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This review article explores the intricate relationship between nutrition, metabolism, brain function and mental health. It highlights two key complementary models: the energy balance model and the more comprehensive carbohydrate-insulin model, to understand the development of obesity and metabolic dysfunctions. It particularly focuses on the role of dopamine in dietary regulation and insulin in the brain, both of which are crucial in the pathogenesis of neurodegenerative and stress-associated mental disorders. Additionally, the significance of sleep and dietary habits, such as medically assisted calorie restriction for mental health and the concept of "brain food" are described. These findings emphasize the importance of nutritional medicine in psychiatry and psychotherapy and the consideration of metabolic states for the prevention and treatment of mental and neurodegenerative diseases., (© 2024. The Author(s).)

Objectives: Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes., Methods: 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined., Results: Patients with blood pressure <120mmHg showed higher depression severity ( p  = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures ( p  = 0.004). Na + /K + ratio was positively and K + -concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively ( p  < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes., Conclusions: We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K + or high Na + /K + ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; https://www.clinicaltrials.gov/ct2/results?term=NCT00974155.

Although the currently available antidepressants are well established in the treatment of the major depressive disorder (MDD), there is strong variability in the response of individual patients. Reliable predictors to guide treatment decisions before or in an early stage of treatment are needed. DNA-methylation has been proven a useful biomarker in different clinical conditions, but its importance for mechanisms of antidepressant response has not yet been determined. 80 MDD patients were selected out of >500 participants from the Early Medication Change (EMC) cohort with available genetic material based on their antidepressant response after four weeks and stratified into clear responders and age- and sex-matched non-responders (N = 40, each). Early improvement after two weeks was analyzed as a secondary outcome. DNA-methylation was determined using the Illumina EPIC BeadChip. Epigenome-wide association studies were performed and differentially methylated regions (DMRs) identified using the comb-p algorithm. Enrichment was tested for hallmark gene-sets and in genome-wide association studies of depression and antidepressant response. No epigenome-wide significant differentially methylated positions were found for treatment response or early improvement. Twenty DMRs were associated with response; the strongest in an enhancer region in SORBS2, which has been related to cardiovascular diseases and type II diabetes. Another DMR was located in CYP2C18, a gene previously linked to antidepressant response. Results pointed towards differential methylation in genes associated with cardiac function, neuroticism, and depression. Linking differential methylation to antidepressant treatment response is an emerging topic and represents a step towards personalized medicine, potentially facilitating the prediction of patients' response before treatment., (© 2022. The Author(s).)

One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Background: Rheumatic and mental disorders are common and affect each other. The comorbidities are often diagnosed too late or not at all but cause considerable suffering for those affected and have a negative effect on the health-related quality of life and therapeutic success., Objectives: Is there any evidence regarding common pathophysiological mechanisms and how can they be considered in terms of therapy?, Methods: Recent findings, reviews and basic literature are analyzed and an update is presented and discussed., Results: The current data suggest a mutual influence of the factors stress and inflammation both in depressive disorders, anxiety disorders and chronic pain, as well as in diseases of the rheumatic type. There is a close relationship between immunological and neuronal processes that bi-directionally regulate the individual's stress response., Conclusions: For sufficient therapy the establishment of an interdisciplinary treatment concept in clinical everyday life is to be striven for. In addition to rheumatic treatment, this should include a multimodal approach to both pharmacological and psycho-socio-therapeutic components. In particular, potential interactions must be taken into account.

Objectives: Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF). Methods: In 110 MDD patients with executive dysfunctions (percentile <16), executive functions and plasma BDNF levels were analysed at baseline, and days 14 and 56 of an antidepressant treatment. BDNF exon IV and P11 methylation status was studied at baseline. Results: Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions ( F 1 = 10.18; P  = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance. Conclusions: Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Background: Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy., Methods: Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method., Results: The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates., Conclusions: Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD., Trial Registration: clinicaltrials.gov Identifier: NCT00974155 . Registered at the 10th of September 2009. Retrospectively registered.

