Wolfgang Weber-Fahr

Effects of age, medication, and illness duration on the N-acetyl aspartate signal of the anterior cingulate region in schizophrenia

The authors performed a MRSI study of the anterior cingulate gyrus in 19 schizophrenic patients under stable medication and 16 controls in order to corroborate previous findings of reduced NAA in the anterior cingulate region in schizophrenia. Furthermore, correlations between NAA in the anterior cingulate gyrus and age or illness duration have been determined. A decreased NAA signal was found in the anterior cingulate gyrus of patients compared to controls. Subdividing the patient group into two groups depending on medication revealed that the group of patients receiving a typical neuroleptic medication showed a lower mean NAA in comparison to the group of patients receiving atypical antipsychotic drugs. No significant group differences in the creatine and phosphocreatine signal or the signal from choline-containing compounds were found. The NAA signal significantly correlated with age, and therefore, individual NAA values were corrected for the age effect found in the control group. The age-corrected NAA signal in schizophrenia correlated significantly with the duration of illness. The detected correlations of NAA decrease with age and illness duration are consistent with recent imaging studies where progressing cortical atrophy in schizophrenia was found. Further studies will be needed to corroborate a possible favorable effect of atypical antipsychotics on the NAA signal.

Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats.

BACKGROUND In alcoholism, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome and as a key signal for dependence-related neuroplasticity. Our understanding of this pathophysiological mechanism originates largely from animal studies, but human data are needed for translation into successful medication development. METHODS We measured brain glutamate levels during detoxification in alcohol-dependent patients (n = 47) and in healthy control subjects (n = 57) as well as in a rat model of alcoholism by state-of-the-art ¹H-magnetic magnetic resonance spectroscopy at 3 and 9.4 T, respectively. RESULTS We found significantly increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions of treatment-seeking alcoholic patients and alcohol-dependent rats versus respective control subjects. The augmented spectroscopic glutamate signal is likely related to increased glutamatergic neurotransmission because, enabled by the high field strength of the animal scanner, we detected a profoundly elevated glutamate/glutamine ratio in alcohol-dependent rats during acute withdrawal. All dependence-induced metabolic alterations normalize within a few weeks of abstinence in both humans and rats. CONCLUSIONS Our data provide first-time direct support from humans for the glutamate hypothesis of alcoholism, demonstrate the comparability of human and animal magnetic resonance spectroscopy responses, and identify the glutamate/glutamine ratio as potential biomarker for monitoring disease progression.

Antipsychotic drug effects on motor activation measured by functional magnetic resonance imaging in schizophrenic patients

Brain function and laterality in schizophrenia were investigated by means of a simple motor task with a self-generated left-hand sequential finger opposition (SFO) using a whole-brain high-speed (100 ms per slice) functional imaging technique. Neuroleptic-naïve, acutely ill schizophrenic patients were compared to schizophrenic patients under stable neuroleptic medication and matched controls. The goal was to evaluate both the motor function in first-episode patients and possible effects of different neuroleptic treatments on functional MRI results. Forty patients satisfying ICD 10 criteria (F20.x) for schizophrenia and sex- and age-matched healthy volunteers participated in this study. All subjects underwent fMRI examinations on a conventional 1.5 T MR unit. The primary sensorimotor cortex and the high-order supplementary motor area (SMA) were evaluated. There was a close similarity in the activation of the primary and high-order (SMA) sensorimotor areas between first-episode schizophrenic patients and controls. In contrast, a significant reduction in the overall blood oxygen level dependent (BOLD) response was seen in sensorimotor cortices (contra- and ipsilateral) in schizophrenic patients under stable medication with typical neuroleptics. This effect was not present in patients treated with atypical antipsychotics. Both antipsychotic treatments, however, led to a significant reduction in activation of the SMA region compared to controls and neuroleptic-naïve subjects. Thus, the present study provides no evidence for the localized involvement of the primary motor cortex or the SMA as a relatively stable vulnerability marker in schizophrenia. There is, however, strong evidence that neuroleptics themselves influence fMRI activation patterns and that there are major differences between typical neuroleptics and atypical antipsychotics.

