Dorothee P. Auer

The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis

The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.

Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study

BACKGROUND Functional imaging studies suggest a specific role of the anterior brain regions in the pathogenesis of major depression. The aim of this study was to evaluate possible neurochemical alterations in the frontomesial cortex in patients with major depressive episode using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). METHODS Single voxel (1)H-MRS was performed in 19 patients with major depressive episodes and 18 age-matched healthy controls within the anterior cingulate cortex and the parietal white matter. Absolute concentrations were estimated for N-acetyl-aspartate, choline-containing compounds, total creatine, myo-inositol, unresolved glutamate and glutamine (Glx) and glutamate alone (Glu). Voxel composition was analyzed by image segmentation into cerebrospinal fluid (CSF), grey and white matter. RESULTS MANOVA test for Glx and Glu using age, percent CSF and percent grey matter contribution as covariates yielded a significant group effect within the anterior cingulate due to decrease of Glx in patients (-10.4%, p =.013). Considering only severely depressed patients, both Glx and Glu (-14.3%, p =.03) showed a significant decrease. There was no significant group effect for the neuronal marker NAA, creatine, choline or myo-inositol in either localization. CONCLUSIONS This study suggests a possible role of altered glutamatergic neurotransmission within the anterior cingulate in the pathogenesis of mood disorders. The otherwise unremarkable findings of major brain metabolites confirms lack of neurodegenerative or membrane metabolic changes in major depression.

Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis

Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been studied. We apply tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) in a cohort of multiple sclerosis patients to identify loci where reduced white matter tract fractional anisotropy (FA) predicts impaired performance in cognitive testing. Thirty-seven multiple sclerosis patients in remission (median age 43.5 years; Expanded Disability Status Scale range 1.5-6.5; 35 relapsing remitting, two secondary-progressive) underwent 3 T MRI including high-resolution DTI. Multiple sclerosis patients underwent formal testing of performance in multiple cognitive domains. Normalized cognitive scores were used for voxel-wise statistical analysis using TBSS, while treating age as a covariate of no interest. Permutation-based inference on cluster size (t > 2, P <0.05 corrected) was used to correct for multiple comparisons. Statistical mapping revealed differential patterns of FA reduction for tests of sustained attention, working memory and processing speed, visual working memory and verbal learning and recall. FA was not associated with frontal lobe function or visuospatial perception. Cognitively relevant tract localizations only partially overlapped with areas of high FLAIR lesion probability, confirming the contribution of normal-appearing white matter abnormality to cognitive dysfunction. Of note, tract localizations showing significant associations with cognitive impairment were found to interconnect cortical regions thought to be involved in processing in these cognitive domains, or involve possible compensatory processing pathways. This suggests that TBSS reveals functionally relevant tract injury underlying cognitive dysfunction in patients with multiple sclerosis.

Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events.

BACKGROUND Carotid endarterectomy is beneficial in severe (>70%) symptomatic carotid stenosis. The risk of stroke in moderate carotid stenosis (50%-69%) is modest, and so the role of carotid endarterectomy in this group is unclear. Intraplaque hemorrhage is associated with advanced atherosclerosis and can be detected in the carotid arteries by magnetic resonance imaging. This study evaluates whether magnetic resonance imaging detected intraplaque hemorrhage (MR IPH) can identify patients with symptomatic mild to moderate carotid stenosis who are at higher risk of ipsilateral transient ischemic attack (TIA) and stroke. METHODS Prospective longitudinal cohort study of symptomatic patients with mild to moderate (30%-69%) carotid stenosis followed up for 2 years after imaging for IPH using magnetic resonance imaging. RESULTS Sixty four participants were followed up for a median of 28 months (interquartile range 26-30) after MRI of the carotid arteries. Thirty-nine (61%) ipsilateral arteries showed intraplaque hemorrhage. During follow-up, five ipsilateral strokes and a total of 14 ipsilateral ischemic events were observed. Thirteen of these ischemic events, of which five were strokes, occurred in those with ipsilateral carotid intraplaque hemorrhage (hazard ratio = 9.8, 95% confidence interval 1.3-75.1, P = .03). CONCLUSIONS MR IPH is a good predictor of ipsilateral stroke and TIA in patients with symptomatic mild to moderate (30%-69%) carotid stenosis. This technique could help in the selection of patients for carotid endarterectomy.

