based on measures of surface area and cortical thickness. Results revealed changes in topological properties in brain regions known to be abnormal in dyslexia (left supramarginal gyrus, left inferior frontal gyrus) in the FH+ group mainly in the network constructed from measures of cortical surface area. We also found alterations in topological properties in regions that are not often advertised as dyslexia but nonetheless play important role in reading (left posterior cingulate, hippocampus, and left precentral gyrus). To our knowledge, this is the first report of altered topological properties of structural correlation networks in children at risk for reading difficulty, and motivates future studies that examine the mechanisms underlying how these brain networks may mediate the influences of family history on reading outcome.

Maternal history of reading difficulty is associated with reduced language-related gray matter in beginning readers.

Family history and poor preliteracy skills (referred to here as familial and behavioral risk, respectively) are critical predictors of developmental dyslexia. This study systematically investigated the independent contribution of familial and behavioral risks on brain structures, which had not been explored in past studies. We also examined the differential effects of maternal versus paternal history on brain morphometry, and familial risk dimensionally versus categorically, which were also novel aspects of the study. We assessed 51 children (5 to 6 years of age) with varying degrees of familial and behavioral risks for developmental dyslexia and examined associations with brain morphometry. We found that greater maternal history of reading disability was associated with smaller bilateral prefrontal and parieto-temporal gray, but not white matter volumes. Regressing out behavioral risk, socioeconomic status, and maternal education and other confounds did not change the results. No such relationship was observed for paternal reading history and behavioral risk. Results of cortical surface area and thickness further showed that there was a significant negative relationship between cortical surface area (but not thickness) and greater severity of maternal history, in particular within the left inferior parietal lobule, suggesting prenatal influence of maternal history on childrens brain morphometry. The results suggested greater maternal, possibly prenatal, influence on language-related brain structures. These results help to guide future neuroimaging research focusing on environmental and genetic influences and provide new information that may help predict which child will develop dyslexia in the future.

Genomic imprinting effects of the X chromosome on brain morphology.

There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (Xm) and 17 from their father (Xp). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with Xp demonstrated thicker cortex than those with Xm in the temporal regions bilaterally, while Xm individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with Xp. These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.

Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome

Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes

Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4–10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome

PURPOSE To identify whether patients with chronic fatigue syndrome (CFS) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms. MATERIALS AND METHODS Fifteen patients with CFS were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging (DTI) acquisitions and arterial spin labeling (ASL). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy (FA) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI, FA was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL. RESULTS In the CFS population, FA was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA was also increased in the right inferior longitudinal fasciculus (ILF) (P = .0008). In patients with CFS, right anterior arcuate FA increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF end point, the occipital lobe (T = 5.36). ASL showed no significant differences. CONCLUSION Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS.

Cognitive and behavioral correlates of caudate subregion shape variation in fragile X syndrome

Individuals with fragile X syndrome (FXS) exhibit frontal lobe‐associated cognitive and behavioral deficits, including impaired general cognitive abilities, perseverative behaviors, and social difficulties. Neural signals related to these functions are communicated through frontostriatal circuits, which connect with distinct regions of the caudate nucleus (CN). Enlargement of the CN is the most robust and reproduced neuroanatomical abnormality in FXS, but very little is known on how this affects behavioral/cognitive outcomes in this condition. Here, we investigated topography within focal regions of the CN associated with prefrontal circuitry and its link with aberrant behavior and intellect in FXS. Imaging data were acquired from 48 individuals with FXS, 28 IQ‐matched controls without FXS (IQ‐CTL), and 36 typically developing controls (TD‐CTL). Of the total participant count, cognitive and behavioral assessment data were obtained from 44 individuals with FXS and 27 participants in the IQ‐CTL group. CN volume and topography were compared between groups. Correlations were performed between CN topography and cognitive as well as behavioral measures within FXS and IQ‐CTL groups. As expected, the FXS group had larger CN compared with both IQ‐CTL and TD‐CTL groups. Correlations between focal CN topography and frontal lobe‐associated cognitive and behavioral deficits in the FXS group supported the hypothesis that CN enlargement is related to abnormal orbitofrontal‐caudate and dorsolateral‐caudate circuitry in FXS. These findings deepen our understanding of neuroanatomical mechanisms underlying cognitive‐behavioral problems in FXS and hold promise for informing future behavioral and psychopharmacological interventions targeting specific neural pathways. Hum Brain Mapp 35:2861–2868, 2014.