Josep M. Serra-Grabulosa

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.

Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging.

It has been suggested that the pathophysiology of panic disorder (PD) may involve abnormalities in several brain structures, including the amygdala. To date, however, no study has used quantitative structural neuroimaging techniques to examine amygdalar anatomy in this disorder. Volumetric magnetic resonance imaging (MRI) studies of the amygdalas, hippocampi, and temporal lobes were conducted in 12 drug-free, symptomatic PD patients (six females and six males), and 12 case-matched healthy comparison subjects. Volumetric MRI data were normalized for brain size. PD patients were found to have smaller left-sided and right-sided amygdalar volumes than controls. No differences were found in either hippocampi or temporal lobes. These findings provide new evidence of changes in amygdalar structure in PD and warrant further anatomical and MRI brain studies of patients with this disorder.

Spatiotemporal dynamics of the auditory novelty-P3 event-related brain potential

The spatiotemporal dynamics of the cerebral network involved in novelty processing was studied by means of scalp current density (SCD) analysis of the novelty P3 (nP3) event-related brain potential (ERP). ERPs were recorded from 30 scalp electrodes at the occurrence of novel unpredictable environmental sounds during the performance of a visual discrimination task. Increased SCD was observed at left frontotemporal (FT3), bilateral temporoparietal (TP3 and TP4) and prefrontal locations (F8-F4 and F7-F3), suggesting novelty-P3 generators located in the left auditory cortex, and bilaterally in temporoparietal and prefrontal association regions. Additional increased SCD was found at a central location (Cz) and at superior parietal locations (P3-Pz-P4). The SCD of the nP3 was therefore generated at three successive, partially overlapping, stages of neuroelectric activation. At the central location, SCD started to be significant before the onset of the nP3 waveform, contributing solely to its early phase. At temporoparietal and left frontotemporal locations, nP3 electrophysiological activity was characterized by sustained current density, starting at about 210 ms and continuing during the full latency range of the response, including its early and late phases. At its late phase, the nP3 was characterized by sharp phasic current density at prefrontal and superior parietal locations, starting at about 290 ms and vanishing at around 385 ms. Taken together, these results provide the first evidence of the cerebral spatio-temporal dynamics underlying novelty processing.

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.

Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury

We investigated residual brain damage in subjects who suffered severe traumatic brain injury (TBI) in childhood, and its relationship with declarative memory impairment. Magnetic resonance imaging (MRI) volumetric data and memory performance were compared between 16 adolescents with antecedents of severe TBI and 16 matched normal controls. Volumes of grey matter, white matter, cerebrospinal fluid (CSF), hippocampus, and caudate nuclei were measured. Verbal memory was assessed by the Rey’s Auditory Verbal Learning test and visual memory by the Rey’s Complex Figure. TBI patients performed significantly worse than controls in both verbal and visual memory. Patients presented decreased white matter volume and increased CSF. The hippocampus was reduced, but not the caudate nuclei. Memory performance correlated with CSF. Plasticity is incomplete for structural and functional deficits in children with TBI. Hippocampal atrophy, white matter loss, and memory impairment remain until adolescence. Memory sequelae are related more to diffuse brain injury, as reflected by MRI findings of increased CSF, than to hippocampal injury.

Effects of caffeine and glucose, alone and combined, on cognitive performance

To study the effects of consuming caffeine and glucose, alone and combined, on cognitive performance.

MRI and genetic correlates of cognitive function in elders with memory impairment

The present study investigated the relationship between genetic variation, MRI measurements and neuropsychological function in a sample of 58 elders exhibiting memory decline. In agreement with previous reports, we found that the epsilon4 allele of the apolipoprotein E (APOE) and the D allele of the angiotensin converting enzyme (ACE) polymorphisms negatively modulated the cognitive performance. Further, we found an association between the A allele of the apolipoprotein C1 (APOC1) polymorphism and poorer memory and frontal lobe function. No clear associations emerged between MRI measures of white matter lesions (WML) or hippocampal sulcal cavities (HSC) and the cognitive performance after controlling for age effects. Further, the degree of WML or HSC lesions was in general not predisposed genetically except for the presence of the A allele of the APOC1 polymorphism that was related to a higher severity of HSC scores. Our results suggest that WML or HSC do not represent important brain correlates of genetic influences on cognitive performance in memory impaired subjects.

Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects

We studied the relationship among dopamine receptor D2 (DRD2) Taq I genetic polymorphism, caudate nucleus volumetry as measured using MRI and neuropsychological functions in 49 memory impaired older people. Compared with DRD2 A1 carriers, subjects homozygous for the DRD2 A2 allele performed poorer in a measure of general cognitive functioning (MMSE) and in long term verbal memory, and presented reduced left caudate nucleus volumes. Caudate nucleus atrophy correlated with cognitive measures influenced by the genetic polymorphism and with visual memory performance. Our findings suggest that among the aged with cognitive impairments, the homozygous status for the A2 allele of the DRD2 Taq I polymorphism is associated with diminished cognitive performance and increased atrophy in the striatum.

Glucose and caffeine effects on sustained attention: an exploratory fMRI study.

Caffeine and glucose can have beneficial effects on cognitive performance. However, neural basis of these effects remain unknown. Our objective was to evaluate the effects of caffeine and glucose on sustained attention, using functional magnetic resonance imaging (fMRI).

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.