Salvador Sarró

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.

Frequency based mutual information measures between clusters of brain regions in functional magnetic resonance imaging.

Mutual information tools have been recently applied to quantify the connectivity between brain regions in functional magnetic resonance imaging (fMRI). Here we develop measures of mutual information between clusters of brain regions in the frequency domain. The properties and limitations of the method are exemplified through a single resting state fMRI dataset, and with a comparison involving frontostriatal connections in schizophrenic patients and healthy controls.

Bipolar depressed patients show both failure to activate and failure to de-activate during performance of a working memory task

BACKGROUND Bipolar depression has been found to be associated with changes in prefrontal cortex activity during performance of cognitive tasks. However, the role of task-related de-activations has been little investigated. METHOD Forty-one bipolar depressed patients and 41 matched normal controls underwent fMRI scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups. RESULTS The bipolar depressed patients showed reduced activation in the dorsolateral prefrontal cortex (DLPFC) bilaterally and several other regions. After controlling for differences in task performance only differences in the DLPFC and cerebellum remained. Left DLPFC activation was inversely correlated with Hamilton and MADRS scores. The patients showed failure to de-activate in the medial prefrontal cortex, an area corresponding to the anterior medial node of the default mode network. LIMITATIONS To confirm default mode network dysfunction demonstration of resting-state connectivity abnormalities would also be required. The study was carried out on treated patients, and did not assess for presence of depressive symptoms in the healthy controls. CONCLUSIONS Both prefrontal cortical and default mode network dysfunction appear to characterise bipolar depression. The former, but not the latter, is associated with symptom severity.

Cross-cultural adaptation and validation of the Spanish version of the Calgary Depression Scale for Schizophrenia

BACKGROUND The Calgary Depression Scale for Schizophrenia (CDSS) is a valid tool to assess depression in schizophrenics and has been translated, adapted, and validated to be used in different non-English languages. Therefore, it may be predicted that a Spanish version of this scale will be also a valid instrument to assess symptoms of depression in patients with schizophrenia. OBJECTIVE We determined the validity of the Spanish version of the Calgary scale (CDSS-S). METHODS Outpatients and inpatients (n=93) diagnosed as having schizophrenia by DSM-IV criteria confirmed by SCID-IV interview were included. The Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS-17 and HDRS-21 items), Montgomery-Asberg Depression Rating Scale (MADRS), Extrapyramidal Symptoms Rating Scale (ESRS), and Barnes Acathisia Rating Scale were administered by a first rater, whereas the CDSS-S was assessed by a second independent rater. RESULTS The internal consistency (Cronbachs alpha 0.83) and the interrater reliability (>0.73 intraclass correlation coefficient [ICC] for single items and 0.92 for total score) were good. The test-retest reliability was high (ICC of 0.89). The scale showed a good construct validity with statistically significant correlations with HDRS-17, HDRS-21, MADRS, and G6 item (depression) of PANSS. The CDSS showed no correlation with the positive subscale of PANSS and a weak correlation with the negative subscale, general psychopathology subscale, and total score of PANSS. A cut point of five showed 94.7% sensitivity, 86.5% specificity, and 70% and 98% positive and negative predictive values, respectively. CONCLUSIONS The Spanish version of CDSS is a valid instrument to assess depressive episodes for stabilized and acute patients with schizophrenia.

Structural Abnormalities in Bipolar Euthymia: A Multicontrast Molecular Diffusion Imaging Study

BACKGROUND Evidence from decades of magnetic resonance imaging (MRI) research in bipolar disorder has been summarized in meta-analyses of various MRI modalities. Notably, although structural MRI studies suggest gray matter reductions are restricted to specific cortical regions, functional MRI has also shown involvement of subcortical dysfunction. Such disparity in results is open to discussion and requires further exploration with additional MRI modalities. METHODS We applied whole-brain high angular resolution molecular diffusion imaging to compare different properties of the water diffusion process in brain tissues, using different contrasts. Specifically, we looked at fractional anisotropy, mean diffusivity, probability of return to the origin, and generalized fractional anisotropy in a sample of 40 euthymic patients with bipolar disorder and 40 well-matched healthy control subjects. RESULTS Convergent abnormalities were detected by contrasts in various tissue types. Apart from alterations in white matter (in corpus callosum, cingulum bundle, corona radiata, and superior fronto-occipital fasciculus) and cortical gray matter (in medial frontal cortex, left insula, Heschls gyrus, and cerebellum), three of the contrasts (fractional anisotropy, mean diffusivity, and generalized fractional anisotropy) revealed abnormalities in subcortical structures, including the hippocampus, the thalamus and the caudate nucleus. CONCLUSIONS Our findings point to a wider pattern of axonal pathology in bipolar disorder than previously thought. Although findings related to cortical gray matter are consistent with structural meta-analyses, subcortical abnormalities suggest a cytoarchitectonic basis for previously reported subcortical dysfunction. Diffusion results could be interpreted in terms of loss of tissue volume and/or altered membrane permeability, agreeing with both hypotheses of mitochondrial malfunction and neuroinflammation.

Failure of de-activation in the medial frontal cortex in mania: evidence for default mode network dysfunction in the disorder

Abstract Objectives. Manic patients have been found to show reduced activation in the prefrontal cortex and other regions during performance of cognitive tasks. However, little is known about de-activations associated with the disorder. This study aimed to examine, at the whole-brain level, abnormal patterns of task-related activation and de-activation during performance of a working memory task. Methods. Twenty-nine DSM-IV bipolar patients and 46 healthy controls underwent fMRI during performance of the n-back task. The patients were scanned while they were in a manic episode. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups. Results. The manic patients showed reduced activation compared to the controls in the bilateral dorsolateral prefrontal cortex and the right parietal cortex. They also showed failure of de-activation in the medial frontal cortex, extending to the temporal poles and parts of the limbic system bilaterally. The failure of activation in the dorsolateral prefrontal cortex disappeared when differences in task performance were controlled for in the analysis. However, the medial frontal failure of de-activation survived controlling for this. Conclusions. This study suggests that, in addition to reduced prefrontal activation, failure of de-activation is an important functional imaging abnormality in mania. This, together with its location in the medial prefrontal cortex, implies default mode network dysfunction in the disorder.

First-episode psychosis is characterized by failure of deactivation but not by hypo- or hyperfrontality.

BACKGROUND It is not known whether first-episode psychosis is characterized by the same prefrontal cortex functional imaging abnormalities as chronic schizophrenia. METHOD Thirty patients with a first episode of non-affective functional psychosis and 28 healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Voxel-based analyses of brain activations and deactivations were carried out and compared between groups. The connectivity of regions of significant difference between the patients and controls was also examined. RESULTS The first-episode patients did not show significant prefrontal hypo- or hyperactivation compared to controls. However, they showed failure of deactivation in the medial frontal cortex. This area showed high levels of connectivity with the posterior cingulate gyrus/precuneus and parts of the parietal cortex bilaterally. Failure of deactivation was significantly greater in first-episode patients who had or went on to acquire a DSM-IV diagnosis of schizophrenia than in those who did not, and in those who met RDC criteria for schizophrenia compared to those who did not. CONCLUSIONS First-episode psychosis is not characterized by hypo- or hyperfrontality but instead by a failure of deactivation in the medial frontal cortex. The location and connectivity of this area suggest that it is part of the default mode network. The failure of deactivation seems to be particularly marked in first-episode patients who have, or progress to, schizophrenia.

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.