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1.  Abnormal Cerebellar Structure Is Dependent on Phenotype of Isolated Cleft of the Lip and/or Palate 
Cerebellum (London, England)  2013;12(2):236-244.
Isolated cleft lip and/or palate (ICLP) is one of the most common congenital birth defects in the USA, affecting roughly 1 in 600 births annually. Along with the facial deformity, this population has been found to have abnormal neurodevelopment and gross structural abnormalities in the brain, particularly within the cerebellum. The current study examined cerebellar structure within the two primary subtypes of ICLP: cleft lip with/without cleft palate (CL/P) and cleft palate alone (CPO). A large sample of 107 subjects aged 7 to 27 years with ICLP was compared to 127 healthy controls. Samples were separated by sex. Brain structure was obtained via magnetic resonance imaging. For males, after controlling for intracranial volume, cerebellum volume was significantly lower in the ICLP group (F= 12.351, p=0.001). Regionally in the cerebellum, males with ICLP had proportionally larger anterior lobes (F=4.022, p= 0.047) and smaller superior posterior lobes (F=5.686, p= 0.019). CL/P males showed only a reduction in overall cerebellum volume, with no regional changes. CPO males showed only regional changes, with no reduction in overall volume. Females with ICLP showed no overall or regional cerebellar abnormalities. However, females with CPO did have significantly lower cerebellum volumes than controls. The results reveal both global and regional cerebellar abnormalities within subjects with ICLP. They also establish the existence of abnormal cerebellar morphologies that are dependent on cleft subtype as well as sex. This lends further support to the claim that CL/P and CPO are distinct conditions.
doi:10.1007/s12311-012-0418-y
PMCID: PMC3566318  PMID: 23055082
Isolated cleft; Cleft lip with/without cleft palate; Cleft palate alone; Cerebellum; Magnetic resonance imaging; Brain structure
2.  Memory Processes in Learning Disability Subtypes of Children Born Preterm 
The purpose of this study was to evaluate immediate auditory and visual memory processes in learning disability subtypes of 40 children born preterm. Three subgroups of children were examined: (a) primary language disability group (n = 13), (b) perceptual-motor disability group (n = 14), and (c) no learning disability diagnosis group without identified language or perceptual-motor learning disability (n = 13). Between-group comparisons indicate no significant differences in immediate auditory or visual memory performances between language and perceptual-motor learning disability groups. Within-group comparisons revealed that both learning disability groups performed significantly lower on a task of immediate memory when the mode of stimulus presentation and mode of response were visual.
doi:10.1080/09297049.2011.648922
PMCID: PMC3968320  PMID: 22375897
3.  Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington’s disease 
Background
Huntington’s disease (HD) is a progressive, neuropsychiatric disorder, and limited reports indicate that risperidone might improve motor and psychiatric functioning for these patients.
Methods
In an open label, retrospective study to evaluate the effectiveness of risperidone on motor, psychiatric, and cognitive functioning in HD, 17 patients taking risperidone and 12 patients not taking any antipsychotic medication were compared across a year.
Results
Patients taking risperidone demonstrated significantly improved psychiatric functioning and motor stabilization, whereas patients not taking risperidone were stable psychiatrically and worsened motorically.
Conclusions
Although controlled clinical trials are clearly needed, these preliminary results support the use of risperidone in patients with HD in treating their psychiatric and possibly motor symptoms.
doi:10.1080/10401230701844802
PMCID: PMC3806309  PMID: 18297579
Huntington’s disease; Risperidone; Treatment; Psychiatric symptoms; Motor; Cognition
4.  Measures of growth in children at risk for Huntington disease 
Neurology  2012;79(7):668-674.
Objective:
The effect of mHTT on human development was examined by evaluating measures of growth in children at risk for Huntington disease (HD).
Methods:
Children at risk for HD with no manifest symptoms (no juvenile HD included) were enrolled and tested for gene expansion for research purposes only. Measurements of growth (height, weight, body mass index [BMI], and head circumference) in children tested as gene-expanded (n = 20, 7–18 years of age, CAG repeats ≥39) were compared to those of a large database of healthy children (n = 152, 7–18 years of age).
