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Growing evidence indicates that physical exercise increases hippocampal volume. This has consistently been shown in mice and men using magnetic resonance imaging. On the other hand, histological studies have reported profound alterations on a cellular level including increased adult hippocampal neurogenesis after exercise. A combined investigation of both phenomena has not been documented so far although a causal role of adult neurogenesis for increased hippocampal volume has been suggested before. We investigated 20 voluntary wheel running and 20 sedentary mice after a period of 2 month voluntary wheel running. Half of each group received focalized hippocampal irradiation to inhibit neurogenesis prior to wheel running. Structural MRI and histological investigations concerning newborn neurons (DCX), glial cells (GFAP), microglia, proliferating and pyknotic cells, neuronal activation, as well as blood vessel density and arborisation were performed. In a regression model, neurogenesis was the marker best explaining hippocampal gray matter volume. Individual analyses showed a positive correlation of gray matter volume with DCX-positive newborn neurons in the subgroups, too. GFAP-positive cells significantly interacted with gray matter volume with a positive correlation in sham-irradiated mice and no correlation in irradiated mice. Although neurogenesis appears to be an important marker of higher hippocampal gray matter volume, a monocausal relationship was not indicated, requesting further investigations.

Electroconvulsive therapy (ECT) is a treatment of choice for severe and therapy resistant forms of major depressive episodes (MDE). Temporal brain volume alterations in MDE have been described for more than two decades. In our prospective study we aimed to investigate individual pre-post ECT treatment whole brain gray matter (GM) volume changes (quantified with voxel-based morphometry) in a sample of 18 patients with MDE. In addition, we studied the effect of ECT on voxel-based cortical thickness in cortical brain regions. The most prominent longitudinal GM increases (significant at a whole brain corrected level) occurred in temporal lobe regions. Within specific region of interest analyses we detected highly significant increases of GM in the hippocampus and the amygdala and to a lesser extent in the habenula (left p=0.003, right p=0.032). A voxel based cortical thickness analysis revealed an increase in cortical temporal regions (basically temporal pole and insula) further corroborating our cortical voxel-based morphometry results. Neither GM decreases or white matter increases nor correlations of GM changes with basic psychopathological parameters were detected. We corroborate earlier findings of hippocampal and amygdala GM volume increase following an acute ECT series in patients with MDE. Temporal GM volume increase was significant on a whole brain level and further corroborated by a cortical thickness analysis. Our data widely exclude white matter loss as an indirect cause of GM growth. Our data add further evidence to the hypothesis that ECT enables plasticity falsifying older ideas of ECT induced "brain damaging"., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal-limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down-regulation with neurofeedback have not been addressed yet. Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N=16). In contrast, a control group (N=16) receiving sham feedback did not alter amygdala connectivity (Group×Condition t-contrast: p<.05 at cluster-level). Task-dependent increases in amygdala-vmPFC connectivity were predicted by picture arousal (β=.59, p<.05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp=.90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p<.05 at cluster-level). Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study investigated the impact of "life kinetik" training on brain plasticity in terms of an increased functional connectivity during resting-state functional magnetic resonance imaging (rs-fMRI). The training is an integrated multimodal training that combines motor and cognitive aspects and challenges the brain by introducing new and unfamiliar coordinative tasks. Twenty-one subjects completed at least 11 one-hour-per-week "life kinetik" training sessions in 13 weeks as well as before and after rs-fMRI scans. Additionally, 11 control subjects with 2 rs-fMRI scans were included. The CONN toolbox was used to conduct several seed-to-voxel analyses. We searched for functional connectivity increases between brain regions expected to be involved in the exercises. Connections to brain regions representing parts of the default mode network, such as medial frontal cortex and posterior cingulate cortex, did not change. Significant connectivity alterations occurred between the visual cortex and parts of the superior parietal area (BA7). Premotor area and cingulate gyrus were also affected. We can conclude that the constant challenge of unfamiliar combinations of coordination tasks, combined with visual perception and working memory demands, seems to induce brain plasticity expressed in enhanced connectivity strength of brain regions due to coactivation.

Borderline personality disorder (BPD) and attention-deficit-hyperactivity disorder (ADHD) are both characterized by high impulsivity and difficulties in controlling anger and aggression. In BPD, comorbid ADHD may further increase impulsivity. For both disorders, altered MR spectroscopy levels of the neurotransmitters glutamate and GABA as well as some correlations with impulsivity were previously reported. The objective of this study was to investigate the neurotransmitters glutamate and GABA in relation to impulsivity and aggression as expressed in the anterior cingulate cortex (ACC) in groups of female patients with BPD and ADHD, respectively. Associations of glutamate and GABA levels with further BPD (symptom severity) and ADHD aspects (hyperactivity and inattention) were exploratively evaluated. 1H MR spectra were acquired at 3T to determine glutamate to total creatine ratios (Glu/tCr) and GABA levels from the ACC in a BPD group (n=26), an ADHD group (n=22), and a healthy control (HC) group (n=30); all participants were females. Both patient groups showed higher scores on self-reported impulsivity, anger, and aggression compared with HCs. ACC GABA levels were significantly lower in ADHD than HC. Although measures of impulsivity were positively related to glutamate and negatively to GABA, for aggression only a negative correlation with GABA could be demonstrated. These data provide human in vivo evidence for the role of ACC Glu/tCr and GABA in impulsivity and aggression. If distinct associations of Glu/tCr and GABA for BPD and ADHD can be confirmed in future studies, this might yield implications for more specific pharmacological treatments.

We explored brain volume recovery in terms of cortical thickness (CTh; gyral, sulcal pattern) and surface area (SA), as well as subcortical volume recovery in the first 2 weeks of abstinence in 49 alcohol-dependent patients (ADPs). A widespread reduction of CTh in ADPs at day 1 of abstinence compared to healthy controls, with more pronounced differences in sulci relative to gyri was found. After 2 weeks of abstinence, partial recovery to varying degrees of CTh loss in ADPs was observed for several regions. The longitudinal CTh changes were greater in sulci than in gyri of affected regions. No longitudinal change in SAs and subcortical volumes was found. Alterations of CTh contribute to brain volume loss in alcoholism and recovery during early abstinence. Sulci seem to be more vulnerable to excessive alcohol consumption and to drive abstinence-induced volume recovery. During the initial 2 weeks of abstinence no subcortical volume regain was observed. Either the time span was too short or the lower subcortical volume could represent a predisposing trait marker., (© 2015 S. Karger AG, Basel.)

