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RationaleThe psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are attributed to the effects of N,N-dimethyltryptamine (DMT) at brain serotonin 5-HT2A receptors. To make oral DMT bioavailable, ayahuasca additionally contains reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation in the brain. ObjectivesTherefore, we measured the pharmacokinetic profile of harmine and DMT in the rat brain. Additionally, we investigated the pharmacodynamic properties of DMT and/or harmine. MethodsWe first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored influences of DMT and/or harmine in the lower dose group on brain glucose metabolism with [18F]FDG-PET. ResultsResults confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in the brain, while increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 µM at moderate doses. We did not observe strong influences of low dose DMT and/or harmine on [18F]FDG-PET. ConclusionsThe present preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on receptor occupancy and on cerebral metabolism.

Ketamine is a promising treatment option for patients with Major Depressive Disorder (MDD) and has become an important research tool to investigate antidepressant mechanisms of action. However, imaging studies attempting to characterise ketamine's mechanism of action using blood oxygen level-dependent signal (BOLD) imaging have yielded inconsistent results- at least partly due to intrinsic properties of the BOLD contrast, which measures a complex signal related to neural activity. To circumvent the limitations associated with the BOLD signal, we used arterial spin labelling (ASL) as an unambiguous marker of neuronal activity-related changes in cerebral blood flow (CBF). We measured CBF in 21 MDD patients at baseline and 24 h after receiving a single intravenous infusion of subanesthetic ketamine and examined relationships with clinical outcomes. Our findings demonstrate that increase in thalamus perfusion 24 h after ketamine administration is associated with greater improvement of depressive symptoms. Furthermore, lower thalamus perfusion at baseline is associated both with larger increases in perfusion 24 h after ketamine administration and with stronger reduction of depressive symptoms. These findings indicate that ASL is not only a useful tool to broaden our understanding of ketamine's mechanism of action but might also have the potential to inform treatment decisions based on CBF-defined regional disruptions.

Background Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy. Methods We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan. Results Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome. Conclusions Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.

Meditation and psychedelics have played key roles in humankind’s search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 μg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin’s positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications.

Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (1H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine. Subjects were investigated before and during an intravenous ketamine infusion. The MRS voxel was placed in the pregenual anterior cingulate cortex (pgACC), as this region has been repeatedly shown to be involved in ketamine’s effects. Our results showed functional connectivity changes from the pgACC to the right frontal pole and anterior mid cingulate cortex (aMCC). Absolute glutamate and glutamine concentrations in the pgACC did not differ significantly from baseline. However, we found that stronger pgACC activation during ketamine was linked to lower glutamine concentration in this region. Furthermore, reduced functional connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine. Our results thereby demonstrate how multimodal investigations in a single brain region could help to advance our understanding of the association between metabolic and functional changes.

Ketamine was recently approved for treatment resistant depression. However, despite its therapeutic potential, about 50% of patients do not show improvement under this therapy. In this prospective two-site study, we investigated baseline brain structural predictors for rapid symptom improvement after a single subanesthetic ketamine infusion. Furthermore, given the preclinical evidence and findings from a pilot study in a clinical population that ketamine induces rapid neuroplasticity, we performed an exploratory investigation of macroscopic changes 24 h post-treatment. T1-weighted MRI brain images from 33 depressed patients were acquired before and 24 h after a single ketamine infusion and analyzed using voxel-based morphometry (VBM). Additionally, we performed a region of interest (ROI)-based analysis of structures that have previously been shown to play a role in the antidepressant effects of ketamine: bilateral hippocampus, nucleus accumbens, anterior cingulate cortex, and thalamus. A whole-brain regression analysis showed that greater baseline volume of the bilateral rostral anterior cingulate cortex (rACC) significantly predicts rapid symptom reduction. The right ACC showed the same association in the ROI analysis, while the other regions yielded no significant results. Exploratory follow-up analyses revealed no volumetric changes 24 h after treatment. This is the first study reporting an association between pretreatment gray matter volume of the bilateral rACC and the rapid antidepressant effects of ketamine. Results are in line with previous investigations, which highlighted the potential of the rACC as a biomarker for response prediction to different antidepressant treatments. Ketamine-induced volumetric changes may be seen at later time points.