Results:
Gene-expanded children had significantly lower measures of head circumference, weight, and BMI. Head circumference was abnormally low even after correcting for height, suggesting a specific deficit in brain growth, rather than a global growth abnormality.
Conclusions:
These results indicate that, compared to a control population, children who were estimated to be decades from HD diagnosis have significant differences in growth. Further, they suggest that mHTT may play a role in atypical somatic, and in particular, brain development.
doi:10.1212/WNL.0b013e3182648b65
PMCID: PMC3414667  PMID: 22815549
5.  Neuropsychological, Behavioral, and Academic Sequelae of Cleft: Early Developmental, School Age, and Adolescent/Young Adult Outcomes 
This article reviews behavioral, neuropsychological, and academic outcomes of individuals with cleft across three age levels: 1) infancy/early development, 2) school age, and 3) adolescence/young adulthood. The review points out that attachment, neurocognitive functioning, academic performance/learning, and adjustment outcomes are the result of a complex interaction between biological and environmental factors and vary with developmental level, sex, and craniofacial anomaly diagnosis. The degree to which associated genetic or neurodevelopmental conditions may explain inconsistent findings is unknown and suggests the need for caution in generalizing from group data on cleft.
doi:10.1597/10-237
PMCID: PMC3408555  PMID: 21905907
cleft lip and palate; craniofacial; neuropsychological; behavior; learning; adjustment
6.  Antipsychotic Dose Equivalents and Dose-Years: A Standardized Method for Comparing Exposure to Different Drugs 
Biological psychiatry  2009;67(3):255-262.
Background
A standardized quantitative method for comparing dosages of different drugs is a useful tool for designing clinical trials and for examining the effects of long-term medication side effects such as tardive dyskinesia. Such a method requires establishing dose equivalents. An expert consensus group has published charts of equivalent doses for various antipsychotic medications for first- and second-generation medications. These charts were used in this study.
Methods
Regression was used to compare each drug in the experts' charts to chlorpromazine and haloperidol and to create formulas for each relationship. The formulas were solved for chlorpromazine 100 mg and haloperidol 2 mg to derive new chlorpromazine and haloperidol equivalents. The formulas were incorporated into our definition of dose-years such that 100 mg/day of chlorpromazine equivalent or 2 mg/day of haloperidol equivalent taken for 1 year is equal to one dose-year.
Results
All comparisons to chlorpromazine and haloperidol were highly linear with R2 values greater than .9. A power transformation further improved linearity.
Conclusions
By deriving a unique formula that converts doses to chlorpromazine or haloperidol equivalents, we can compare otherwise dissimilar drugs. These equivalents can be multiplied by the time an individual has been on a given dose to derive a cumulative value measured in dose-years in the form of (chlorpromazine equivalent in mg) × (time on dose measured in years). After each dose has been converted to dose-years, the results can be summed to provide a cumulative quantitative measure of lifetime exposure.
doi:10.1016/j.biopsych.2009.08.040
PMCID: PMC3677042  PMID: 19897178
7.  Changes in cortical morphology resulting from long-term amygdala damage 
The amygdala's contribution to emotion, cognition and behavior depends on its interactions with subcortical and cortical regions. Amygdala lesions result in altered functional activity in connected regions, but it is not known whether there might be long-term structural sequelae as well. We hypothesized that developmental bilateral amygdala lesions would be associated with specific gray matter morphometric abnormalities in the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC) and the ventral visual stream. We conducted regions of interest and vertex-based analyses of structural MRI data acquired in two patients with long-standing focal bilateral amygdala lesions (S.M. and A.P.), compared to gender- and age-matched healthy comparison subjects. Both patients showed significant proportional increases in gray matter volume of the vmPFC. Cortical thickness was increased in the vmPFC and ACC and decreased in the ventral visual stream. There were no morphometric changes in dorsolateral prefrontal cortex or dorsal visual stream cortices. These findings support the hypothesis that cortical regions strongly connected with the amygdala undergo morphometric changes with long-standing amygdala damage. This is the first evidence in humans of the remote alteration of brain morphology in association with amygdala lesions, and will help in interpreting the structural and functional consequences of amygdala pathology in neuropsychiatric disorders.
