Jesus J. Gomar

A simple view of the brain through a frequency-specific functional connectivity measure

Here we develop a measure of functional connectivity describing the degree of covariability between a brain region and the rest of the brain. This measure is based on previous formulas for the mutual information (MI) between clusters of regions in the frequency domain. Under the current scenario, the MI can be given as a simple monotonous function of the multiple coherence and it leads to an easy visual representation of connectivity patterns. Computationally efficient formulas, adequate for short time series, are presented and applied to functional magnetic resonance imaging (fMRI) data measured in subjects (N=34) performing a working memory task or being at rest. While resting state coherence in high (0.17-0.25 Hz) and middle (0.08-0.17 Hz) frequency intervals is bilaterally salient in several limbic and temporal areas including the insula, the amygdala, and the primary auditory cortex, low frequencies (<0.08 Hz) have greatest connectivity in frontal structures. Results from the comparison between resting and N-back conditions show enhanced low frequency coherence in many of the areas previously reported in standard fMRI activation studies of working memory, but task related reductions in high frequency connectivity are also found in regions of the default mode network. Finally, potentially confounding effects of head movement and regional volume on MI are identified and addressed.

Overall brain connectivity maps show cortico-subcortical abnormalities in schizophrenia.

Abnormal interactions between areas of the brain have been pointed as possible causes for schizophrenia. However, the nature of these disturbances and the anatomical location of the regions involved are still unclear. Here, we describe a method to estimate maps of net levels of connectivity in the resting brain, and we apply it to look for differential patterns of connectivity in schizophrenia. This method uses partial coherences as a basic measure of covariability, and it minimises the effect of major physiological noise. When overall (net) connectivity maps of a sample of 40 patients with schizophrenia were compared with the maps from a matched sample of 40 controls, a single area of abnormality was found. It is an area of patient hyper‐connectivity and is located frontally, in medial and orbital structures, clearly overlapping the anterior node of the default mode network (DMN). When this area is used as a region of interest in a second‐level analysis, it shows functional hyper‐connections with several cortical and subcortical structures. Interestingly, the most significant abnormality is found with the caudate, which has a bilateral pattern of abnormality, pointing to a possible DMN–striatum deviant relation in schizophrenia. However, hyper‐connectivity observed with other regions (right hippocampus and amygdala, and other cortical structures) suggests a more pervasive alteration of brain connectivity in this disease. Hum Brain Mapp, 2010.

APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms.

The common APOE2 gene variant is neuroprotective against Alzheimer’s disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Extension and refinement of the predictive value of different classes of markers in ADNI: Four year follow-up data

This study examined the predictive value of different classes of markers in the progression from mild cognitive impairment (MCI) to Alzheimers disease (AD) over an extended 4‐year follow‐up in the Alzheimers Disease Neuroimaging Initiative (ADNI) database.

Conditional Mutual Information Maps as Descriptors of Net Connectivity Levels in the Brain

There is a growing interest in finding ways to summarize the local connectivity properties of the brain through single brain maps. Here we propose a method based on the conditional mutual information (CMI) in the frequency domain. CMI maps quantify the amount of non-redundant covariability between each site and all others in the rest of the brain, partialling out the joint variability due to gross physiological noise. Average maps from a sample of 45 healthy individuals scanned in the resting state show a clear and symmetric pattern of connectivity maxima in several regions of cortex, including prefrontal, orbitofrontal, lateral–parietal, and midline default mode network components; and in subcortical nuclei, including the amygdala, thalamus, and basal ganglia. Such cortical and subcortical hotspots of functional connectivity were more clearly evident at lower frequencies (0.02–0.1 Hz) than at higher frequencies (0.1–0.2 Hz) of endogenous oscillation. CMI mapping can also be easily applied to perform group analyses. This is exemplified by exploring effects of normal aging on CMI in a sample of healthy controls and by investigating correlations between CMI and positive psychotic symptom scores in a sample of 40 schizophrenic patients. Both the normative aging and schizophrenia studies reveal functional connectivity trends that converge with reported findings from other studies, thus giving further support to the validity of the proposed method.