Impulsivity is central to borderline personality disorder (BPD). Response inhibition, addressing the ability to suppress or stop actions, is one aspect of behavioral impulse control which is frequently used to assess impulsivity. BPD patients display deficits in response inhibition under stress condition or negative emotions. We assessed whether response inhibition and its neural underpinnings are impaired in BPD when tested in an emotionally neutral setting and when co-morbid attention-deficit/hyperactivity disorder (ADHD) is excluded. To this end, we studied response inhibition in unmedicated BPD patients and healthy controls (HC) in two independent samples using functional magnetic resonance imaging during Simon-, Go/nogo-, and Stopsignal tasks. BPD patients and HC did not differ significantly in their performance in the Go/nogo and the Stopsignal tasks. Response interference in the Simon task was increased in BPD patients in one sample, but this could not be replicated in the second sample. In both samples, no significant differences in brain activation patterns during any of the tasks were present while the neural impulse control network was robustly activated during the inhibition tasks in both groups. Our results provide evidence that under emotionally neutral conditions response inhibition is not impaired in patients with BPD without co-occurring ADHD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The membrane anchored ligand ephrinB2 belongs to the broad Eph/ephrin system and is able to activate different Eph receptors. The Eph receptors belong to the huge group of receptor-tyrosine kinases. Eph receptors as well as their corresponding ephrin ligands are cell-membrane attached proteins. Therefore, direct cell-cell contact is essentially for interaction. It is known that ephrinB2 plays a pivotal role in developmental and in tumour angiogenesis. Previous studies point to a crucial role of the EphA4-receptor in the process of monocyte adhesion. Since ephrinB2 is known as an interaction partner of EphA4, the aim of the present study was to investigate a possible interplay of EphA4-receptor with ephrinB2 during monocyte adhesion to the endothelium. As verified by bulk adhesion assays and atomic-force microscopy based single-cell force spectroscopy, temporary stimulation of endothelial cells from different sources with the soluble ligand ephrinB2 increased monocyte adhesion to endothelial cells. The proadhesive effect of ephrinB2 was independent of an active transcription, but is mediated via the Rho signaling pathway with subsequent modulation of the actin cytoskeleton. Furthermore, ephrinB2 mediated its impact on monocyte adhesion via the receptor EphA4 as shown by siRNA-mediated silencing. Interestingly, ephrinB2 was induced by TNF-α treatment. Silencing of ephrinB2 led to a lowering of the TNF-α mediated monocyte adhesion to endothelial cells. Furthermore, immunohistochemical staining of human atherosclerotic plaque revealed expression of ephrinB2 in macrophages. The results of the present study point to a crucial role of ephrinB2 induced EphA4 forward signaling in the context of monocyte adhesion to endothelial cells. This transcription-independent effect is mediated by Rho signaling induced actin-filament polymerization., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: It has previously been reported that even social alcohol consumption affects the magnetic resonance spectroscopy (MRS) signals of choline-containing compounds (tCho). The purpose of this study was to investigate whether the consumption of alcohol affects the concentrations of the metabolites tCho, N-acetylaspartate, creatine, or myo-inositol and/or their T 2 relaxation times., Materials and Methods: (1)H MR spectra were obtained at 3 T from a frontal white matter voxel of 25 healthy subjects with social alcohol consumption (between 0 and 25.9 g/day). Absolute brain metabolite concentrations and T 2 relaxation times of metabolites were examined via MRS measurements at different echo times. Metabolite concentrations and their T 2 relaxation times were correlated with subjects' alcohol consumption, controlling for age., Results: We observed positive correlations of absolute tCho and phosphocreatine and creatine (tCr) concentrations with alcohol consumption but no correlation between any metabolite T 2 relaxation time and alcohol consumption., Conclusions: This study shows that even social alcohol consumption affects the concentrations of tCho and tCr in cerebral white matter. Future studies assessing brain tCho and tCr levels should control for the confounding factor alcohol consumption.

Proton Magnetic Resonance Spectroscopy (MRS) has been widely used to study the healthy and diseased brain in vivo. The availability of whole body MR scanners with a field strength of 3 Tesla and above permit the quantification of many metabolites including the neurotransmitters glutamate (Glu) and γ-aminobutyric acid (GABA). The potential link between neurometabolites identified by MRS and cognition and behavior has been explored in numerous studies both in healthy subjects and in patient populations. Preliminary findings suggest direct or opposite associations between GABA or Glu with impulsivity, anxiety, and dexterity. This chapter is intended to provide an overview of basic principles of MRS and the literature reporting correlations between GABA or Glu and results of neuropsychological assessments.

Purpose: Phosphomono- and diesters, the major components of the choline peak in (1) H magnetic resonance spectroscopy, are associated with membrane anabolic and catabolic mechanisms. With the refocused insensitive nuclei-enhanced polarization transfer technique, these phospholipids are edited and enhanced in the (31) P MR spectrum. In depressed patients, alterations of the choline peak and cerebral volume have been found, indicating a possible relation. Thus, combining MR phosphorous spectroscopy and volumetry in depressed patients seems to be a promising approach to detect underlying pathomechanisms., Methods: Depressed in-patients were either treated with antidepressive medication or with electroconvulsive therapy and compared to matched healthy controls. (31) P magnetic resonance spectroscopy imaging was conducted before and after the treatment phases. A 3D MRI dataset for volumetry was acquired in a dedicated (1) H head coil., Results: Phosphocholine and phosphoethanolamine were increased in depressed patients. Though patients responded to the treatments, phospholipids were not significantly altered. An increased age-related gray matter loss in fronto-limbic regions along with an altered relation of phosphomonoesters/phosphodiesters with age were found in depressed patients., Discussion: The findings of increased phosphomonoesthers and an age*group interaction for gray matter volumes need further research to define the role of phospholipids in major depression and possible associations to gray matter loss., (© 2014 Wiley Periodicals, Inc.)