doi:10.1093/scan/nsr047
PMCID: PMC3375891  PMID: 21896493
amygdala; lesions; morphometry; plasticity; prefrontal cortex; ventromedial
8.  Long-term Outcome of Brain Structure in Premature Infants 
Objective
To assess the long-term outcome of brain structure in preterm infants, at an average age of 12 years, who received a red blood cell transfusion for anemia of prematurity.
Design
As neonates, this cohort of infants participated in a clinical trial in which they received red blood cell transfusions based on a high pretransfusion hematocrit threshold (liberal group) or a low hematocrit threshold (restricted group). These 2 preterm groups were compared with a group of full-term healthy control children.
Setting
Tertiary care hospital.
Participants
Magnetic resonance imaging scans for 44 of the original 100 subjects were obtained.
Intervention
Liberal vs restricted transfusion.
Main Outcome Measures
Intracranial volume, total brain tissue, total cerebrospinal fluid, cerebral cortex and cerebral white matter volume, subcortical nuclei volume, and cerebellum volume.
Results
Intracranial volume was substantially smaller in the liberal group compared with controls. Intracranial volume in the restricted group was not different from controls. Whole-cortex volume was not different in either preterm group compared with controls. Cerebral white matter was substantially reduced in both preterm groups, more so for the liberal group. The subcortical nuclei were substantially decreased in volume, equally so for both preterm groups compared with controls. When sex effects were evaluated, the girls in the liberal group had the most significant abnormalities.
Conclusion
Red blood cell transfusions affected the long-term outcome of premature infants as indicated by reduced brain volumes at 12 years of age for neonates who received transfusions using liberal guidelines.
doi:10.1001/archpediatrics.2010.269
PMCID: PMC3622941  PMID: 21199970
9.  Effects of Unilateral Clefts on Brain Structure 
Objective
To evaluate potential abnormalities in brain structure of children and adolescents with unilateral clefts.
Design
Case-control study.
Setting
Tertiary care center.
Participants
Boys aged 7 to 17 years with right (n=14) and left (n=19) clefts were compared with healthy age-matched boys (n=57).
Main Exposures
Structural brain measures were obtained using magnetic resonance imaging.
Outcome Measure
It was explored whether laterality of clefts had a significant effect on brain structure. To this end, volumes of tissue types and various brain regions were evaluated.
Results
Total white matter was significantly lower in boys with right clefts compared with boys with left clefts and healthy boys. Gross regional analyses demonstrated that reductions in white matter were evident in both the cerebellum and the cerebrum in boys with right clefts. Furthermore, within the cerebrum, white matter volumes were particularly low in the frontal lobes and the occipital lobes.
Conclusions
These preliminary results suggest that right clefts may be associated with more abnormalities in brain structure. More generally, laterality of a birth defect may have a significant effect on a developing organism.
doi:10.1001/archpediatrics.2010.123
PMCID: PMC3612276  PMID: 20679168
10.  Sex Differences in Parietal Lobe Structure and Development 
Gender Medicine  2012;9(1):44-55.
Structural MRI studies provide evidence for sex differences in the human brain. Differences in surface area and the proportion of gray to white matter volume are observed, particularly in the parietal lobe. To our knowledge, there are no studies examining sex differences of parietal lobe structure in younger populations or in the context of development. The current study evaluated sex difference in the structure of the parietal lobe in children (7-17 years of age). Also, by adding the cohort of previously studied adults (18-50 years of age), sex differences of parietal lobe morphology were examined across the age span of 7-50 years. In the youth sample, we found that, similar to adults, the ratio of parietal lobe cortex to white matter was greater in females. Unlike the adult sample, there were no sex differences in surface area. When examining effects of age, surface area had a significant sex-by-age interaction. Males had essentially no decrease in surfaces area over time, but females had a significant decrease in surface area over time. These findings support the notion of structural sex differences in the parietal lobe, not only in the context of cross sectional assessment, but also in terms of differences of developmental trajectories.