In vivo voxel based morphometry: Detection of increased hippocampal volume and decreased glutamate levels in exercising mice☆

Voluntary exercise has tremendous effects on adult hippocampal plasticity and metabolism and thus sculpts the hippocampal structure of mammals. High-field (1)H magnetic resonance (MR) investigations at 9.4 T of metabolic and structural changes can be performed non-invasively in the living rodent brain. Numerous molecular and cellular mechanisms mediating the effects of exercise on brain plasticity and behavior have been detected in vitro. However, in vivo attempts have been rare. In this work a method for voxel based morphometry (VBM) was developed with automatic tissue segmentation in mice using a 9.4 T animal scanner equipped with a (1)H-cryogenic coil. The thus increased signal to noise ratio enabled the acquisition of high resolution T2-weighted images of the mouse brain in vivo and the creation of group specific tissue class maps for the segmentation and normalization with SPM. The method was used together with hippocampal single voxel (1)H MR spectroscopy to assess the structural and metabolic differences in the mouse brain due to voluntary wheel running. A specific increase of hippocampal volume with a concomitant decrease of hippocampal glutamate levels in voluntary running mice was observed. An inverse correlation of hippocampal gray matter volume and glutamate concentration indicates a possible implication of the glutamatergic system for hippocampal volume.

Functioning and neuronal viability of the anterior cingulate neurons following antipsychotic treatment: MR-spectroscopic imaging in chronic schizophrenia

Magnetic resonance spectroscopic imaging provides a non-invasive approach for testing the hypothesis that neuronal function can improve under atypical antipsychotic medication leading to improvement in cognitive function. We studied two groups of schizophrenic patients, one treated exclusively with typical neuroleptics, the other with atypical medications. 1H MR-spectroscopic imaging of the anterior cingulate gyrus was performed in all patients. Perseveration errors in the Wisconsin Card Sorting Test (WCST) served as an additional marker for cingulate gyrus function. Our results showed that N-acetylaspartate (NAA), a measure of neuronal function, was closely correlated with perseveration errors seen on the WCST. Patients treated with atypical medications had fewer errors on the WCST and higher NAA levels than those on typical medications, and there was a correlation between the time treated with atypical medication, higher NAA levels and better test performance. These results suggest that atypical antipsychotics modify the function of anterior cingulate neurons in a specific manner.

Monitoring the Effects of Chronic Alcohol Consumption and Abstinence on Brain Metabolism: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

BACKGROUND This study focused on metabolic brain alterations in recently detoxified alcohol-dependent patients (S1) and their possible reversibility after 3 (S2) and 6 months (S3) of abstinence. METHODS Thirty-three alcohol-dependent patients and 30 healthy control subjects were studied with multislice proton magnetic resonance spectroscopic imaging (echo time = 135 msec at 1.5 T at three time points). RESULTS In the patient group, we found that choline-containing compounds (Ch) in three frontal and cerebellar subregions at S1 were significantly below normal, whereas N-acetyl aspartate (NAA) differences did not reach significance but showed a trend toward below-normal values in frontal white matter. Abstinent patients showed a significant increase of Ch in all subregions at S2. At S3, no further significant metabolite changes in abstinent patients compared with S2 could be detected. No significant increase of NAA could be detected at follow-up. CONCLUSIONS The increase of the Ch signal in the follow-up measurement after 3 months in abstinent alcohol-dependent patients supports the hypotheses of an alcohol- or alcohol detoxification-induced altered cerebral metabolism of lipids in membranes or myelin, which seems to be reversible with duration of alcohol abstinence.

