Núria Bargalló

Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects.

Two limiting factors of dopamine activity are the catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT), which terminate dopamine activity by degradation and uptake, respectively. Genetic variants of COMT and DAT have been related to the enzymatic activity and protein availability, respectively. The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability. Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task, with subjects homozygous for the Val and the 9-repeat alleles showing the highest activation for the same level of performance. Moreover, the Val allele was related to higher number of perseverative errors on the WCST and with a higher number of commission errors on the CPT. The 10-repeat allele was associated with faster reaction times but also with a higher number of commission errors. Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition.

Hippocampal head atrophy after traumatic brain injury

Traumatic brain injury (TBI) causes hippocampal damage. The hippocampus can be macroscopically divided into the head, body and tail, which differ in terms of their sensitivity to excitability and also in terms of their cortical connections. We investigated whether damage also varies according to the hippocampal area involved, and studied the relationship of hippocampal reductions with memory performance. Twenty TBI patients and matched controls were examined. MRI measurements were performed separately for the hippocampal head, body and tail. Memory outcome was measured by Reys auditory verbal learning test, Reys complex figure test and a modified version of Warringtons facial recognition memory test. Group comparison showed that patients had bilateral hippocampal atrophy, mainly involving the hippocampal head. Moreover, TBI subjects showed verbal memory deficits which presented slight correlations with left hippocampal head atrophy.

Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: a magnetic resonance imaging study.

Previous evidence suggests that preterm newborns with intrauterine growth restriction (IUGR) have specific neurostructural and neurodevelopmental anomalies, but it is unknown whether these effects persist in early childhood. We studied a sample of 18 preterm IUGR, 15 preterm AGA - born between 26 and 34 weeks of gestational age (GA) - and 15 healthy born-term infants. Infants were scanned at 12 months corrected age (CA), in a 3T scanner, without sedation. Analyses were made by automated lobar volumetry and voxel-based morphometry (VBM). The neurodevelopmental outcome was assessed in all subjects at 18 months CA with the Bayley Scale for Infant and Toddler Development, third edition. IUGR infants had reduced relative volumes for the insular and temporal lobes. According to VBM, IUGR infants had bilateral reduced gray matter (GM) in the temporal, parietal, frontal, and insular regions compared with the other groups. IUGR infants had increased white matter (WM) in temporal regions compared to the AGA group and in frontal, parietal, occipital, and insular regions compared to the term group. They also showed decreased WM in the cerebellum and a non-significant trend in the hippocampus compared to term infants. IUGR infants had reduced neurodevelopmental scores, which were positively correlated with GM in various regions. These data suggest that the IUGR induces a distinct brain pattern of structural changes that persist at 1 year of life and are associated with specific developmental difficulties.

Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity

Using optimized voxel-based morphometry (VBM), we compared the relationship between hippocampal and thalamic gray matter loss and memory impairment in 22 adolescents with history of prematurity (HP) and 22 normal controls. We observed significant differences between groups in verbal learning and verbal recognition, but not in visual memory. VBM analysis showed significant left hippocampal and bilateral thalamic reductions in HP subjects. Using stereological methods, we also observed a reduction in hippocampal volume, with left posterior predominance. We found correlations between left hippocampal gray matter reductions (assessed by VBM) and verbal memory (learning and percentage of memory loss) in the premature group. The stereological analysis showed a correlation between verbal learning and the left posterior hippocampus. Our results suggest that left hippocampal tissue loss may be responsible for memory impairment and is probably related to the learning disabilities that HP subjects present during schooling.

White matter volume and concentration reductions in adolescents with history of very preterm birth: a voxel-based morphometry study.

Very preterm birth (VPTB) is an important risk factor for white matter (WM) damage. We used voxel-based morphometry (VBM) to examine regional WM brain abnormalities in 50 adolescents with antecedents of very preterm birth (VPTB) without evidence of WM damage on T2-weighted MRI. This group was compared with a group of 50 subjects born at term and matched for age, handedness and socio-cultural status. We also examined the relationship between WM changes and gestational age (GA) and weight (GW) at birth in VPTB subjects. Both modulated and unmodulated VBM analyses showed significant abnormalities in several WM brain regions in the VPTB group, involving all the cerebral lobes. However, density analyses (unmodulated data) mainly identified periventricular damage and the involvement of the longitudinal fascicles while volume analyses (modulated data) detected WM decreases in regions distant from the ventricular system, located at the origin and end of the long fascicles. A significant correlation was found between WM decreases and both GA and GW in various brain regions: the lower the GA and GW, the lower the WM integrity. This study supports the current view that widespread white matter impairment is associated with immature birth.