doi:10.1016/j.genm.2012.01.003
PMCID: PMC3326392  PMID: 22333522
development; parietal lobe; sex differences; surface area
11.  Automated parcellation of the brain surface generated from magnetic resonance images 
We have developed a fast and reliable pipeline to automatically parcellate the cortical surface into sub-regions. The pipeline can be used to study brain changes associated with psychiatric and neurological disorders. First, a genus zero cortical surface for one hemisphere is generated from the magnetic resonance images at the parametric boundary of the white matter and the gray matter. Second, a hemisphere-specific surface atlas is registered to the cortical surface using geometry features mapped in the spherical domain. The deformation field is used to warp statistic labels from the atlas to the subject surface. The Dice index of the labeled surface area is used to evaluate the similarity between the automated labels with the manual labels on the subject. The average Dice across 24 regions on 14 testing subjects is 0.86. Alternative evaluations have also chosen to show the accuracy and flexibility of the present method. The point-wise accuracy of 14 testing subjects is above 86% in average. The experiment shows that the present method is highly consistent with FreeSurfer (>99% of the surface area), using the same set of labels.
doi:10.3389/fninf.2013.00023
PMCID: PMC3804771  PMID: 24155718
cerebral cortex; cortical parcellation; surface registration; spherical demons; cytoarchitecture; magnetic resonance imaging
12.  Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia 
Biological psychiatry  2011;70(7):672-679.
Background
Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals.
Methods
The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake.
Results
A repeated-measures analysis showed significant age-by-group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures.
Conclusions
Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia.
doi:10.1016/j.biopsych.2011.05.017
PMCID: PMC3496792  PMID: 21784414
First episode; longitudinal studies; neurodevelopment; neuroprogression; schizophrenia; structural magnetic resonance imaging
13.  Neurocognitive Profiles of Preterm Infants Randomly Assigned to Lower or Higher Hematocrit Thresholds for Transfusion 
Objective
Preterm infants are frequently transfused with red blood cells based on standardized guidelines or clinical concern that anemia taxes infants’ physiological compensatory mechanisms and thereby threatens their health and well-being. The impact of various transfusion guidelines on long-term neurocognitive outcome is not known. The purpose of this study is to evaluate long-term neurocognitive outcome on children born prematurely and treated at birth with different transfusion guidelines.
Methods
Neurocognitive outcomes were examined at school age for 56 preterm infants randomly assigned to a liberal (n = 33) or restrictive (n = 23) transfusion strategy. Tests of intelligence, achievement, language, visual-spatial/motor, and memory skills were administered. Between-group differences were assessed.
Results
Those in the liberal transfusion group performed more poorly than those in the restrictive group on measures of associative verbal fluency, visual memory, and reading.
Conclusions
Findings highlight possible long-term neurodevelopmental consequences of maintaining higher hematocrit levels.
doi:10.1080/09297049.2010.544647
PMCID: PMC3115491  PMID: 21360360
Preterm; Neuropsychology; Red Blood Cell Transfusion; Hematocrit; Longitudinal
14.  Neonatal leptin administration alters regional brain volumes and blocks neonatal growth restriction-induced behavioral and cardiovascular dysfunction in male mice 
Pediatric research  2011;69(5 Pt 1):406-412.
Premature delivery is often complicated by neonatal growth restriction and neurodevelopmental impairment. Because global over-nutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal growth restriction decrease circulating levels of the neurotrophic hormone leptin. We hypothesized leptin supplementation would normalize the outcomes of mice with incipient neonatal growth restriction. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from day 4–14. At 4 months, mice underwent tail cuff blood pressure measurement, behavioral testing and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal growth restriction or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes.
doi:10.1203/PDR.0b013e3182110c7d
PMCID: PMC3095021  PMID: 21258265
15.  Estimating Premorbid Functioning in Huntington's Disease: The Relationship between Disease Progression and the Wide Range Achievement Test Reading Subtest 
The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular word reading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning.
doi:10.1093/arclin/acq088
PMCID: PMC3021970  PMID: 21147861
Huntington's disease; movement disorders; basal ganglia; assessment; dementia
16.  Behavioral effects of congenital ventromedial prefrontal cortex malformation 
BMC Neurology  2011;11:151.
Background
A detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC.
Case Presentation
B.W.'s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance.
Conclusions
The vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process.
doi:10.1186/1471-2377-11-151
PMCID: PMC3265436  PMID: 22136635
17.  Amygdala volume correlates positively with fearfulness in normal healthy girls 
Research into the neural underpinnings of fear and fear-related pathology has highlighted the role of the amygdala. For instance, bilateral damage to the amygdaloid complex is associated with decreased appreciation of danger and recognition of fear in humans, whereas enlarged amygdala volume is associated with internalizing syndromes. It is unknown whether amygdala volume and fearfulness are related in the absence of pathology. We examined the correlation between normal fearfulness and amygdala morphology in 116 healthy children and adolescents (60 boys, 56 girls, age 7–17 years). Fearfulness was measured using the parent ratings on the Pediatric Behavior Scale and amygdala volumes were determined by manual tracing. We found a positive correlation between right amygdala volume in girls (r = 0.29). This relationship was more robust and present bilaterally when analyses were limited to girls with a positive nuclear family history of depression (for left r = 0.63; for right r = 0.58). In boys there was no significant relationship which may suggest that biological mechanisms differ between sexes. Given the role of enlarged amygdala volume in pathology, these findings may indicate that variation in amygdala morphology marks susceptibility to internalizing disorders.
doi:10.1093/scan/nsq009
PMCID: PMC2999759  PMID: 20150341
amygdala volume; fearfulness; endophenotype; sex differences
18.  NEUROPSYCHOLOGICAL FUNCTIONING IN CHILDREN WITH NON-SYNDROMIC CLEFT OF THE LIP AND/OR PALATE 
Objective
Evaluate neuropsychological functioning in children with non-syndromic cleft of the lip and/or palate (NSCL/P) through profile variance within type of cleft and comparisons to controls.
Methods
Children ages 7 to 17 years participated; 66 had a diagnosis of NSCL/P and 87 were healthy controls. Neuropsychological tests of language, visual-perceptual, executive functioning, and memory skills were administered. Between- and within-group differences were assessed.
Results
Within cleft types, children with NSCLP had an even profile with equal Verbal and Performance IQ (VIQ and PIQ, respectively). Children with non-syndromic cleft palate only (NSCP) had significantly lower VIQ than PIQ, while children with non-syndromic cleft lip only (NSCL) showed a nonsignificant trend for higher VIQ than PIQ. Overall, subjects with NSCL/P performed lower on measures of expressive language and verbal memory than controls.
Conclusions
While deficits in verbal and memory skills for children with NSCL/P remain apparent, there is still uncertainty around the possible influence of cleft type on the pattern of deficits.
doi:10.1080/09297040802691120
PMCID: PMC3218568  PMID: 19184778
Cleft; Children; Cognition; Verbal skill; Non-syndromic
19.  Cerebellum Structure Differences and Relationship to Speech in Boys and Girls With Nonsyndromic Cleft of the Lip and/or Palate 
Objective
To identify regional cerebellar structural differences in boys and girls with nonsyndromic cleft of the lip and/or palate and determine whether these differences are related to speech impairment.
Design
Between 2003 and 2007, measures on cerebellar volume were obtained on 43 children with nonsyndromic cleft of the lip and/or palate and 43 age- and sex-matched, healthy controls. Children with the cleft condition also received speech evaluations. Children with nonsyndromic cleft of the lip and/or palate were recruited from clinic records, and controls (screened for medical, psychiatric, speech/language, and behavioral concerns) were recruited from the local community. All tests were administered at a large midwestern hospital. Boys and girls with nonsyndromic cleft of the lip and/or palate were compared with the healthy controls on global and regional measures of cerebellar volume. Areas of significant difference were then correlated with measures of speech to assess relationships in children with nonsyndromic cleft of the lip and/or palate.