A Fully Automated Method for Tissue Segmentation and CSF-Correction of Proton MRSI Metabolites Corroborates Abnormal Hippocampal NAA in Schizophrenia

In this report, we describe the implementation and application of a fully automated segmentation routine using SPM99 algorithms and MATLAB for clinical Magnetic Resonance Spectroscopic Imaging (MRSI) studies. By segmenting high-resolution 3-D image data and coregistering the results to the spatial localizer slices of a spectroscopy examination, the program offers the possibility to easily calculate segmentation maps for a large variety of MRSI experiments. The segmented data are corrected for the individual point-spread function, slice and VOI profiles for measurement sequences with selective pulses as well as for the chemical shifts of different metabolites. The new method was applied to investigate discrete hippocampal metabolite abnormalities in a small sample of schizophrenic patients in comparison to healthy controls (15 patients, 15 controls). Only after correction was the N-acetyl-aspartate (NAA) signal significantly lower in patients compared to controls. No differences were found for the corrected signals from the creatine/phosphocreatine (Cr) or choline-containing compounds (Ch). These results are in good agreement with neuropathological and previous MR spectroscopy studies of the hippocampus in schizophrenic patients.

Sub-Anesthetic Ketamine Modulates Intrinsic BOLD Connectivity Within the Hippocampal-Prefrontal Circuit in the Rat

Dysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague–Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior–posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine’s effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.

Correlation of Glutamate Levels in the Anterior Cingulate Cortex With Self-reported Impulsivity in Patients With Borderline Personality Disorder and Healthy Controls

CONTEXT Dysfunction and deficits in the structure of the anterior cingulate cortex have been reported in borderline personality disorder (BPD). To our knowledge, there is only 1 published study to date investigating anterior cingulate cortex metabolism in subjects with BPD and co-occurring attention-deficit/hyperactivity disorder using proton magnetic resonance spectroscopy. Impulsivity is a key feature of BPD and can be related to anterior cingulate cortex function. OBJECTIVE To investigate whether anterior cingulate cortex metabolism may be altered in BPD and correlates with BPD pathology. DESIGN Cross-sectional proton magnetic resonance spectroscopy study. SETTING Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS AND PATIENTS Thirty unmedicated female subjects meeting DSM-IV criteria for BPD and 31 age-matched healthy female control participants. MAIN OUTCOME MEASURES Neurometabolite concentrations in the anterior cingulate cortex and correlation of glutamate levels with self-reported measures of impulsivity and severity of borderline symptoms. RESULTS Significantly higher levels of glutamate in the anterior cingulate cortex were found in subjects with BPD as compared with healthy controls. A positive correlation between glutamate concentration and the Barratt Impulsiveness Scale total score as well as between glutamate concentration and the subscore for cognitive impulsivity were observed irrespective of diagnosis. We also found a positive correlation between glutamate concentrations and dissociation as well as between glutamate concentration and subscores of the Borderline Symptom List in the patient group. CONCLUSIONS Our results support the hypothesis that higher glutamate concentration in the anterior cingulate cortex is associated with both severity of BPD symptoms and subjective impulsivity ratings, the latter independent of BPD. Further studies should confirm the association between enhanced glutamate concentration in the anterior cingulate cortex and behavioral measures of impulsivity.

Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: A MEGA‐PRESS study with symmetric editing pulse frequencies for macromolecule suppression

Despite MEGA‐PRESS being a robust method for editing the GABA resonance, there are macromolecule resonances at the same chemical shift that are coedited with this sequence. Although this is a known problem, it is still often overlooked. We aimed to evaluate the amount of macromolecule signal coedited, as well as the gender and age dependencies for the GABA resonance at 3.01 ppm using MEGA‐PRESS with two different editing pulse frequencies. Forty‐five healthy subjects (21–52 years) were included in an in vivo single voxel MEGA‐PRESS study at 3.0 T. Phantom measurements were conducted to measure the signal loss when switching the editing pulse between 1.5 and 1.9 ppm instead of the mostly used switching between 1.9 and 7.5 ppm. The in vivo GABA signal detected by switching the editing pulse frequencies between 1.5 and 1.9 ppm was only 50% of the mean GABA detected by switching the editing pulse frequencies between 1.9 and 7.5 ppm. No gender differences were detected. A small age dependency was observed for GABA plus macromolecules, but not for GABA, suggesting an age‐dependent macromolecule increase. Magn Reson Med, 2013.