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy ((1)HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.

A tremendous amount of effort has been dedicated to unravel the functional neuroanatomy of the processing and regulation of emotion, resulting in a well-described picture of limbic, para-limbic and prefrontal regions involved. Studies applying functional magnetic resonance imaging (fMRI) often use the block-wise presentation of stimuli with affective content, and conventionally model brain activation as a function of stimulus or task duration. However, there is increasing evidence that regional brain responses may not always translate to task duration and rather show stimulus onset-related transient time courses. We assume that brain regions showing transient responses cannot be detected in block designs using a conventional fMRI analysis approach. At the same time, the probability of detecting these regions with conventional analyses may be increased when shorter stimulus timing or a more intense stimulation during a block is used. In a within-subject fMRI study, we presented aversive pictures to 20 healthy subjects and investigated the effect of experimental design (i.e. event-related and block design) on the detection of brain activation in limbic and para-limbic regions of interest of emotion processing. In addition to conventional modeling of sustained activation during blocks of stimulus presentation, we included a second response function into the general linear model (GLM), suited to detect transient time courses at block onset. In the conventional analysis, several regions like the amygdala, thalamus and periaqueductal gray were activated irrespective of design. However, we found a positive BOLD response in the anterior insula (AI) in event-related but not in block-design analyses. GLM analyses suggest that this difference may result from a transient response pattern which cannot be captured by the conventional fMRI analysis approach. Our results indicate that regions with a transient response profile like the AI can be missed in block designs if analyses do not account for transient responses. This may bias conclusions from empirical reports and meta-analyses towards an underestimation of these regions and their role in emotion and emotion regulation. The cognitive processes underlying differential time courses are discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The ligand ephrin A1 is more often discussed to play a role in the development of the atherosclerotic plaque and in this context especially in the monocyte adhesion to endothelial cells. As tumor necrosis factor-α (TNF-α) is known to induce monocyte adhesion to endothelium and ephrin A1 expression, the present study focuses on the involvement of ephrin A1 in TNF-α-mediated monocyte adhesion. The analysis of different members of the Eph/ephrin system in TNF-α-treated human umbilical vein endothelial cells (HUVEC) revealed that especially ephrinA1 was found to be highly regulated by TNF-α compared to other members of the Eph family. This effect is also present in arterial endothelial cells from the umbilical artery and from the coronary artery. This regulation is dependent on NFκB-activation as shown by the expression of a constitutive-active IκB-mutant. By using siRNA-mediated silencing and adenoviral overexpression of ephrinA1 in HUVEC, the involvement of ephrinA1 in the TNF-α triggered monocyte adhesion to endothelial cells could be demonstrated. In addition, these results could be verified by quantitative adhesion measurement using atomic force microscopy-based single-cell force spectroscopy and under flow conditions. Furthermore, this effect is mediated via the EphA4 receptor. EphrinA1 does not influence the mRNA or protein expression of the adhesion receptors VCAM-1 and ICAM-1 in endothelial cells. However, the surface presentation of these adhesion receptors is modulated in an ephrinA1-dependent manner. In conclusion, these data demonstrate that ephrinA1 plays an important role in the TNF-α-mediated adhesion of monocytes to endothelial cells, which might be of great importance in the context of atherosclerosis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Psychiatric conditions of emotion dysregulation are often characterized by difficulties in regulating the activity of limbic regions such as the amygdala. Real-time functional magnetic resonance imaging (rt-fMRI) allows to feedback brain activation and opens the possibility to establish a neurofeedback (NF) training of amygdala activation, e.g., for subjects suffering from emotion dysregulation. As a first step, we investigated whether feedback of the amygdala response to aversive scenes can improve down-regulation of amygdala activation. One group of healthy female participants received amygdala feedback (N = 16) and a control group was presented with feedback from a control region located in the basal ganglia [N(sum) = 32]. Subjects completed a one-session rt-fMRI-NF training where they viewed aversive pictures and received continuous visual feedback on brain activation (REGULATE condition). In a control condition, subjects were advised to respond naturally to aversive pictures (VIEW), and a neutral condition served as the non-affective control (NEUTRAL). In an adjacent run, subjects were presented with aversive pictures without feedback to test for transfer effects of learning. In a region of interest (ROI) analysis, the VIEW and the REGULATE conditions were contrasted to estimate brain regulation success. The ROI analysis was complemented by an exploratory analysis of activations at the whole-brain level. Both groups showed down-regulation of the amygdala response during training. Feedback from the amygdala but not from the control region was associated with down-regulation of the right amygdala in the transfer test. The whole-brain analysis did not detect significant group interactions. Results of the group whole-brain analyses are discussed. We present a proof-of-concept study using rt-fMRI-NF for amygdala down-regulation in the presence of aversive scenes. Results are in line with a potential benefit of NF training for amygdala regulation.

The last two decades have seen a strong rise in empirical research in the mechanisms of emotion dysregulation in borderline personality disorder. Major findings comprise structural as well as functional alterations of brain regions involved in emotion processing, such as amygdala, insula, and prefrontal regions. In addition, more specific mechanisms of disturbed emotion regulation, e.g. related to pain and dissociation, have been identified. Most recently, social interaction problems and their underlying neurobiological mechanisms, e.g. disturbed trust or hypersensitivity to social rejection, have become a major focus of BPD research. This article covers the current state of knowledge and related relevant research goals. The first part presents a review of the literature. The second part delineates important open questions to be addressed in future studies. The third part describes the research agenda for a large German center grant focusing on mechanisms of emotion dysregulation in BPD.

Objectives: Physical activity (PA) was found to influence human brain morphology. However, the impact of PA on brain morphology was mainly demonstrated in seniors. We investigated healthy individuals across a broad age range for the relation between habitual PA and brain morphology., Methods: Ninety-five participants (19-82 years) were assessed for self-reported habitual PA with the "Baecke habitual physical activity questionnaire", and T1-weighted magnetic resonance images were evaluated with whole brain voxel based morphometry for gray and white matter volumes and densities., Results: Regression analyses revealed a positive relation between the extent of physical activity and gray matter volume bilaterally in the anterior hippocampal and parahippocampal gyrus independent of age and gender. Age as well as leisure and locomotion activities were linked to enhanced white matter volumes in the posterior cingulate gyrus and precuneus, suggesting a positive interaction especially in seniors., Conclusions: Habitual physical activity is associated with regional volumetric gray and white matter alterations. The positive relation of hippocampal volume and physical activity seems not to be restricted to seniors. Thus, habitual physical activity should be generally considered as an influencing factor in studies investigating medial temporal lobe volume and associated cognitive functions (memory), especially in psychiatric research.

MRI and MRS in small rodents demand very high sensitivity. Cryogenic transmit/receive radiofrequency probes (CryoProbes) designed for (1) H MRI of mouse brain provide an attractive option for increasing the performance of small-animal MR systems. As the Larmor frequency of (13) C nuclei is four times lower than that for (1) H nuclei, an even larger sensitivity improvement is expected for (13) C applications. The aim of this work was to evaluate the performance of a prototype (13) C CryoProbe™ for mouse brain MRS. To investigate the possible gain of the (13) C CryoProbe™, we acquired localized single-voxel (13) C spectra and chemical shift images of a dimethyl sulfoxide phantom with the CryoProbe™, as well as with two room temperature resonators. The cryogenically cooled resonator achieved approximately four-fold higher signal-to-noise ratio in phantom tests when compared with the best-performing room temperature coil. In addition, we present localized (13) C spectra of mouse brain obtained with the CryoProbe™, as well as with one of the room temperature coils, demonstrating the performance in vivo. In summary, the cryogenic cooling technique significantly enhances the (13) C signal sensitivity at 9.4 T and enables the investigation of metabolism within mouse brain., (Copyright © 2014 John Wiley & Sons, Ltd.)

Recently, a larger hippocampus was found in exercising mice and men. Here we studied the morphological underpinnings in wheel running mice by longitudinal magnetic resonance imaging. Voxel-based morphometry revealed that running increases hippocampal volume by inhibiting an early age-related gray matter loss. Disruption of neurogenesis-related neuroplasticity by focalized irradiation is sufficient to block positive effects of exercise on macroscopic brain morphology., (Copyright © 2013 Wiley Periodicals, Inc.)

Previously reported MRS findings in the aging brain include lower N-acetylaspartate (NAA) and higher myo-inositol (mI), total creatine (Cr) and choline-containing compound (Cho) concentrations. Alterations in the sodium channel voltage gated type I, alpha subunit SCN1A variant rs10930201 have been reported to be associated with several neurological disorders with cognitive deficits. MRS studies in SCN1A-related diseases have reported striking differences in the mI concentrations between patients and controls. In a study on 'healthy aging', we investigated metabolite spectra in a sample of 83 healthy volunteers and determined their age dependence. We also investigated a potential link between SCN1A and mI. We observed a significantly negative association of NAA (p = 0.004) and significantly positive associations of mI (p ≤ 0.001), Cr (p ≤ 0.001) and Cho (p = 0.034) with age in frontal white matter. The linear association of Cho ends at the age of about 50 years and is followed by an inverted 'U'-shaped curve. Further, mI was higher in C allele carriers of the SCN1A variant rs10930201. Our results corroborated the age-related changes in metabolite concentrations, and found evidence for a link between SCN1A and frontal white matter mI in healthy subjects., (Copyright © 2013 John Wiley & Sons, Ltd.)

Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

MiRNAs are a class of endogenous tiny RNAs that act as inhibitors of translation or promote RNA degradation by duplex-formation within the 3'-UTR of target mRNAs. They play an important role during a wide range of cellular processes by fine-tuning of gene expression. The differentiation of monocytes to macrophages plays a pivotal role in physiological as well as pathophysiological processes such as atherosclerosis. Monocytes which can be found in well-oxygenated blood migrate into areas with a high inflammation, such as the atherosclerotic plaque. There, they differentiate into macrophages. Interestingly, macrophages were found mainly at hypoxic sites of the plaque. Key regulators for the adaptation to hypoxia are the hypoxia-inducible factors (Hif). Therefore the aim of the present study was to investigate the regulation of the Hif-system by miRNAs during the process of monocyte differentiation. The present study shows that during the differentiation of monocytes into macrophages a dramatically change in the expression pattern of Hif-1α and Hif-2α took place. This was associated with a downregulation of microRNAs encoded by the miR-17-92 cluster. An in silico analysis of the 3'-UTR of Hif-α subunits for binding sites of miRNAs was performed using different miRNA databases in concert with a secondary structure prediction algorithm. This analysis revealed that both 3'-UTRs contain binding sites for miRNAs of the miR-17-92 cluster. Transfection of HeLa cells with miR-17 and miR-20a led to an inhibition of Hif-1α and -2α mRNA and protein expression and a lowered Hif DNA binding activity. Using a Luciferase-Reporter assay, it could be shown, that both Hif-α subunits are targeted by miR-17 and miR-20a. Furthermore, miR-overexpression in primary human macrophages demonstrates the important role of this microRNA-mediated regulation of the Hif-system for adaption of macrophages to hypoxia. In conclusion, the present study shows that the Hif-system is activated during monocyte-to-macrophage differentiation. This activation is in part mediated by a miRNA-dependent mechanism, which seems to be crucial for the adaption of macrophages to hypoxia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Evidence suggests that the anterior cingulate cortex (ACC) plays a key role in the development of posttraumatic stress disorder (PTSD). Owing to the region's highly variable patterns, three different studies of PTSD have yielded inconsistent volume reductions. Accordingly, in order to measure the correct borders and volumes, the different patterns of the ACC must be considered separately. We examined 15 victims with chronic symptoms of PTSD, all traumatized at the same accident in 1988, comparing them to 15 matched control subjects. After categorizing the ACC according to single, single segmented, double or double segmented cingulate sulcus (CS), we measured the area with a semi-automated procedure using Brain2 software. Fifty-three percent of our PTSD subjects had single segmented CS compared to 23% in control subjects and 25% in the literature. Furthermore, the four patterns showed differences in mean volume over all subjects of up to 13%. We detected no differences in absolute ACC volumes when differentiating between the patterns or in correlation with brain volumes or clinical parameters. This is the first study to differentiate ACC structure into different patterns in PTSD. We found that one pattern was overrepresented which, in turn, could signal vulnerability to develop PTSD. Because of the remarkable volume differences between patterns, future studies should categorize this highly variable region into different patterns for volumetric measurements. However, future investigations in larger samples should confirm our findings and assess to which extend alterations of ACC patterns may influence the incidence of PTSD.

The Eph receptors represent the largest family of receptor tyrosine kinases. Both Eph receptors and their ephrin ligands are cell-surface proteins, and they typically mediate cell-to-cell communication by interacting at sites of intercellular contact. The major aim of the present study was to investigate the involvement of EphA4-ephrin-A1 interaction in monocyte adhesion to endothelial cells, as this process is a crucial step during the initiation and progression of the atherosclerotic plaque. Immunohistochemical analysis of human atherosclerotic plaques revealed expression of EphA4 receptor and ephrin-A1 ligand in major cell types within the plaque. Short-time stimulation of endothelial cells with the soluble ligand ephrin-A1 leads to a fourfold increase in adhesion of human monocytes to endothelial cells. In addition, ephrin-A1 further increases monocyte adhesion to already inflamed endothelial cells. EphrinA1 mediates its effect on monocyte adhesion via the activated receptor EphA4. This ephrinA1/EphA4 induced process involves the activation of the Rho signaling pathway and does not require active transcription. Rho activation downstream of EphA4 leads to increased polymerization of actin filaments in endothelial cells. This process was shown to be crucial for the proadhesive effect of ephrin-A1. The results of the present study show that ephrin-A1-induced EphA4 forward signaling promotes monocyte adhesion to endothelial cells via activation of RhoA and subsequent stress-fiber formation by a non-transcriptional mechanism., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The development and maintenance of alcohol use disorders (AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter (WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS)-detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms., Methods: Single-voxel MR spectra optimized for Glu assessment (TE 80 ms) were acquired at 3T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption., Results: The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed., Conclusions: In contrast to the rather unspecific rise in choline-containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone., (Copyright © 2013 by the Research Society on Alcoholism.)

Experimental social neuroscience has shown that being socially excluded is processed in the anterior cingulate cortex (ACC). We hypothesize that a chronic form of social exclusion resembling one aspect of social stigmatization is associated with altered neural plasticity reflected by neurometabolic alterations in the ACC. To test this hypothesis, a highly stigmatized patient group of heroin addicts (N = 15) during opiate maintenance therapy rated a questionnaire about being stigmatized, and neurometabolic markers in the ACC were determined using (1)H MR spectroscopy. We found a negative correlation between discrimination experience and N-acetylaspartate (NAA), indicating attenuated neuron functioning in the anterior cingulate cortex in those patients reporting high discrimination experience. Furthermore, perceived stigmatization showed an association with anxiety that was mediated by NAA. Although the correlative analysis cannot give evidence for a causal relationship, the relation of NAA in the ACC and discrimination experience indicates a malfunction of the neural system involved in cognitive control over emotionally relevant social stimuli in discrimination reporting heroin addicts. Further research is needed to elucidate factors associated with chronic stigmatization.

Objectives:  Assess the efficacy of an outpatient-based interdisciplinary pain rehabilitation program for patients with active workers compensation claims., Patients:  Data were available for 101 patients, primarily with chronic low back pain (75%), who participated in the program., Methods: Treatment included a 4-week (Monday to Friday), 8-hours/day graded progressive program that included individual and group therapies (pain psychology, physical therapy, occupational therapy, relaxation training/biofeedback, aerobic conditioning, pool therapy, vocational counseling, patient education and medical management). Outcome measures included program completion status, release-to-work status, return-to-work status, total scores on the Beck depression inventory, state-trait anxiety inventory, pain catastrophizing scale, and the McGill pain questionnaire visual analogue scale (MPQ VAS). The majority of the patients (65%) graduated from the program. Pre-postoutcome data were available for those who graduated from the program. For noncompleters, last obtained MPQ VAS was compared with their initial MPQ VAS scores., Results: Of those completing the program, most patients (91%)were released to return to work; with 80% released to full-time status and 11% released to gradual return. Approximately half (49%) of the program completers returned to work. Paired-samples t-tests showed that program completers had significant reductions in depression (P = 0.000), pain-related catastrophizing (P = 0.033), and pain intensity (P = 0.000), but not in anxiety (P = 0.098). Interestingly, the last obtained (at early discharge/withdrawal) pain intensity scores (M = 70.33) were higher than at baseline (M = 61.20) in the noncompleters. This difference was not statistically significant (P = 0.127) but may be clinically meaningful., Discussion:  Our results support the efficacy of an outpatient-based 4-week interdisciplinary pain rehabilitation program in decreasing emotional distress, reducing pain intensity, and improving return-to-work status in the majority of completers in this challenging population. Patients reporting increased pain at discharge or those discharged early may have been due to operant factors., (© 2012 The Authors. Pain Practice © 2012 World Institute of Pain.)

Background: Chronic alcohol abuse leads to severe damage of the nervous system, including a change in cerebral metabolism and brain morphology. Global volume reductions of gray matter (GM) and white matter and an increase in cerebrospinal fluid (CSF) occur after severe alcohol consumption, but abstinent alcoholics also demonstrate a brain volume recovery. The aim of this study was to investigate whether volumetric amelioration takes place already within the first 2 weeks of abstinence., Methods: All 49 alcohol-dependent patients included in this study were scanned within the first 24 hours of detoxification and after 2 weeks of supervised abstinence. Amelioration of volumetric brain loss in alcohol-dependent patients has been investigated, and brain volumes have been compared with 55 healthy control subjects using whole-brain segmentation and a voxel-based morphometric approach., Results: On the first day of abstinence, the global CSF volume was larger and the GM volume was smaller in alcohol-dependent patients compared with healthy controls. The largest clusters with significant volumetric differences were in the cingulate gyrus, precentral and middle frontal gyrus, cerebellum, and insula. Already after 2 weeks of abstinence, a significant albeit partial recovery of GM volume occurred in several brain regions., Conclusions: Our results show that recovery of GM volume in alcohol-dependent patients starts within a few days after detoxification but varies between brain regions. This suggests that the general ability to recover and the rate as well as onset of the recovery diverges for different brain regions., (Copyright © 2012 by the Research Society on Alcoholism.)

This chapter summarizes the peer-reviewed literature of proton magnetic resonance spectroscopy ((1)H MRS) studies on the effects of chronic and excessive alcohol consumption in both the animal and human brain. After a brief summary of the neuropathology of alcohol use disorders (AUD), we describe the primary brain metabolites measured by in vivo (1)H MRS. We then focus on published MRS studies of animal models of alcohol dependence and of treatment-seeking humans with AUD. We also summarize the scant MRS research on the much larger fraction of treatment-naïve individuals with AUD and the similarities and discrepancies relative to treatment-seekers. It is exceedingly apparent that premorbid and/or comorbid disorders/conditions, especially chronic smoking, among individuals with AUD contribute to the considerable variability in the pattern and magnitude of neurobiological and neurocognitive abnormalities in AUD. Therefore, we also review studies on the neurobiological consequences of the combined effects of chronic drinking and smoking in AUD. Finally, as AUD is characterized by a chronically relapsing/remitting course over lifetime and identification of those at greatest risk for relapse is important, we review (1)H MRS studies on brain spectroscopic measures that contribute to the prediction of relapse in AUD. We conclude with an overall assessment of the MRS research literature on brain alcohol effects, the role of animal and human studies in understanding the disease, and discuss the need of widely integrative MRS studies of cohorts that include individuals with comorbidies that are reflective of the general population with AUD.

Background: The aging of the human brain is accompanied by changes in cortical structure as well as functional activity and variable degrees of cognitive decline. One-third of the observable inter-individual differences in cognitive decline are thought to be heritable. SCN1A encodes the sodium channel α subunit and is considered to be a susceptibility gene for several neurological disorders with prominent cognitive deficits. In a recent genome-wide association study the C allele of the SCN1A variant rs10930201 was observed to be significantly associated with poor short-term memory performance. rs10930201 was further observed to be related to differences in neural activity during a working memory task., Methods: The aim of the present study was to explore whether SCN1A modifies the vulnerability to aging processes of the human brain. Therefore we assessed the interacting effects of the SCN1A vulnerability allele rs10930201 and age in terms of brain activity and brain morphology in 62 healthy volunteers between 21 and 82 years of age., Results: In C allele carriers, activity in the right inferior frontal cortex and the posterior cingulate cortex increased with age. Moreover, exploratory analysis revealed regional effects of rs10930201 on brain structure, indicating reduced gray matter densities in the frontal and insular regions in the C allele carriers., Conclusions: Collectively, the present results suggest that the SCN1A polymorphism has modulatory effects on brain morphology and vulnerability to age-related alterations in brain activity of cortical regions that subserve working memory., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Recent evidence suggests that alterations in hippocampal glutamate and γ-aminobutyric acid (GABA) are associated with the pathomechanism of depression and treatment effects of electroconvulsive therapy (ECT). Thus, proton magnetic resonance spectroscopy (¹H MRS) at a 9.4 T animal system seems a promising tool to study underlying mechanisms since it allows for an accurate quantification of metabolites with distinction of glutamate, GABA and glutamine, as well as separation of taurine from choline., Methods: A well-validated animal model of treatment resistant depression (congenital learned helpless rats = cLH) was investigated by hippocampal in vivo ¹H MRS with and without a 1-week course of electroconvulsive shocks (ECS), an animal model of ECT, and compared to wild type (WT) animals, while saline and clomipramine injections served as additional controls., Results: Untreated cLH rats showed significantly lower glucose and higher taurine concentrations compared to WT animals. Besides alterations on these metabolites, ECS increased glutamate in WT and cLH and choline in cLH rats. Moreover, correlations between glutamate and GABA concentrations with learned helpless behaviour were revealed., Conclusions: These findings support the idea of disordered hippocampal metabolism in an animal model of treatment resistant depression and suggest an early impact of ECS on MR-detectable hippocampal metabolites.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Despite the beneficial impact on the reduction of addictive behavior, opiate maintenance therapy has been associated with negative effects on cognitive and psychomotor functioning. This may limit the outcome of behavioral strategies, rehabilitation, and reintegration into society. The objective of the study at hand was to investigate the effect of buprenorphine and methadone maintenance therapy on visuospatial working memory performance., Methods: Visuospatial working memory performance of 13 patients, receiving either methadone or buprenorphine, was investigated and compared to 13 control participants using functional magnetic resonance imaging., Results: Altered neuronal activation was found in the patients, including brain areas associated with working memory performance and addiction. Behavioral performance on the visuospatial working memory task was similar across groups., Conclusions: Results indicate that there are no robust impairments of visuospatial capabilities in patients on opiate maintenance, but altered neuronal activation in working memory-related brain areas-due to chronic presence of opiates-may limit cognitive performance on complex cognitive tasks. Factors in therapeutic strategies that may support rehabilitation of patients' cognitive performance are discussed.

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., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Pre-clinical research indicates that opioids reduce extracellular glutamate in acute opioid treatment, whereas during withdrawal, glutamatergic neurotransmission is increased and withdrawal symptoms can be blocked by glutamate receptor antagonists. The glutamate hypothesis of addiction suggests that withdrawal-associated hyperglutamatergic states destabilize the glutamatergic system chronically and contribute to relapse. magnetic resonance spectroscopy at three tesla optimized for glutamate assessment (TE 80 ms) was performed in the anterior cingulate gyrus (ACC) and frontal white matter (fWM) of 17 opiate-dependent patients during opiate maintenance therapy and 20 healthy controls. Controlling for age and gray matter content, glutamate in the ACC was positively associated with the number of previous withdrawals. For glutamate + glutamine (Glx), a significant group-age interaction was found. Whereas Glx declines with age in healthy controls, Glx increases with age in opiate-dependent patients. The number of previous withdrawals did not correlate with age. In fWM spectra, increased Cho concentrations were observed in opiate-dependent patients. Both new findings, the positive correlation of glutamate and previous withdrawals and increasing Glx with age in contrast to an age-dependent Glx decrease in controls indicate a destabilization of the glutamate system in opiate-dependent patients and support the glutamate hypothesis of addiction. Increased Cho concentrations in fWM corroborate findings of WM abnormalities in opioid-dependent subjects., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Background: Alcohol abuse has detrimental effects on cerebral function, metabolism, and volume. Some of these effects were found to be at least partially reversible with continued abstinence. Furthermore, it has been reported that there are different effects of alcohol on brain volumes for women compared with men, but the results concerning the interaction between alcohol dependence and gender are inconsistent. With this study, we aimed to further investigate this question by examining the global gray matter (GM) and white matter (WM) changes as well as regional and local GM changes detected by voxel-based morphometry (VBM) in male and female alcoholic patients a few weeks after detoxification and the corresponding changes in a subgroup of these patients 3 months later., Methods: A total of 50 patients, consecutively admitted for alcohol withdrawal treatment, participated in this study and were followed up for at least 3 months into abstinence. High-resolution structural images were processed with SPM8 using an optimized VBM protocol., Results: Global cerebrospinal fluid (CSF) volume was increased and WM and GM volume decreased equally in male and female patients. A gender by diagnosis interaction was found neither for global nor for regional volumes or VBM data. VBM whole brain analysis yielded a significant GM volume loss in the patient group in the cingulate gyrus and the insula in both hemispheres. Region of interest analysis for the initial and 3 months follow-up scans yielded significant gains in regional volumes, particularly the cingulate gyrus and the insula in the group of abstinent patients, whereas no volume change at all is found in the patients who had relapsed., Conclusions: Our study confirms widespread cerebral volume loss in recently detoxified alcoholics. The effects of alcohol dependence seem to have equally adverse effects on brain morphometry in males and females., (2011 by the Research Society on Alcoholism.)

Background: Chronic cannabis use has been associated with memory deficits and a volume reduction of the hippocampus, but none of the studies accounted for different effects of tetrahydrocannabinol (THC) and cannabidiol (CBD)., Methods: Using a voxel based morphometry approach optimized for small subcortical structures (DARTEL) gray matter (GM) concentration and volume of the hippocampus were measured in 11 chronic recreational cannabis users and 13 healthy controls, and correlated with THC and CBD from hair analyses. GM volume was calculated by modulating VBM using Jacobian determinants derived from the spatial normalization., Results: Cannabis users showed lower GM volume located in a cluster of the right anterior hippocampus (P(uncorr)=0.002; effect size Cohen's d=1.34). In a regression analysis an inverse correlation of the ratio THC/CBD with the volume of the right hippocampus (P(uncorr) p<0.001, Cohen's d=3.43) was observed. Furthermore Cannabidiol correlated positively with GM concentration (unmodulated VBM data), but not with GM volume (modulated VBM) in the bilateral hippocampus (P=0.03 after correction for hippocampal volume; left hippocampus Cohen's d=4.37 and right hippocampus 4.65)., Conclusions: Lower volume in the right hippocampus in chronic cannabis users was corroborated. Higher THC and lower CBD was associated with this volume reduction indicating neurotoxic effects of THC and neuroprotective effects of CBD. This confirms existing preclinical and clinical results. As a possible mechanism the influence of cannabinoids on hippocampal neurogenesis is suggested., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β42 (Aβ42), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial function, the correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production.

Aims: During the development of drug addiction, initial hedonic effects decrease when substance use becomes habitual and ultimately compulsive. Animal research suggests that these changes are represented by a transition from prefrontal cortical control to subcortical striatal control and within the striatum from ventral to dorsal domains of the striatum, but only limited evidence exists in humans. In this study we address this hypothesis in the context of alcohol dependence., Design, Setting and Participants: Non-abstinent heavy social drinkers (n = 21, 5.0 ± 1.5 drinks/day, 13 of them were alcohol-dependent according to DSM-IV) and light social drinkers (n = 10, 0.4 ± 0.4 drinks/day) were examined., Measurements: We used a cue-reactivity functional magnetic resonance imaging (fMRI) design during which pictures of alcoholic beverages and neutral control stimuli were presented., Findings: In the dorsal striatum heavy drinkers showed significant higher activations compared to light drinkers, whereas light social drinkers showed higher cue-induced fMRI activations in the ventral striatum and in prefrontal areas compared to heavy social drinkers [region of interest analyses, P < 0.05 false discovery rate (FDR)-corrected]. Correspondingly, ventral striatal activation in heavy drinkers correlated negatively with obsessive-compulsive craving, and furthermore we found a positive association between cue-induced activation in the dorsal striatum and obsessive-compulsive craving in all participants., Conclusions: In line with our hypothesis we found higher cue-induced activation of the ventral striatum in social compared to heavy drinkers, and higher dorsal striatal activation in heavy drinkers. Increased prefrontal activation may indicate that social drinkers activate cortical control when viewing alcohol cues, which may prevent the development of heavy drinking or alcohol dependence. Our results suggest differentiating treatment research depending on whether alcohol use is hedonic or compulsive., (© 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.)