Results
Boys with nonsyndromic cleft of the lip and/or palate had smaller cerebellums than controls (p = .002); whereas, for girls, only regional reductions in size reached significance (corpus medullare, p = .040). Cerebellum size was correlated with articulation for boys (p = .045).
Conclusions
These findings lend support to previous research documenting abnormal brain structure in children with nonsyndromic cleft of the lip and/or palate and suggest that the cerebellum may play a role in speech deficits along with other structural causes, at least in boys.
doi:10.1597/08-228
PMCID: PMC3218570  PMID: 20180711
cerebellum; children; cleft; speech
20.  Correlation of CAG repeat length between the maternal and paternal allele of the Huntingtin gene: evidence for assortative mating 
Triplet repeats contribute to normal variation in behavioral traits and when expanded, cause brain disorders. While Huntington's Disease is known to be caused by a CAG triplet repeat in the gene Huntingtin, the effect of CAG repeats on brain function below disease threshold has not been studied. The current study shows a significant correlation between the CAG repeat length of the maternal and paternal allele in the Huntingtin gene among healthy subjects, suggesting assortative mating.
doi:10.1186/1744-9081-7-45
PMCID: PMC3219594  PMID: 22008211
21.  Diffusion Tensor Imaging in Preclinical Huntington’s Disease 
Brain imaging and behavior  2009;3(1):77-84.
Diffusion tensor imaging was used to study brain related changes in white matter that may be associated with Huntington’s Disease progression. Thirty-one preclinical gene-mutation carriers were imaged cross-sectionally using diffusion tensor and anatomical brain imaging. Subjects were individuals who had a known gene mutation for HD but did not manifest motor diagnostic criteria for HD. Fractional anisotropy scalar maps showed a positive correlation with five year probability of diagnosis (based upon gene repeat length and current age) in the putamen and a negative correlation in the external capsule. This study shows that scalar maps generated from diffusion tensor imaging may be directly related to the earliest stages of disease progression within HD, even before a diagnosis is given. Findings suggest that DTI measures, therefore, may have the ability to act as a biomarker for disease progression in clinical trials of pre-manifest subjects.
doi:10.1007/s11682-008-9051-2
PMCID: PMC3057188  PMID: 21415933
Diffusion tensor imaging; fractional anisotropy; Huntington’s disease; preclinical; presymptomatic
22.  Biological and Environmental Predictors of Behavioral Sequelae in Children Born Preterm 
Pediatrics  2009;125(1):e83-e89.
OBJECTIVE
By using behavioral outcome measures of children who were born preterm, we evaluated differences between children who were born at term and children who were born at extremely low (ELBW; <1000 g) and very low birth weights (VLBW; 1000 –1499 g) and assessed the relationship of birth weight, socioeconomic status, and cognitive ability to behavioral outcome.
METHODS
We studied a total of 104 children (aged 7–16 years). Of these, 49 had a preterm birth (31 of ELBW and 18 of VLBW). The remaining 55 were healthy control subjects. Children were administered tests of cognitive ability. Parents and teachers completed behavioral assessments. Multivariate analyses of covariance assessed differences between children who were born at term and those who were born of ELBW and of VLBW on behavioral measures. Hierarchical linear regressions were used to assess relationships among biological (birth weight), environmental (socioeconomic status), intellectual, and behavioral variables.
RESULTS
Children who were born at term had fewer parent reports of hyperactivity/inattention and depression/anxiety symptoms than children of ELBW and VLBW. Teacher ratings were not significant between groups. Birth weight was consistently the strongest predictor of parent ratings of behavioral outcome, and intelligence level did not seem to mediate this relationship.
CONCLUSIONS
Negative behavioral sequelae of preterm birth remain significant in middle childhood and adolescence, although the contribution of multiple factors to neurobehavioral outcome is complex. Research to assess these relationships, integrated with anatomic and functional neuroimaging, is needed to advance knowledge and improve outcomes for children who are born preterm.
doi:10.1542/peds.2009-0634
PMCID: PMC2857764  PMID: 20008432
prematurity; behavior; predictors
23.  Sex Differences in Parietal Lobe Morphology: Relationship to Mental Rotation Performance 
Brain and cognition  2008;69(3):451-459.
