Ralf G.M. Schlösser

Functional magnetic resonance imaging of human brain activity in a verbal fluency task

OBJECTIVES Functional MRI (fMRI) holds the promise of non-invasive mapping of human brain function in both health and disease. Yet its sensitivity and reliability for mapping higher cognitive function are still being determined. Using verbal fluency as a task, the objective was to ascertain the consistency of fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes. Comparison was made with previous PET studies. METHODS Using a 1.5 Tesla magnet and an echoplanar pulse sequence, whole brain fMRI was obtained from 12 normal right handed subjects (6 males and 6 females) as they performed a verbal fluency task. RESULTS A broadly consistent pattern of response was seen across subjects. Areas showing activation changes included the left prefrontal cortex and right cerebellum, in agreement with previous PET 15O-H2O studies. In addition, significantly decreased responses were seen in the posterior cingulate and over an extensive area of mesial and dorsolateral parietal and superior temporal cortices. The male cohort showed a slight asymmetry of parietal deactivation, with more involvement on the right, whereas the female cohort showed a small region of activation in the right orbitofrontal cortex. There were individual task related regional changes in all 12 subjects with the area showing the most significant change being the left prefrontal cortex in all cases. CONCLUSIONS Magnetic resonance scanners of conventional field strength can provide functional brain mapping data with a sensitivity at least that of PET. Activation was seen in left prefrontal and right cerebellar regions, as with PET. However, decremental responses were seen over a much larger area of the posterior cortex than had been anticipated by prior studies. The ability to see a response in each subject individually suggests that fMRI may be useful in the preinterventional mapping of pathological states, and offers a non-invasive alternative to the Wada test for assessment of hemispheric dominance. There were no gross differences in the pattern of activation between male and female subjects.

Cortical inefficiency in patients with unipolar depression: an event-related FMRI study with the Stroop task.

BACKGROUND The present study is aimed to examine the neuronal correlates of Stroop interference in medication-free patients with major depressive disorder. METHODS Sixteen patients fulfilling Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for unipolar depression and 16 healthy control subjects matched for age, gender, and education were included. All subjects underwent an event-related functional magnetic resonance imaging (fMRI) design with an adapted version of the Stroop task including congruent and incongruent task conditions. The fMRI experiment was conducted on a 1.5 T magnetic resonance (MR) scanner, and item responses were given manually by the subjects. RESULTS With regard to behavioral performance, patients revealed no differences in both reaction time and accuracy relative to control subjects. With regard to brain activations, direct comparison of patients with control subjects in the interference condition revealed hyperactivity in rostral anterior cingulate gyrus (rACG) and left dorsolateral prefrontal cortex (DLPFC) in depressive patients, which correlated strongly with the Stroop interference. CONCLUSIONS The study provides new evidence for the functioning and dissociation of the anterior cingulate in depressed patients. The greater prefrontal activation may reflect a cortical inefficiency due to hyperactivity in rACG enhancing the cognitive interferences from the emotional state.

White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study

Diffusion tensor imaging (DTI) studies of schizophrenia have revealed white matter abnormalities in several areas of the brain. The functional impact on either psychopathology or cognition remains, however, poorly understood. Here we analysed both functional MRI (during a working memory task) and DTI data sets in 18 patients with schizophrenia and 18 controls. Firstly, DTI analyses revealed reductions of fractional anisotropy (FA) in the right medial temporal lobe adjacent to the right parahippocampal gyrus, likely to contain fibres of the inferior cingulum bundle, and in the right frontal lobe. Secondly, functional MRI revealed prefrontal, superior parietal and occipital relative hypoactivation in patients with the main effect of task. This was accounted for by reduced prefrontal activation during the encoding phase of the task, but not during maintenance or retrieval phases. Thirdly, we found a direct correlation in patients between the frontal FA reduction (but not medial temporal reductions) and fMRI activation in regions in the prefrontal and occipital cortex. Our study combining fMRI and DTI thus demonstrates altered structure-function relationships in schizophrenia. It highlights a potential relationship between anatomical changes in a frontal-temporal anatomical circuit and functional alterations in the prefrontal cortex.

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

Reduced cortical thickness in first episode schizophrenia

OBJECTIVE Previous morphometric studies are suggesting altered cortical thickness mainly in prefronto-temporal regions in first episode schizophrenia. In an extension of these earlier studies, we used an entire cortex vertex-wise approach and an automated clustering for the detection and exact quantification of cortical thickness alterations in first episode schizophrenia. METHODS A group of 54 patients with first episode schizophrenia according to DSM-IV and 54 age and gender matched healthy control subjects were included. All participants underwent high-resolution T1-weighted MRI scans on a 1.5 T scanner. Cortical thickness was estimated as the distance between the gray-white matter border and the pial surface using an automated computerized algorithm (Freesurfer Software). Statistical cortical maps were created to estimate differences of cortical thickness between groups based on this entire cortex analysis. RESULTS Significant cortical thinning was observed in first episode schizophrenia patients relative to controls in a number of cortical areas including the dorsolateral and frontopolar cortices, the anterior cingulate cortex, a ventrolateral-orbitofrontal cluster, as well as the superior temporal cortices and superior parietal lobe. Cortical thinning within these regions was on average 4.4-5.7% with strongest reductions in orbitofrontal regions (7.1%). CONCLUSIONS The present findings suggest widespread reduction of cortical thickness, mostly in heteromodal cortices of fronto-temporal networks to be present at an early stage of schizophrenia. Taken together, the present morphometric data in first episode schizophrenia provide further evidence for potential neurodevelopmental deficits and disruption of cortical maturation in this disorder.

Structural brain alterations in patients with major depressive disorder and high risk for suicide: Evidence for a distinct neurobiological entity?

Major depressive disorder (MDD) is associated with a considerably increased risk for suicide. There is evidence to suggest that a predisposition to suicidal behavior may exist which is independent of the disorder itself. Furthermore, suicide attempters with mood disorders have an up to sixfold higher rate of suicidal behavior in first-degree relatives than non-suicidal patients. Genetic and nongenetic factors may play a role in the familial transmission of suicidal behavior. One of these factors may be neurobiological alterations, the knowledge about which is still limited. The main goal was therefore to study morphometric brain abnormalities in the hypothesized fronto-limbic network in depressed patients with high risk for suicide in contrast to non-high risk depressed patients. 15 patients with MDD and with own suicidal behavior and/or with suicidal behavior in first-degree relatives defined as a high risk group, 15 depressed patients with non-high risk for suicide and 30 matched healthy controls participated in the study. We applied the voxel-based morphometry protocol to structural T1-weighted volumes. Patients with high risk for suicide showed significantly decreased gray matter density in a fronto-striato-limbic network in contrast to matched healthy controls and in caudate and rostral anterior cingulate cortex in contrast to non-high risk patients. In the latter patient group no significant gray matter alterations were detected. This new finding provides evidence for structural brain alterations in depressed patients with high risk for suicide in a brain network strongly involved in emotional and motivational control reflecting a potentially distinct neurobiological entity.

Increased Prefrontal Activation During Pain Perception in Major Depression

BACKGROUND To further elucidate the close interrelation of pain and depression, we investigated cerebral responses to parametrically varied thermal pain intensities in female patients suffering from major depressive disorder (MDD) (n = 13) and matched control subjects (n = 13) by means of functional magnetic resonance imaging (fMRI). METHODS After the assessment of the individual thermal pain threshold, an fMRI-compatible thermode was used to deliver thermal painful stimuli to the right arm. All stimuli were initiated for 10 sec from a baseline resting temperature (32 degrees C) in three different conditions (37 degrees C, 42 degrees C, 45 degrees C). Statistical Parametric Mapping 2 (SPM2) software was used for image processing and statistical analyses. RESULTS Patients displayed significantly increased thermal pain thresholds. A comparable increase in blood oxygenation level-dependent (BOLD) signal was observed in key structures of the pain matrix in patients and control subjects. Patients displayed hyperactivation in comparison with control subjects for the painful 45 degrees C condition in the left ventrolateral thalamus, in the right ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC), as well as a stronger parametric BOLD signal increase in the right VLPFC, DLPFC, and in the contralateral insula. Symptom severity correlated positively with the BOLD signal in the left ventrolateral nucleus of the thalamus. CONCLUSIONS We present evidence that cortical structures of the pain matrix are similarly activated in depressed patients and healthy subjects. We report increased prefrontal and lateral thalamic activation during the presentation of painful stimuli, which might explain reduced thermal pain perception on the skin in depressed patients.