Alcohol drinking is highly prevalent in many cultures and contributes to the global burden of disease. In fact, it was shown that alcohol constitutes 3.2% of all worldwide deaths in the year 2006 and is linked to more than 60 diseases, including cancers, cardiovascular diseases, liver cirrhosis, neuropsychiatric disorders, injuries and foetal alcohol syndrome. Alcoholism, which has been proven to have a high genetic load, is one potentially fatal consequence of chronic heavy alcohol consumption, and may be regarded as one of the most prevalent neuropsychiatric diseases afflicting our society today. The aim of the integrated genome research network 'Genetics of Alcohol Addiction'--which is a German inter-/trans-disciplinary life science consortium consisting of molecular biologists, behavioural pharmacologists, system biologists with mathematicians, human geneticists and clinicians--is to better understand the genetics of alcohol addiction by identifying and validating candidate genes and molecular networks involved in the aetiology of this pathology. For comparison, addictive behaviour to other drugs of abuse (e.g. cocaine) is studied as well. Here, we present an overview of our research consortium, the current state of the art on genetic research in the alcohol field, and list finally several of our recently published research highlights. As a result of our scientific efforts, better insights into the molecular and physiological processes underlying addictive behaviour will be obtained, new targets and target networks in the addicted brain will be defined, and subsequently, novel and individualized treatment strategies for our patients will be delivered., (© 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.)

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.

Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimer's disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies.

Background: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults., Methods: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive-Compulsive Drinking Scale-OCDS), alcohol use of the last 90 days, and general intelligence., Results: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants., Conclusions: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts.

Background: Emotional dysfunction in a frontolimbic network has been implicated in the pathophysiology of borderline personality disorder (BPD). The amygdala is a key region of the limbic system and plays an important role in impulsivity, affect regulation, and emotional information processing and thus is likely related to BPD symptoms. Alterations of the metabolism in the amygdala might be of interest for understanding the pathophysiology of BPD. However, the amygdala is a difficult region from which to acquire magnetic resonance spectra. We implemented a method for proton magnetic resonance spectroscopy ((1)H MRS) at 3.0 T in which we acquire data within only the small amygdala. The purpose of this study was to determine alterations of the metabolism in the amygdala in BPD patients., Methods: Twenty-one unmedicated BPD patients and 20 age-matched healthy control participants underwent (1)H MRS to determine neurometabolite concentrations in the left amygdala. All participants underwent psychometric assessments., Results: Significantly reduced total N-acetylaspartate (tNAA) and total creatine (tCr) concentrations in the left amygdala of patients with BPD were found. BPD patients with comorbid posttraumatic stress disorder (PTSD) showed lower levels of tCr compared with BPD patients without PTSD and healthy control subjects. No significant correlations between neurochemical concentrations and psychometric measures were found., Conclusions: Decreased tNAA and tCr might indicate disturbed affect regulation and emotional information processing in the amygdala of BPD patients. These findings are consistent with many functional and structural neuroimaging studies and may help to explain the greater emotional reactivity of BPD patients., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Although brain structural deficits have been repeatedly associated with bipolar disorder (BD), inconsistency in morphometric results has been a feature of neuroimaging studies. We hypothesize that this discrepancy is related to the heterogeneity of BD, and examine the question of whether or not more homogeneous clinical subgroups display a more coherent pattern of morphometric abnormalities., Methods: In a case-control design, we examined differences in gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) concentration in 42 BD patients and 42 healthy matched controls using optimized voxel-based morphometry (VBM). Subgroup analyses of patients with a lifetime history of psychotic symptoms (BDP, n=30) and patients with mood-incongruent psychotic symptoms in the form of persecutory delusions (BDPD, n=15) were performed to accord with previous genetic findings., Results: Analysis of the total BD sample was largely inconclusive, but the BDPD patient subgroup displayed a widespread pattern of significant decreases in GM concentration in the dorsolateral prefrontal (DLPFC), temporal and cingulate cortices, and a significant CSF increase in the adjacent outer ventricular sulci. Comparison of BDPD patients versus BD and BDP patients without persecutory delusions revealed a significant GM decrease in the left DLPFC for the former group., Conclusions: BDPD show pronounced structural abnormalities of the prefrontal and temporal lobes which are similar to the deficits previously reported for schizophrenia (SCZ). Our findings suggest that stratification based solely on psychotic symptoms is insufficient for the differentiation of BD into biologically meaningful subgroups, but also question the pathophysiological validity of the dichotomy in classification between schizophrenia and BD.

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit-specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory-related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit-specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication., (2009 Wiley-Liss, Inc.)

Magnetic resonance spectroscopy enables the in vivo analysis of certain aspects of brain biochemistry. Reduced N-acetylaspartate in key regions of schizophrenia has been reported repeatedly but not without controversy. Our objective is to investigate whether reduced N-acetylaspartate concentrations determined without correction for individual T2 relaxation time (referred to as 'apparent tNAA concentration') are due to a reduced absolute N-acetylaspartate concentration or to altered relaxation properties. For this purpose we measured absolute concentrations while evaluating individual T2 relaxation times. We evaluated the metabolite concentrations and metabolite/water relaxation times of a frontal white matter voxel from 23 patients who met DSM-IV criteria for schizophrenia and 29 healthy control subjects with similar age at a 3 T magnetic resonance scanner. A significantly reduced N-acetylaspartate concentration as well as shortened N-acetylaspartate's T2 relaxation time in the schizophrenic patient group was found. The apparent N-acetylaspartate concentration difference between healthy controls and patients with schizophrenia increased with the echo time due to a decreased N-acetylaspartate's T2 in the schizophrenic group. No group difference was found for any other metabolite concentration or metabolite/brain water relaxation time. These findings of reduced N-acetylaspartate as well as shortened N-acetylaspartate's T2 relaxation time give further evidence for microstructural white matter changes in schizophrenia. Furthermore, they elucidate why reports of a reduced N-acetylaspartate concentration in schizophrenia were not always corroborated.

Comparison of positive and negative naturally read adjectives to neutral adjectives yielded an overlapping higher BOLD response in the occipital and the orbitofrontal cortex (gyrus rectus). Superior medial frontal gyrus and posterior cingulate gyrus showed higher BOLD response to negative adjectives and inferior frontal gyrus to positive adjectives. The overlap of activated regions and lack of pronounced distinct regions supports the assumption that the processing of negative and positive words mainly takes place in overlapping brain regions.