Structural magnetic resonance imaging (MRI) studies of the human brain have reported evidence for sexual dimorphism. In addition to sex differences in overall cerebral volume, differences in the proportion of gray matter (GM) to white matter (WM) volume have been observed, particularly in the parietal lobe. To our knowledge there have been no studies examining the relationship between the sex differences in parietal lobe structure and function. The parietal lobe is thought to be involved in spatial ability, and particularly involved in mental rotation. The purpose of this study is to examine whether sex differences in parietal lobe structure are present, and if present to relate these differences to performance on the Mental Rotations Test (MRT). We found that women had proportionately greater gray matter volume in the parietal lobe compared to men, and this morphologic difference was disadvantageous for women in terms of performance on the MRT. In contrast, we found that men compared to women had proportionately greater parietal lobe surface area, and this morphologic difference was associated with a performance advantage for men on mental rotation. These findings support the possibility that the sexual dimorphism in the structure of the parietal lobe is a neurobiological substrate for the sex difference in performance on the Mental Rotations Test.
doi:10.1016/j.bandc.2008.09.004
PMCID: PMC2680714  PMID: 18980790
sex differences; mental rotation; parietal lobe; spatial ability
24.  Right ventromedial prefrontal cortex: a neuroanatomical correlate of impulse control in boys 
Emerging data on the neural mechanisms of impulse control highlight brain regions involved in emotion and decision making, including the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC) and amygdala. Variation in the development of these regions may influence one's propensity for impulsivity and, by extension, one's vulnerability to disorders involving low impulse control (e.g. substance abuse). Here we test the hypothesis that lower impulse control is associated with structural differences in these regions, particularly on the right side, in 61 normal healthy boys aged 7–17. We assessed parent- and teacher-reported behavioral ratings of impulse control (motor impulsivity and non-planning behavior) in relation to vmPFC, ACC and amygdala volume, measured using structural magnetic resonance imaging and FreeSurfer. A regression analysis showed that the right vmPFC was a significant predictor of impulse control ratings. Follow-up tests showed (i) a significant correlation between low impulse control and decreased right vmPFC volume, especially the medial sector of the vmPFC and (ii) significantly lower right vmPFC volume in a subgroup of 20 impulsive boys relative to 20 non-impulsive boys. These results are consistent with the notion that right vmPFC provides a neuroanatomical correlate of the normal variance in impulse control observed in boys.
doi:10.1093/scan/nsn035
PMCID: PMC2656876  PMID: 19015086
impulsive; FreeSurfer; brain development; structural MRI; attention deficit hyperactivity disorder; externalizing
25.  Ventral frontal cortex in children: morphology, social cognition and femininity/masculinity 
The ventral frontal cortex (VFC) has been shown to differ morphologically between sexes. Social cognition, which many studies demonstrate involves the VFC, also differs between sexes, with females being more adept than males. In a previous study of subregions of the VFC in our lab, in an adult population, size of the straight gyrus (SG) but not the orbitofrontal cortex (OFC), differed between sexes and correlated with better performance on a test of social cognition and with greater identification with feminine characteristics. To investigate the relationship between VFC structure and social cognition in children, VFC gray matter volumes were measured on MRIs from 37 boys and 37 girls aged 7 to 17. The VFC was subdivided into the OFC and SG. Subjects were also administered a test of social perceptiveness and a rating scale of femininity/masculinity. In contrast to our findings in adults, the SG was slightly smaller in girls than boys. In girls, but not boys, smaller SG volumes significantly correlated with better social perception and higher identification with feminine traits. No volume differences by sex or significant correlations were found with the OFC. These data suggest a complex relationship between femininity, social cognition and SG morphology.
doi:10.1093/scan/nsn010
PMCID: PMC2555466  PMID: 19015107
brain morphology; femininity; gender differences; social perception; straight gyrus

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