The special involvement of the rostrolateral prefrontal cortex in planning abilities: An event-related fMRI study with the Tower of London paradigm

Planning abilities are essential for the successful management of everyday life activities. Although several neuroimaging studies provide evidence that the prefrontal cortex is crucially involved in planning, the differential roles of its subregions are still a matter of debate. The aim of this study was to investigate the neural correlates of planning by focusing on the functional differentiation between the dorsolateral and rostrolateral prefrontal cortex using the Tower of London (ToL) task and a parametric event-related functional MRI design. In order to control for activations unspecific to planning, two control conditions were presented, which were matched for the length of single events in the ToL task. Seventeen right-handed healthy subjects participated in this study. All statistics were reported with corrections for multiple comparisons (p < 0.05). Compared to control conditions, activations in the ToL task were observed in the dorsolateral prefrontal cortex bilaterally, the right ventrolateral and left rostrolateral prefrontal cortex along with the thalamus, as well as in the parietal and premotor cortex bilaterally. Task complexity dependent analyses revealed that only the left rostrolateral prefrontal cortex showed a BOLD signal increase over the four planning levels, which could not be observed in the control conditions. Hence, current findings suggest that planning involves an extensive fronto-parieto-thalamic network. Within this network, the rostrolateral prefrontal cortex seems to be the only region that is exclusively reactive to planning specific processes, which we described in terms of simultaneous monitoring of internally generated and externally presented information.

Fronto-cingulate effective connectivity in major depression: a study with fMRI and dynamic causal modeling.

Functional imaging studies are indicating disrupted error monitoring and executive control in a fronto-cingulate network in major depression. However, univariate statistical analyses allow only for a limited assessment of directed neuronal interactions. Therefore, the present study used dynamic causal modeling (DCM) of a fronto-cingulate network to re-analyze the data from a preceding fMRI study in 16 drug-free patients with major depression and 16 healthy controls using the Stroop Color-Word Test (Wagner et al., 2006). In both groups, a significant reciprocal interregional connectivity was found in a cognitive control network including prefrontal cortex (PFC) and dorsal anterior cingulate cortex (ACC). With regard to intrinsic connections we detected a significant difference for dorsal to rostral ACC connectivity between depressive patients and controls in terms of higher connectivity in patients. Additionally, a task by group interaction was observed for the bilinear interaction signaling enhanced task-related input from the dorsal to rostral ACC in subjects with depression. This could be related to the inability of patients to down-regulate rostral ACC activation as observed in the previous univariate analysis. The correlation between interference scores and intrinsic connections from dorsal ACC to dorsolateral PFC (DLPFC) was significant for both groups together, but no significant group differences in correlations could be detected. Thus, the observed relationship between control functions of the dorsal ACC exerted over DLPFC and interference scores appears to be valid in both patients with depression and controls. The findings are consistent with current models of a differential involvement of the fronto-cingulate system in the pathophysiology of major depression.

Assessing the working memory network: studies with functional magnetic resonance imaging and structural equation modeling.

A considerable body of evidence supports the notion that the neurofunctional substrate of working memory is not only related to the integrity of the prefrontal cortex, but also to the concerted interplay of widespread interacting networks including the parietal cortex, subcortical regions and cerebellar areas. Modern functional brain imaging techniques such as functional magnetic resonance imaging (fMRI) have provided a detailed picture of functional neuroanatomy subserving working memory functions. Most of the earlier functional studies were directed toward the identification of brain areas subserving specific cognitive domains in terms of a functional segregation. More recently, different multivariate techniques were employed to specifically address measures of functional or effective connectivity. Structural equation modeling (SEM) or path analysis is one of the most often used methods to model interactions among covarying brain areas in an explicitly model-based approach. The present review will focus on basic methodological issues of SEM for the analysis of fMRI datasets in studies of working memory. Aside from a discussion of previous studies and their essential findings, advanced methodological issues and caveats as well as future perspectives of the method will be addressed.