COMT Val158Met polymorphism in relation to activation and de-activation in the prefrontal cortex: A study in patients with schizophrenia and healthy subjects.

The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia.

Structural brain changes associated with tardive dyskinesia in schizophrenia

BACKGROUND The pathological basis of tardive dyskinesia is unknown. Although its clinical features implicate the basal ganglia, imaging studies have not found clear evidence that it is associated with volume changes in these or other brain structures. AIMS To determine, using voxel-based structural imaging, whether there are regions of grey matter volume change in people with schizophrenia who also have tardive dyskinesia compared with those without tardive dyskinesia. METHOD A total of 81 people with chronic schizophrenia, 32 with tardive dyskinesia and 49 without, were examined using magnetic resonance imaging (MRI) and whole-brain, optimised voxel-based morphometry. A comparison group of 61 healthy controls was also examined. RESULTS Compared with those without tardive dyskinesia, patients with tardive dyskinesia showed a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions were seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, showed significant volume reductions in the basal ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas. CONCLUSIONS The pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure.

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent.

Neural correlates of cognitive impairment in schizophrenia

BACKGROUND Cognitive impairment is an established feature of schizophrenia. However, little is known about its relationship to the structural and functional brain abnormalities that characterise the disorder. Aims To identify structural and/or functional brain abnormalities associated with schizophrenic cognitive impairment. METHOD We carried out structural magnetic resonance imaging (MRI) and voxel-based morphometry in 26 participants who were cognitively impaired and 23 who were cognitively preserved, all with schizophrenia, plus 39 matched controls. Nineteen of those who were cognitively impaired and 18 of those who were cognitively preserved plus 34 controls also underwent functional MRI during performance of a working memory task. RESULTS No differences were found between the participants who were cognitively intact and those who were cognitively impaired in lateral ventricular volume or whole brain volume. Voxel-based morphometry also failed to reveal clusters of significant difference in grey and white matter volume between these two groups. However, during performance of the n-back task, the participants who were cognitively impaired showed hypoactivation compared with those who were cognitively intact in the dorsolateral prefrontal cortex among other brain regions. CONCLUSIONS Cognitive impairment in schizophrenia is not a function of the structural brain abnormality that accompanies the disorder but has correlates in altered brain function.

Development and Cross-Validation of the UPSA Short Form for the Performance-Based Functional Assessment of Patients With Mild Cognitive Impairment and Alzheimer Disease

BACKGROUND Functional capacity includes basic and complex behaviors necessary to independently live in the community. It has been found that patients with cognitive impairment have daily living functional skills altered at very early stages of illness. OBJECTIVES 1) To develop and validate a brief scale derived from the University of California, San Diego, performance-based skills assessment (UPSA); 2) to cross-validate this new UPSA short form with an independent healthy elderly sample. METHOD Fifty-one healthy elderly subjects, 26 mild cognitive impairment (MCI) subjects defined per Petersens criteria, and 22 probable Alzheimer Disease (AD) subjects according to National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association criteria were included. For cross-validation purpose, a comparison group of 108 older healthy subjects with Mini-Mental scores of 25 or greater was also recruited. A modified four-functional domain version of the UPSA was administered. RESULTS Communication and comprehension/planning domains accounted for almost 90% of the variance (R = 0.89) and in all models entered first and second, respectively. An UPSA short form using these two domains was significantly correlated with the full UPSA scale in all the groups examined: 0.86 for healthy controls; 0.87 for MCI; and 0.88 for AD. Acceptable sensitivity and specificity values for the UPSA short form were found in receiver operating characteristic (ROC) analysis. A correlation of 0.80 was found between the short and the full UPSA scales in the cross-validation sample. CONCLUSIONS The UPSA short form is a rapid, reliable, and efficient measure of functional capacity that is able to detect performance impairment in an ecologically valid setting in much less time compared with the extended form of the scale. Furthermore, it demonstrated adequate discriminative properties among healthy subjects, MCI patients, and AD patients.