Brain structures mediating cardiovascular arousal and interoceptive awareness

Different emotions are accompanied by different bodily states and it is unclear which brain structures are involved in both, the cerebral representation of the bodily change and the representation of its perception. Structures connecting bodily signals and interoceptive awareness could trigger, in a feedforward manner, behavioral responses appropriate to maintain a desired state of the cardiovascular system. The present functional magnetic resonance imaging study aimed at identifying brain structures that are mutually activated during interoceptive awareness of heartbeats and during cardiovascular arousal. Additionally, we searched for brain regions connecting interoception with feelings. During the interoceptive task (directing attention towards heartbeats in relation to an exteroceptive task) the thalamus, the insula, the medial frontal/dorsal cingulate and the inferior frontal gyrus, as well as the somatomotor cortex were activated. The conjunction of the interoceptive awareness of heartbeats and cardiovascular arousal revealed structures presumably connecting both conditions, i.e. the right thalamus, insula, somatomotor cortex, and the dorsal cingulate as well as medial frontal gyrus. Furthermore, the degree of interoceptive awareness predicted the degree of activation of both the insula and the medial frontal/dorsal cingulate gyrus. Negative feelings correlated with the BOLD response of the interoceptive awareness condition in the dorsal cingulate gyrus extending into the dorsomedial prefrontal cortex. We provide evidence that the insula, the dorsal cingulate gyrus, and the dorsomedial prefrontal cortex are specifically involved in processing cardiac sensations. The dorsal cingulate gyrus and the dorsomedial prefrontal cortex presumably represent the neural substrates of experiencing negative emotions.

Carotid Intraplaque Hemorrhage Predicts Recurrent Symptoms in Patients With High-Grade Carotid Stenosis

Background and Purpose— Carotid intraplaque hemorrhage (IPH), known to be associated with plaque instability, may convey a higher stroke risk. The aim of this study was to assess whether the identification of IPH by MRI predicts recurrent clinical cerebrovascular events. Methods— Sixty-six patients with high-grade symptomatic carotid stenosis underwent MRI of the carotid arteries and were followed until carotid endarterectomy or 30 days. Results— Of the 66 patients with a median follow up of 33.5 days, 44 (66.7%) were found on MRI to have ipsilateral carotid IPH. Fifteen recurrent events were associated with ipsilateral carotid IPH. Only 2 recurrent events occurred in the absence of IPH. IPH increased the risk of recurrent ischemia (hazard ratio=4.8; 95% CI=1.1 to 20.9, P<0.05). Conclusion— IPH as detected by MRI predicts recurrent cerebrovascular events in patients with symptomatic high-grade carotid stenosis.

Spontaneous low-frequency blood oxygenation level-dependent fluctuations and functional connectivity analysis of the ‘resting’ brain

Functional magnetic resonance imaging techniques using the blood oxygenation level-dependent (BOLD) contrast are widely used to map human brain function by relating local hemodynamic responses to neuronal stimuli compared to control conditions. There is increasing interest in spontaneous cerebral BOLD fluctuations that are prominent in the low-frequency range (<0.1 Hz) and show intriguing spatio-temporal correlations in functional networks. The nature of these signal fluctuations remains unclear, but there is accumulating evidence for a neural basis opening exciting new avenues to study human brain function and its connectivity at rest. Moreover, an increasing number of patient studies report disease-dependent variation in the amplitude and spatial coherence of low-frequency BOLD fluctuations (LFBF) that may afford greater diagnostic sensitivity and easier clinical applicability than standard fMRI. The main disadvantage of this emerging tool relates to physiological (respiratory, cardiac and vasomotion) and motion confounds that are challenging to disentangle requiring thorough preprocessing. Technical aspects of functional connectivity fMRI analysis and the neuroscientific potential of spontaneous LFBF in the default mode and other resting-state networks have been recently reviewed. This review will give an update on the current knowledge of the nature of LFBF, their relation to physiological confounds and potential for clinical diagnostic and pharmacological studies.

Altered Processing of Acoustic Stimuli during Sleep: Reduced Auditory Activation and Visual Deactivation Detected by a Combined fMRI/EEG Study

Although there is evidence that acoustic stimuli are processed differently during sleep and wakefulness, little is known about the underlying neuronal mechanisms. In the present study, the processing of an acoustic stimulus was investigated during different non rapid eye movement (NREM) sleep stages using a combined EEG/fMRI approach in healthy human volunteers: A text stimulus was presented to sleep-deprived subjects prior to and after the onset of sleep, and single-slice silent fMRI were acquired. We found significantly different blood oxygenation level-dependent (BOLD) contrast responses during sleep compared to wakefulness. During NREM sleep stages 1 and 2 and during slow wave sleep (SWS) we observed reduced activation in the auditory cortex and a pronounced negative signal in the visual cortex and precuneus. Acoustic stimulation during sleep was accompanied by an increase in EEG frequency components in the low delta frequency range. Provided that neurovascular coupling is not altered during sleep, the negative transmodal BOLD response which is most pronounced during NREM sleep stages 1 and 2 reflects a deactivation predominantly in the visual cortex suggesting that this decrease in neuronal activity protects the brain from the arousing effects of external stimulation during sleep not only in the primary targeted sensory cortex but also in other brain regions.

Gray Matter-Changes and Correlates of Disease Severity in Schizophrenia: A Statistical Parametric Mapping Study

Voxel-based morphometry has recently been used successfully to detect gray matter volume reductions in schizophrenic patients. The aim of the present study was to confirm the findings on gray-matter changes and to complement these by applying the methodology to CSF-differences. Also, we wanted to determine whether a correlation exists between a clinically defined parameter of disease severity and brain morphology in schizophrenic patients. We investigated 48 schizophrenic patients and compared them with 48 strictly age- and sex-matched controls. High-resolution whole-brain MR-images were segmented and analyzed using SPM99. In a further analysis, the covariate effect of the global assessment of functioning-score (GAF) was calculated. Main findings were (i) left-dominant frontal, temporal, and insular GM-reductions and (ii) GM-increases in schizophrenic patients in the right basal ganglia and bilaterally in the superior cerebellum; (iii) CSF-space increases in patients complementary to some GM-reductions; (iv) a correlation between the GAF-score and local GM-volume in the left inferior frontal and inferior parietal lobe of schizophrenic patients. This study confirms and extends some earlier findings on GM-reduction and detected distinct GM-increases in schizophrenic patients. These changes were corroborated by complementary CSF-increases. Most importantly, a correlation could be established between two particular gray matter-regions and the overall disease severity, with more severely ill patients displaying a local GM-deficit. These findings may be of potentially large importance for both the future interpretation and design of neuroimaging studies in schizophrenia and the further elucidation of possible pathophysiological processes occurring in this disease.

On the reliability of quantitative clinical magnetic resonance spectroscopy of the human brain.

The reliability of a single‐voxel, localized proton magnetic resonance spectroscopy protocol suitable for clinical studies was investigated by means of in vitro, single‐subject in vivo and multi‐subject in vivo examinations of healthy adults aged from 19 to 67 years. The study was performed at 1.5 T using a standard quadrature head coil and a single voxel PRESS sequence (in vitro TR/TE = 1500/30 ms, in vivo TR/TE=2000/35 ms). Eighty‐four in vitro and 30 single‐subject examinations were statistically evaluated after quantification, including the calculation of the coefficients of variations (CV) for choline (Cho), creatine (Cr), myo‐inositol (mI), lactate (Lac), N‐acetyl‐aspartate (NAA) and unresolved glutamine, glutamate and GABA (Glx). The CVs for absolute concentrations of the main metabolites Cho, Cr and NAA, ranged from 3.3% (3.8) to 4.0% (6.4%) (the in vivo results are given in brackets). Multi‐subject CVs of absolute concentrations for Cho, Cr and NAA ranged from 7.6% to 15.0%. CVs of relative in vivo concentrations were found to be higher than CVs of absolute concentrations. Due to the better reproducibility of intra‐individual absolute in vivo concentrations, cross‐over studies using institutional units are recommended. Copyright