The Human Cerebral Cortex Flattens during Adolescence

The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11–17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex (“exposed”) part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter.

Differential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age.

Intrauterine growth restriction (IUGR) is associated with a high risk of abnormal neurodevelopment. Underlying neuroanatomical substrates are partially documented. We hypothesized that at 12 months preterm infants would evidence specific white-matter microstructure alterations and gray-matter differences induced by severe IUGR. Twenty preterm infants with IUGR (26-34 weeks of gestation) were compared with 20 term-born infants and 20 appropriate for gestational age preterm infants of similar gestational age. Preterm groups showed no evidence of brain abnormalities. At 12 months, infants were scanned sleeping naturally. Gray-matter volumes were studied with voxel-based morphometry. White-matter microstructure was examined using tract-based spatial statistics. The relationship between diffusivity indices in white matter, gray matter volumes, and perinatal data was also investigated. Gray-matter decrements attributable to IUGR comprised amygdala, basal ganglia, thalamus and insula bilaterally, left occipital and parietal lobes, and right perirolandic area. Gray-matter volumes positively correlated with birth weight exclusively. Preterm infants had reduced FA in the corpus callosum, and increased FA in the anterior corona radiata. Additionally, IUGR infants had increased FA in the forceps minor, internal and external capsules, uncinate and fronto-occipital white matter tracts. Increased axial diffusivity was observed in several white matter tracts. Fractional anisotropy positively correlated with birth weight and gestational age at birth. These data suggest that IUGR differentially affects gray and white matter development preferentially affecting gray matter. At 12 months IUGR is associated with a specific set of structural gray-matter decrements. White matter follows an unusual developmental pattern, and is apparently affected by IUGR and prematurity combined.

Hippocampal functional magnetic resonance imaging during a face-name learning task in adolescents with antecedents of prematurity.

Functional magnetic resonance imaging (fMRI) was used to map hippocampal activation during a declarative memory task in a sample of 14 adolescents with antecedents of prematurity (AP). The sample with AP was matched by age, sex and handedness with 14 full-term controls with no history of neurological or psychiatric illness. The target task consisted in learning 16 novel face-name pairs, and the control task involved the examination of two repeated face-name pairs. Stereological methods were also used to quantify hippocampal volumes. In both groups, we observed increased activation in the learning condition compared to the control task in the right fusiform gyrus and the left inferior occipital gyrus, but only premature subjects activated the hippocampus. Group comparison of the activation versus control conditions showed that prematures had greater activity in the right hippocampus than controls during the encoding of the word-face association. Volumetric analyses showed a significant left hippocampal volume loss in adolescents with AP. In addition, we found a significant positive correlation in the premature group between right hippocampal activation and face-name recognition. Functional MRI data also correlated with structural MRI data: right hippocampal activation correlated positively with right hippocampal volume. Our findings are consistent with previous studies of brain plasticity after focal lesions. Left hippocampal tissue loss may be related to an increase in contralateral brain activity, probably reflecting a compensatory mechanism. Our data also suggest that this plasticity is not enough to achieve normal performance.

A cross-sectional and follow-up functional MRI study with a working memory task in adolescent anorexia nervosa

Structural and functional brain abnormalities have been described in anorexia nervosa (AN). The objective of this study was to examine whether there is abnormal regional brain activation during a working memory task not associated with any emotional stimuli in adolescent patients with anorexia and to detect possible changes after weight recovery. Fourteen children and adolescents (age range 11-18 years) consecutively admitted with DSM-IV diagnosis of AN and fourteen control subjects of similar age were assessed by means of psychopathological scales and functional magnetic resonance imaging (fMRI) during a working memory task. After seven months of treatment and weight recovery, nine AN patients were reassessed. Before treatment, the AN group showed significantly higher activation than controls in temporal and parietal areas and especially in the temporal superior gyrus during performance of the cognitive task. Control subjects did not show greater activation than AN patients in any region. A negative correlation was found between brain activation and body mass index and a positive correlation between activation and depressive symptomatology. At follow-up after weight recovery, AN patients showed a decrease in brain activation in these areas and did not present differences with respect to controls. These results show that adolescent AN patients showed hyperactivation in the parietal and especially the temporal lobe during a working memory task, suggesting that they must make an additional effort to perform at normal levels. This activation correlated with clinical variables. In these young patients, differences with respect to controls disappeared after weight recovery.

Apolipoproteins E and C1 and brain morphology in memory impaired elders

Previous research has shown that polymorphisms of the apolipoproteins E (APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies.