Rupert Lanzenberger

Correlations and anticorrelations in resting-state functional connectivity MRI: a quantitative comparison of preprocessing strategies.

Resting-state data sets contain coherent fluctuations unrelated to neural processes originating from residual motion artefacts, respiration and cardiac action. Such confounding effects may introduce correlations and cause an overestimation of functional connectivity strengths. In this study we applied several multidimensional linear regression approaches to remove artificial coherencies and examined the impact of preprocessing on sensitivity and specificity of functional connectivity results in simulated data and resting-state data sets from 40 subjects. Furthermore, we aimed at clarifying possible causes of anticorrelations and test the hypothesis that anticorrelations are introduced via certain preprocessing approaches, with particular focus on the effects of regression against the global signal. Our results show that preprocessing in general greatly increased connection specificity, in particular correction for global signal fluctuations almost doubled connection specificity. However, widespread anticorrelated networks were only found when regression against the global signal was applied. Results in simulated data sets compared with result of human data strongly suggest that anticorrelations are indeed introduced by global signal regression and should therefore be interpreted very carefully. In addition, global signal regression may also reduce the sensitivity for detecting true correlations, i.e. increase the number of false negatives. Concluding from our results we suggest that is highly recommended to apply correction against realignment parameters, white matter and ventricular time courses, as well as the global signal to maximize the specificity of positive resting-state correlations.

Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder

Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment. Although the amygdala has a central role in perception and processing of threatening cues, little is known about the involved networks and corresponding dysfunctions in social anxiety. Therefore, this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways. Ten patients with anxiety disorders (social and/or panic) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state. Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region. Group comparisons were done by random-effects analysis in SPM. Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus. The strength of this functional connectivity showed a negative association with the severity of state anxiety. In addition, an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group. Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder. Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing.

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

The Serotonin-1A Receptor in Anxiety Disorders

The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders.

The suppressive influence of SMA on M1 in motor imagery revealed by fMRI and dynamic causal modeling.

Although motor imagery is widely used for motor learning in rehabilitation and sports training, the underlying mechanisms are still poorly understood. Based on fMRI data sets acquired with very high temporal resolution (300 ms) under motor execution and imagery conditions, we utilized Dynamic Causal Modeling (DCM) to determine effective connectivity measures between supplementary motor area (SMA) and primary motor cortex (M1). A set of 28 models was tested in a Bayesian framework and the by-far best-performing model revealed a strong suppressive influence of the motor imagery condition on the forward connection between SMA and M1. Our results clearly indicate that the lack of activation in M1 during motor imagery is caused by suppression from the SMA. These results highlight the importance of the SMA not only for the preparation and execution of intended movements, but also for suppressing movements that are represented in the motor system but not to be performed.

Reward and the serotonergic system

Anhedonia, as a failure to experience rewarding stimuli, is a key characteristic of many psychiatric disorders including depression and schizophrenia. Investigations on the neurobiological correlates of reward and hedonia/anhedonia have been a growing subject of research demonstrating several neuromodulators to mediate different aspects of reward processing. Whereas the majority of research on reward mainly focused on the dopamine and opioid systems, a serotonergic mechanism has been neglected. However, recent promising results strengthen the pivotal role of serotonin in reward processing. Evidence includes electrophysical and pharmacological as well as genetic and imaging studies. Primate research using single-unit recording of neurons within the dorsal raphe nucleus argues for a serotonergic mediation of reward value, whereas studies using intracranial self-stimulation point to an important contribution of serotonin in modulating motivational aspects of rewarding brain stimulation. Pharmacological studies using agonists and antagonists of serotonergic receptor subtypes and approaches investigating an increase or decrease of the extracellular level of serotonin offer strong evidence for a serotonergic mediation, ranging from aversion to pleasure. This review provides an argument for serotonin as a fundamental mediator of emotional, motivational and cognitive aspects of reward representation, which makes it possibly as important as dopamine for reward processing.

Evaluation of preoperative high magnetic field motor functional MRI (3 Tesla) in glioma patients by navigated electrocortical stimulation and postoperative outcome

Objectives: The validity of 3 Tesla motor functional magnetic resonance imaging (fMRI) in patients with gliomas involving the primary motor cortex was investigated by intraoperative navigated motor cortex stimulation (MCS). Methods: Twenty two patients (10 males, 12 females, mean age 39 years, range 10–65 years) underwent preoperative fMRI studies, performing motor tasks including hand, foot, and mouth movements. A recently developed high field clinical fMRI technique was used to generate pre-surgical maps of functional high risk areas defining a motor focus. Motor foci were tested for validity by intraoperative motor cortex stimulation (MCS) employing image fusion and neuronavigation. Clinical outcome was assessed using the Modified Rankin Scale. Results: FMRI motor foci were successfully detected in all patients preoperatively. In 17 of 22 patients (77.3%), a successful stimulation of the primary motor cortex was possible. All 17 correlated patients showed 100% agreement on MCS and fMRI motor focus within 10 mm. Technical problems during stimulation occurred in three patients (13.6%), no motor response was elicited in two (9.1%), and MCS induced seizures occurred in three (13.6%). Combined fMRI and MCS mapping results allowed large resections in 20 patients (91%) (gross total in nine (41%), subtotal in 11 (50%)) and biopsy in two patients (9%). Pathology revealed seven low grade and 15 high grade gliomas. Mild to moderate transient neurological deterioration occurred in six patients, and a severe hemiparesis in one. All patients recovered within 3 months (31.8% transient, 0% permanent morbidity). Conclusions: The validation of clinically optimised high magnetic field motor fMRI confirms high reliability as a preoperative and intraoperative adjunct in glioma patients selected for surgery within or adjacent to the motor cortex.

Finger Somatotopy in Human Motor Cortex

Although qualitative reports about somatotopic representation of fingers in the human motor cortex exist, up to now no study could provide clear statistical evidence. The goal of the present study was to reinvestigate finger motor somatotopy by means of a thorough investigation of standardized movements of the index and little finger of the right hand. Using high resolution fMRI at 3 Tesla, blood oxygenation level-dependent (BOLD) responses in a group of 26 subjects were repeatedly measured to achieve reliable statistical results. The center of mass of all activated voxels within the primary motor cortex was calculated for each finger and each run. Results of all runs were averaged to yield an individual index and little finger representation for each subject. The mean center of mass localizations for all subjects were then submitted to a paired t test. Results show a highly significant though small scale somatotopy of fingerspecific activation patterns in the order indicated by Penfields motor homunculus. In addition, considerable overlap of finger specific BOLD responses was found. Comparing various methods of analysis, the mean center of mass distance for the two fingers was 2--3 mm with overlapping voxels included and 4--5 mm with overlapping voxels excluded. Our data may be best understood in the context of the work of Schieber (1999) who recently described overlapping somatotopic gradients in lesion studies with humans.

NETWORK ATROPHY IN TEMPORAL LOBE EPILEPSY: A VOXEL-BASED MORPHOMETRY STUDY

NETWORK ATROPHY IN TEMPORAL LOBE EPILEPSY: A VOXEL-BASED MORPHOMETRY STUDY To the Editor: We read the article by Riederer at al.1 with interest. The authors confirmed previous findings on mesial temporal lobe epilepsy (mTLE) showing that hippocampal atrophy is associated with a well-defined network of extrahippocampal gray matter loss. They also demonstrated that cryptogenic temporal lobe epilepsy (cTLE) is associated with a pattern of gray matter atrophy.2-4 Their results indicate that there are subtle differences in the anatomic distribution of damage in patients with mTLE compared to those with cTLE. The cTLE and mTLE groups had varying levels of epilepsy severity yet both groups exhibited extrahippocampal atrophy and the pattern in each group was unique. Since VBM traditionally relies on the comparison of means of gray matter volume across different groups, reproducible findings on mTLE may indicate that patients with mTLE comprise a homogenous group. In comparison, patients with cTLE are likely more heterogeneous with outliers having pronounced brain damage. This may explain why the distribution of atrophy in cTLE is scattered across different brain areas and why previous studies have been unable to consistently observe differences between cTLE and controls. What is the primary cause of extrahippocampal atrophy in TLE? Two common hypotheses are that brain atrophy in patients with TLE may be due to excitotoxic effect from seizures as they spread. Alternatively, it may be due to remote deafferentation from loss of hippocampal connections. Riederer et al. suggest that hippocampal atrophy alone is not responsible for causing brain atrophy yet plays a partial role in shaping the location and extent of atrophy. Further studies are needed to replicate these findings while considering the severity of epilepsy. It is possible that both recurrent seizures and hippocampal atrophy are necessary to generate a diffuse and homogeneous pattern of extrahippocampal atrophy.

Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain.

Previous studies suggest organizing effects of sex hormones on brain structure during early life and puberty, yet little is known about the adult period. The aim of the present study was to elucidate the role of 17beta-estradiol, progesterone, and testosterone on cortical sex differences in grey matter volume (GM) of the adult human brain. To assess sexual dimorphism, voxel-based morphometry (VBM) was applied on structural magnetic resonance images of 34 healthy, young adult humans (17 women, 17 men, 26.6+/-5 years) using analyses of covariance. Subsequently, circulating levels of sex hormones were associated with regional GM using linear regression analyses. After adjustment for sex and total GM, significant associations of regional GM and 17beta-estradiol were observed in the left inferior frontal gyrus (beta=0.39, p=0.02). Regional GM was inversely associated with testosterone in the left inferior frontal gyrus (beta=-0.16, p=0.04), and with progesterone in the right temporal pole (beta=-0.39, p=0.008). Our findings indicate that even in young adulthood, sex hormones exert organizing effects on regional GM. This might help to shed further light on the underlying mechanisms of both functional diversities and congruence between female and male brains.