We report on a 54-year-old patient who described a progressive anxiety disorder additionally recurrent sight disorders associated with room-tilt illusions and subjective visual field defects. She also reported disturbances of concentration and attention and of a modified typeface accompanied by difficulty in writing with an increase of grammatical errors. Based on the case, the relevant anamnestic and clinical data, the neuropsychological and neuroimaging findings and also differential diagnosis of the posterior cortical atrophy, a rare neurodegenerative disease, will be discussed., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question., (Copyright © 2016 Elsevier B.V. and ECNP. 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.

Objective: In daily practice of psycho-pharmacotherapy most patients are under polypharmacy which may result in potentially harmful drug-drug interactions. Therefore, we investigated if the risk of drug-drug interactions can be reduced by a consultant clinical pharmacist for the physicians on psychiatric wards., Methods: Drug-drug-interactions and adverse drug reactions of patients on 2 psychiatric intensive care units were investigated retrospectively in 2008 and 2009. Before the second investigation period, a special training was performed and during this period a pharmacist supported the physicians regarding drug therapy., Results: After the introduction of a pharmacist on the ward and 2 teaching lessons relevant drug interactions were reduced by 78 % (p < 0.001), the number of all interactions by 44 % (p < 0.001). The total number of drug interactions decreased by the training sessions, which were offered shortly before starting the second observation period, from 3.4 interactions/patients in 2008 to 2.2 interactions/patients in 2009 (p < 0.04)., Conclusion: A clinical pharmacist on the ward can contribute to a higher drug therapy safety in psychiatric wards. An interdisciplinary approach can relieve the physicians' daily work. The drug therapy can be improved by continuous teaching sessions about drug interactions., (© Georg Thieme Verlag KG Stuttgart · New York.)

Psychiatric diseases and comorbidity have increased over the past years. Commonly used psychotropic drugs contain a high risk of drug interactions and adverse drug events (ADE). With a frequency of 10-12% psychotropic drugs are, among all pharmaceuticals, the most common cause of hospitalisation due to ADE. During a hospital stay the application of psychotropic drugs can also lead to adverse drug events--sometimes due to drug interactions. Currently, ADEs and drug interactions are the most frequent cause of death for in-patients (18% of all causes of death) with an overall mortality of 0.95%. As studies have shown, hospitals as well as insurers could save a considerable amount of resources by implementing a system with on-ward pharmacists, hereby reducing ADE and re-hospitalisation rates. In recent studies a large amount of current ADEs were rated as preventable. Patient impairment due to ADE is leading to an increase in liability cases with an expected 5% increase of compensation payments in 2011. To evaluate these ADE-related cases, a pharmaceutical assessment should be included in the expert trials, especially since a lack of awareness of medication errors is prevalent. When aiming towards a successful drug therapy, physicians must also consider that cheaper substances may often have an unfavourable drug interaction profile.

Background: In Major Depressive Disorder (MDD), treatment outcomes with currently available strategies are often disappointing. Therefore, it is sensible to develop new strategies to increase remission rates in acutely depressed patients. Many studies reported that true drug response can be observed within 14 days (early improvement) of antidepressant treatment. The identical time course of symptom amelioration after early improvement in patients treated with antidepressants of all classes or with placebo strongly suggests a common biological mechanism, which is not specific for a particular antidepressant medication. However, the biology underlying early improvement and final treatment response is not understood and there is no established biological marker as yet, which can predict treatment response for the individual patient before initiation or during the course of antidepressant treatment. Peripheral blood markers and executive functions are particularly promising candidates as markers for the onset of action and thus the prediction of final treatment outcome in MDD., Methods/design: The present paper presents the rationales, objectives and methods of a multi-centre study applying close-meshed repetitive measurements of peripheral blood and neuropsychological parameters in patients with MDD and healthy controls during a study period of eight weeks for the identification of biomarkers for the onset of antidepressants' action in patients with MDD. Peripheral blood parameters and depression severity are assessed in weekly intervals from baseline to week 8, executive performance in bi-weekly intervals. Patients are participating in a randomized controlled multi-level clinical trial, healthy controls are matched according to mean age, sex and general intelligence., Discussion: This investigation will help to identify a biomarker or a set of biomarkers with decision-making quality in the treatment of MDD in order to increase the currently disappointing remission rates of antidepressant treatment.

Structural remodeling has been observed in the human brain over periods of weeks to months, but the molecular mechanisms governing this process remain incompletely characterized. Using multimodal pharmaco-neuroimaging, we found that acute D2 receptor blockade induced reversible striatal volume changes and structural-functional decoupling in motor circuits within hours; these alterations predicted acute extrapyramidal motor symptoms with high precision. Our findings suggest a role for D2 receptors in short-term neural plasticity and identify a potential biomarker for neuroleptic side effects in humans.

Background: Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward., Methods: We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers., Results: Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward., Conclusions: This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction., (Copyright 2010 Society of Biological Psychiatry. All rights reserved.)

Basic and clinical neurosciences have effectively advanced research on aetiology, pathogenesis and therapy options of psychiatric disorders. The objectives of the present short review were to summarise the key findings regarding the neurobiology of major depressive disorder (MDD) on the gene, cell as well as system level. Consistent with structural findings, which report alterations in regions of emotionally relevant networks of the brain in depressive disorders, findings of functional studies point to changes in an ordered interaction of ventral-limbic and dorsal-neocortical regions of the brain. Genetic and stress vulnerabilities as well as social rhythm disrupting interact to initiate a cascade of neurobiological alterations that disrupt this dynamic system. On the cellular level, monoamine as well as glutamate neurotransmission, circadian rhythm disturbance, glucocorticoids, inflammatory cytokines and brain-derived growth factors are relevant mediators of these pathological alterations. Progressive effects of recurrent and chronic MDD may then lead to further structural and functional abnormalities. Thus, treatment providers are directed to recog-nise that the factors that may initiate an MDD episode and those that maintain the illness are likely to be different. Given these long-term consequences, an essential objective of treatment must be to restore as early as possible normative functioning and prevent further neurobiological structural alterations.

Background: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome., Methods/design: The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17

Recent studies have indicated that there are complex interactions between activation changes and structural alterations in aging. To investigate this issue, we combined functional with structural MRI in healthy old and young women. When contrasting correct with incorrect recognition of words, we found decreased right prefrontal as well as increased middle temporal gyrus (MTG) activation in the older adults. Performance was correlated with prefrontal activation in younger and with MTG activation in older subjects, respectively. Furthermore, frontal decrease and MTG increase were associated with reduced gray matter density of the prefrontal cortex (PFC) and the medial temporal lobe (MTL) across young and old subjects. Within older adults, however, left MTG activation and structural integrity were positively correlated. Thus, our data indicates a two-step structure-function interaction of correct retrieval in healthy aging. First, age-related reduced gray matter density is associated with diminished frontal activation, as well as with compensatory activation in the MTG. Second, compensatory utilization of additional resources is dependent upon a certain degree of structural integrity in the PFC and the MTL.

The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation.

Patients with first-episode schizophrenia appear to respond to lower doses of neuroleptics, and to be more sensitive to developing extrapyramidal side-effects. The authors therefore compared in such patients the efficacy and extrapyramidal tolerability of comparatively low dosages of the atypical neuroleptic risperidone and of the conventional neuroleptic haloperidol. Risperidone was hypothesized to have better extrapyramidal tolerability and efficacy in treating negative symptoms. Patients were randomly assigned under double-blind conditions to receive risperidone (n=143) or haloperidol (n=146) for 8 wk. The primary efficacy criterion was the estimated difference in the mean change in the Positive and Negative Symptom Scale (PANSS) negative score between treatment groups; secondary efficacy criteria were changes on the PANSS total score and other PANSS subscores, and several other measures of psychopathology and general functioning. The primary tolerability criterion was the difference in baseline-adjusted occurrence rates of extrapyramidal side-effects measured with the Simpson-Angus Scale (SAS) compared between treatment groups. The main hypothesis was that risperidone would be superior in terms of improving negative symptoms and lowering the risk of extrapyramidal symptoms. Secondary tolerability criteria were the other extrapyramidal symptoms, measured with the Hillside Akathisia Scale (HAS) and the Abnormal Involuntary Movement Scale (AIMS). The average mean daily doses were 3.8 mg (s.d.=1.5) for risperidone and 3.7 mg (s.d.=1.5) for haloperidol. There were similar, significant improvements in both treatment groups in the primary and secondary efficacy criteria. At week 8 nearly all scores of extrapyramidal side-effects indicated a significantly higher prevalence of extrapyramidal side-effects with haloperidol than with risperidone [SAS: risperidone 36.5% of patients; haloperidol 51.5% of patients; likelihood ratio test, chi2(1)=7.8, p=0.005]. There were significantly fewer drop-outs [risperidone n=55, drop-out rate=38.5%; haloperidol n=79, drop-out rate=54.1%, chi2(1)=7.1, p=0.009] and a longer non-discontinuation time [risperidone: average of 50.8 d to drop-out; haloperidol: average of 44.0 d to drop-out; log rank test, chi2(1)=6.4, p=0.011] in the risperidone group. Risperidone and haloperidol appear to be equally effective in treating negative and other symptoms of first-episode schizophrenia. Risperidone has better extrapyramidal tolerability and treatment retention rate than the equivalent dose of haloperidol in these patients.

Objective: Amygdala volume has been associated with drug craving in cocaine addicts, and amygdala volume reduction is observed in some alcohol-dependent subjects. This study sought an association in alcohol-dependent subjects between volumes of reward-related brain regions, alcohol craving, and the risk of relapse., Method: Besides alcohol craving, the authors assessed amygdala, hippocampus, and ventral striatum volumes in 51 alcohol-dependent subjects and 52 age- and education-matched healthy comparison subjects after detoxification. After imaging and clinical assessment, patients were followed for 6 months and alcohol intake was recorded., Results: Alcohol-dependent subjects showed reduced amygdala, hippocampus, and ventral striatum volumes and reported stronger craving in relation to healthy comparison subjects. However, only amygdala volume and craving differentiated between subsequent relapsers and abstainers. A significant decrease of amygdala volume in alcohol-dependent subjects was associated with increased alcohol craving before imaging and an increased alcohol intake during the 6-month follow-up period., Conclusions: These findings suggest a relationship between amygdala volume reduction, alcohol craving, and prospective relapse into alcohol consumption.

Background: Functional imaging studies using emotional stimuli have suggested a role for the ventromedial prefrontal cortex (vmPFC) in the pathophysiology of midlife depression. In contrast, the neural correlates of late-life depression (LLD), a highly prevalent but under-recognized clinical entity in which age-related brain changes might influence disease mechanisms, have not been studied in great detail. With an emotional evaluation task, we conducted a longitudinal study of vmPFC functioning in a homogeneous sample of elderly antidepressant naive female outpatients with isolated, first diagnosed mild to moderate depressive symptoms., Methods: Neural responses of the vmPFC to the emotional evaluation of positive, negative, and neutral words were measured with functional magnetic resonance imaging (fMRI) in LLD (n = 13) and healthy older subjects (n = 13). All patients were rescanned after approximately 7 months., Results: Although there were no performance differences, compared with healthy volunteers, LLD patients showed a decreased response to negative compared with positive stimuli in the vmPFC. This altered pattern was positively correlated with symptom severity. At follow-up, the attenuated neural response in the vmPFC had "normalized," accompanied by a significant improvement in symptoms., Conclusions: These findings indicate vmPFC dysfunction as a biological state marker of geriatric depression. Furthermore, our data underline the pathological significance of mild to moderate LLD and highlight the usefulness of functional neuroimaging for evaluating remission processes in this specific depression subtype.

Purpose: Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects., Methods: Subjects were investigated with positron emission tomography and [(18)F]DOPA for measurements of dopamine synthesis capacity and [(18)F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [(18)F]DOPA net influx constant K(app)(in)/[(18)F]DMFP-binding potential (BP&#95;ND) in the ventral and dorsal striatum., Results: The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio., Conclusions: The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional divisions of the striatum modulates processing of affective stimuli in specific cortical areas.

As shown in non-human primate and human fMRI studies the probability and magnitude of anticipated rewards modulate activity in the mesolimbic dopaminergic system. Importantly, non-human primate data have revealed that single dopaminergic neurons code for both probability and magnitude of expected reward, suggesting an identical system. Using a guessing task that allowed the independent assessment of the factors probability and magnitude we were able to assess the impact of reward probability and magnitude in ventral striatal subregions in a large sample (n=98). We observed more anterior and lateral peak activation foci in the ventral striatum for reward probability and a more posterior and medial activation peak for reward magnitude, suggesting a functional segregation at the mesoscopic level. Importantly, this functional bias observed for the group average was also tested in each individual subject, allowing for proper random effects inference for the spatial dissociation. Taken together, our data point toward a functional dissociation of neuronal assemblies suggesting that certain populations of neurons are more sensitive to expected reward probability and other populations are more sensitive to reward magnitude.

Background: Oxytocin is known to reduce anxiety and stress in social interactions as well as to modulate approach behavior. Recent studies suggest that the amygdala might be the primary neuronal basis for these effects., Methods: In a functional magnetic resonance imaging study using a double-blind, placebo-controlled within-subject design, we measured neural responses to fearful, angry, and happy facial expressions after intranasal application of 24 IU oxytocin compared with placebo., Results: Oxytocin reduced right-sided amygdala responses to all three face categories even when the emotional content of the presented face was not evaluated explicitly. Exploratory whole brain analysis revealed modulatory effects in prefrontal and temporal areas as well as in the brainstem., Conclusions: Results suggest a modulatory role of oxytocin on amygdala responses to facial expressions irrespective of their valence. Reduction of amygdala activity to positive and negative stimuli might reflect reduced uncertainty about the predictive value of a social stimulus and thereby facilitates social approach behavior.

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.

Background: A polymorphism of the human serotonin transporter gene (SCL6A4) has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers. However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers., Methods: Functional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men., Results: Amygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions., Conclusions: This finding suggests that s carriers show stronger amygdala reactivity to stimuli and contexts that are relatively uncertain, which we propose are stressful.

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

Chronic alcohol consumption is associated with neural damage that manifests in deficits in information processing. Previous studies evaluated higher cognitive functions such as working memory, but basic sensory information processing circuits have never been investigated before. Therefore, we applied a simple visual and acoustic stimulation paradigm in this functional magnetic resonance imaging (fMRI) pilot study. Nine recently detoxified male alcohol-dependent patients and nine healthy volunteers were presented a well-established 6-Hz checkerboard and auditory stimuli in the form of drumbeats in a block-design fMRI paradigm. During visual and acoustic stimulation, alcoholics and controls activated widespread occipital and temporal brain areas, as well as parts of the dorsolateral prefrontal cortex and thalamus. In a comparison of the stimulation-induced activation of alcoholics and controls, the alcoholics showed a significantly lower blood oxygen level dependent (BOLD) signal in an extended bilateral occipital area (P < 0.001) as compared with healthy controls. In no region was the BOLD signal significantly higher in the alcohol-dependent subjects compared with controls. The reason for the new finding of a highly significant lower activation of the occipital cortex is unclear. It is in line with studies of neuropsychological tests in recently detoxified alcohol-dependent patients that also reported deficits in visual abilities. Attention deficits or a persisting neuronal alteration in the first weeks of alcohol abstinence may have contributed to this result.

Together with a detailed behavioral analysis, simultaneous measurement of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) permits a better elucidation of cortical pain processing. We applied painful electrical stimulation to 6 healthy subjects and acquired fMRI simultaneously with an EEG measurement. The subjects rated various stimulus properties and the individual affective state. Stimulus-correlated BOLD effects were found in the primary and secondary somatosensory areas (SI and SII), the operculum, the insula, the supplementary motor area (SMA proper), the cerebellum, and posterior parts of the anterior cingulate gyrus (ACC). Perceived pain intensity was positively correlated with activation in these areas. Higher unpleasantness rating was associated with suppression of activity in areas known to be involved in stimulus categorization and representation (ventral premotor cortex, PCC, parietal operculum, insula) and enhanced activation in areas initiating, propagating, and executing motor reactions (ACC, SMA proper, cerebellum, primary motor cortex). Concordant dipole localizations in SI and ACC were modeled. Using the dipole strength in SI, the network was restricted to SI. The BOLD signal change in ACC was positively correlated to the individual dipole strength of the source in ACC thus revealing a close relationship of BOLD signal and possibly underlying neuronal electrical activity in SI and the ACC. The BOLD signal change decreased in SI over time. Dipole strength of the ACC source decreased over the experiment and increased during the stimulation block suggesting sensitization and habituation effects in these areas.

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

Background: Although the major principles of dopamine (DA) signaling have been well described previously, its precise modulatory impact on the prefrontal cortex (PFC) in humans is poorly understood. Two major neurophysiological models propose segregated functional circuits on the systems level as well as D(1) and D(2) receptor-dependent processing states on the cellular level (two-state model)., Methods: We examined the predictive validity of these models in 10 healthy male volunteers with a haloperidol challenge (HLP). Cortico-striatal-thalamo-cortical (CSTC) motor loop functions were examined during functional magnetic resonance imaging (fMRI) with a sequential finger opposition task. Neuropsychological implications of the two-state model were evaluated with a test battery of D(1)- or D(2)-sensitive prefrontal measures., Results: Analysis of fMRI data revealed a significant HLP-induced blood oxygen level dependent-signal decrease in the sensorimotor striatum and a lateralized activation loss of ipsilateral higher order motor cortices and contralateral cerebellum. Neuropsychological evaluation demonstrated a preferential impairment of D(2)-sensitive functions, whereas D(1) or non-dopaminergic domains were unaffected., Conclusions: Our data support the hypothesis that mesocortical D(1) and D(2) receptors exert differential influences in the PFC for cognitive function, but the nigrostriatal CSTC network model for the motor domain could not be confirmed.

The present study aimed to shed light on the neural underpinnings of high vs. low memory confidence. To dissociate memory confidence from accuracy, the Deese-Roediger McDermott (DRM) paradigm was employed, which - compared to other memory paradigms - elicits a rather evenly distributed number of high-confident responses across all possible combinations of memory response types (i.e., hits, false alarms, correct rejections, and misses). In the standard DRM procedure, subjects are first presented with thematically interrelated word lists at encoding, which at recognition are intermixed with related and unrelated distractor items. The signature of a false memory or DRM effect is an increased number of high-confident false memories, particularly for strongly related lure items. For the present study, 17 female subjects were administered a verbal DRM task, whereas neural activation was indexed by fMRI. The behavioral analyses confirmed the expected false memory effect: subjects made more high-confident old responses (both hits and false alarms) the closer the items were related to the central list theme. Across all four memory response types, an increase in confidence at recognition was associated with bilateral activation in the anterior and posterior cingulate cortex along with medial temporal regions. In contrast, increments in doubt were solely related to activation in the superior posterior parietal cortex. To conclude, the study provides some evidence for dissociable systems for confidence and doubt.

Midbrain dopaminergic neurons projecting to the ventral striatum code for reward magnitude and probability during reward anticipation and then indicate the difference between actual and predicted outcome. It has been questioned whether such a common system for the prediction and evaluation of reward exists in humans. Using functional magnetic resonance imaging and a guessing task in two large cohorts, we are able to confirm ventral striatal responses coding both reward probability and magnitude during anticipation, permitting the local computation of expected value (EV). However, the ventral striatum only represented the gain-related part of EV (EV+). At reward delivery, the same area shows a reward probability and magnitude-dependent prediction error signal, best modeled as the difference between actual outcome and EV+. In contrast, loss-related expected value (EV-) and the associated prediction error was represented in the amygdala. Thus, the ventral striatum and the amygdala distinctively process the value of a prediction and subsequently compute a prediction error for gains and losses, respectively. Therefore, a homeostatic balance of both systems might be important for generating adequate expectations under uncertainty. Prevalence of either part might render expectations more positive or negative, which could contribute to the pathophysiology of mood disorders like major depression.

The main goal of the present fMRI-study was to identify the neural correlates underlying the successful encoding of words which can subsequently be freely recalled or recognized but not recalled. We were particularly interested in common as well as distinct neural substrates of both retrieval modes. To assess qualitatively differently activated brain areas, categorical subsequent memory analyses were applied. In addition, we used linear parametric modulation to detect brain regions associated with "memory-strength". Our findings suggest that the successful verbal encoding of words, which were recognized but not recalled relies on a subset of the regions engaged during successful encoding of freely recalled words. Furthermore, it seems to be dependent on the magnitude of relational binding in a prefrontal-hippocampal circuit whether a word can subsequently be recalled freely or only recognized.

Unlabelled: The hippocampus is discussed as one of the key regions in the pathogenesis of Posttraumatic Stress Disorder (PTSD). MRI results concerning the volume of the hippocampus are, however, inconsistent. This may be due to the heterogeneity of patients' traumata or postprocessing of the imaging data. To overcome these problems, the present study investigates volume changes in well-characterized chronic PTSD patients in comparison to controls using two different evaluation methods., Material and Methods: 15 patients with chronic PTSD, traumatized at the same air show plane crash in 1988 (Ramstein, Germany), and 15 matched healthy controls participated in this study. All patients suffered from significant impairment by the PTSD; none had a history of drug or alcohol abuse. Hippocampus volume changes were processed by a semi-automated standard procedure performed with BRAINS2 as well as the voxel based morphometry (VBM) using SPM2., Results: No differences in total brain grey or white matter were detected between patients and controls. No differences in total hippocampal volume or in right and left parts were seen, even when hippocampal volumes were corrected by total brain volume or correlated with clinical data. Finally, no significant differences were detected between patients and controls in hippocampal regions using VBM., Discussion: This is the first study examining long-term changes in hippocampal volumes in chronic PTSD patients compared to matched controls using two different evaluation methods. Neither conventional volumetry nor VBM could detect any differences in the volume and structure. This supports the hypothesis that previously described hippocampal volume reduction is not necessarily due to PTSD or at least that, after 15 years, volume changes have been restored or have not yet developed.

Background: Once alcohol dependence is established, alcohol-associated cues may induce dopamine release in the reward system, which is accompanied by alcohol craving and may lead to relapse. In cocaine addicts, dopamine release in the thalamus was positively correlated with cocaine craving. We tested the effects of the atypical dopamine D(2/3) blocker amisulpride on cue-induced brain activation in a functional magnetic resonance imaging (fMRI) paradigm., Methods: Alcohol-associated and neutral pictures were presented in a block design to 10 male abstinent alcoholics (1-3 weeks after detoxification) and 10 healthy men during fMRI. The fMRI scans were acquired before and 2 hours after the oral application of 400 mg amisulpride. Before and after each scan, alcohol craving was measured with visual analogue scales., Results: Before the application of amisulpride, alcohol versus control cues elicited a higher blood oxygen level-dependent (BOLD) signal in the left frontal and orbitofrontal lobe, left cingulate gyrus, bilateral parietal lobe, and bilateral hippocampus in alcoholics compared with healthy controls. After amisulpride, alcoholics showed a reduced activation in the right thalamus compared with the first scan. Alcoholics no longer showed significant differences in their cue-elicited BOLD response after amisulpride medication compared with medication-free controls. Self-reported craving was not affected by amisulpride medication., Conclusions: Amisulpride medication was associated with reduced cue-induced activation of the thalamus, a brain region closely connected with frontostriatal circuits that regulate behavior and may influence relapse risk.