Major depressive disorder (MDD) is characterized by heterogeneous cognitive, affective and somatic symptoms. Hence, the investigation of differential treatment effects on these symptoms as well as the identification of symptom specific biomarkers might crucially contribute to the development of individualized treatment strategies. We here aimed to examine symptom specific responses to treatment with ketamine, which repeatedly demonstrated rapid antidepressant effects in severe MDD. Additionally, we investigated working memory (WM) related brain activity associated with changes in distinct symptoms in order to identify specific response predictors. In a sample of 47 MDD patients receiving a single sub-anesthetic dose of ketamine, we applied a three-factor solution of the Beck Depression Inventory (BDI) to detect symptom specific changes 24 h post-infusion. A subsample of 16 patients underwent additional fMRI scanning during an emotional working memory task prior to ketamine treatment. Since functional aberrations in the default mode network (DMN) as well as in the dorsolateral prefrontal cortex (DLPFC) have been associated with impaired cognitive and emotional processing in MDD, we investigated neural activity in these regions. Our results showed that ketamine differentially affects MDD symptoms, with the largest symptom reduction in the cognitive domain. WM related neuroimaging results indicated that a more pronounced effect of ketamine on cognitive symptoms is predicted by lower DMN deactivation and higher DLPFC activation. Findings thereby not only indicate that ketamine's antidepressant efficacy is driven by a pro-cognitive mechanism, but also suggest that this might be mediated by increased potential for adaptive adjustment in the circumscribed brain regions.

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behavior. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared with healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared with baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on 2 days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalized medicine approach in addiction.

Rationale We reviewed the concepts and empirical findings in studies with psychedelics and entactogens related to positive psychology – the study of healthy human functioning, well-being and eudaemonia. It is an unresolved question how beneficial effects of psychedelics and entactogens are related to the potential risks of these substances – particularly in non-clinical settings. Methods We searched in PubMed, PsychINFO and the Cochrane Library for controlled clinical and epidemiological studies which applied concepts from positive psychology. We included N = 77 eligible studies with 9876 participants published before November 1st, 2017: (1) quantitative studies (N = 54), (2) preliminary or exploratory studies and reviews not including meta-analyses (N = 17), and (3) studies evidencing primarily negative results (N = 6). Results Positive psychology concepts have been applied for measuring effects of clinical trials, recreational and ceremonial use of psychedelics and entactogens. Psychedelics and entactogens were shown to produce acute and long-term effects on mood, well-being, prosocial behaviours, empathy, cognitive flexibility, creativity, personality factors like openness, value orientations, nature-relatedness, spirituality, self-transcendence and mindfulness-related capabilities. Conclusions There is preliminary evidence for beneficial effects of psychedelics and entactogens on measures of positive psychology in clinical and healthy populations, however their sustainability remains largely unresolved. The reported results must be considered preliminary due to methodological restrictions. Since longitudinal data on both positive and adverse effects of psychedelics are lacking, more rigorous and standardized measures from positive psychology should be applied in less biased populations with prospective longitudinal designs to carefully assess the benefit-risk-ratio. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.

PURPOSE The transverse relaxation times T2 of 17 metabolites in vivo at 3T is reported and region specific differences are addressed. METHODS An echo-time series protocol was applied to one, two, or three volumes of interest with different fraction of white and gray matter including a total number of 106 healthy volunteers and acquiring a total number of 128 spectra. The data were fitted with the 2D fitting tool ProFit2, which included individual line shape modeling for all metabolites and allowed the T2 calculation of 28 moieties of 17 metabolites. RESULTS The T2 of 10 metabolites and their moieties have been reported for the first time. Region specific T2 differences in white and gray matter enriched tissue occur in 16 of 17 metabolites examined including single resonance lines and coupled spin systems. CONCLUSION The relaxation time T2 is regions specific and has to be considered when applying tissue composition correction for internal water referencing. Magn Reson Med 80:452-461, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

The concept of self and self‐referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self‐stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self‐disturbances. We assessed the psychoactive effects of psilocybin (230 μg/kg p.o.), a preferential 5‐HT1A/2A agonist known to induce shifts in self‐perception. Our placebo‐controlled, double‐blind, within‐subject crossover experiment (n = 17) implemented a verbal self‐monitoring task involving vocalizations and participant identification of real‐time auditory source‐ (self/other) and pitch‐modulating feedback. Subjective experience and task performance were analyzed, with time‐point‐by‐time‐point assumption‐free multivariate randomization statistics applied to the spatiotemporal dynamics of event‐related potentials. Psilocybin‐modulated self‐experience, interacted with source to affect task accuracy, and altered the late phase of self‐stimuli encoding by abolishing the distinctiveness of self‐ and other‐related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin‐induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self‐referential processing networks via 5‐HT signaling may be key for understanding self‐disorders. This mechanism may reflect a neural instantiation of altered self–other and relational meaning processing in a stimulus‐locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness., Self‐referential processing pertains to the cognitive organization and perceptual differentiation of self‐stimuli, and its experimental perturbation offers a unique opportunity for elucidating the underlying mechanisms. We assessed the psychoactive effects of the potent preferential 5‐HT1A/2A agonist psilocybin during a verbal self‐monitoring task with assumption‐free multivariate randomization statistics applied to brain event‐related potentials. Treatment with psilocybin modulated self‐experience, interacted with self/other stimuli for task accuracy, and altered the electric field configurations during the P300 timeframe.

Major depressive disorder (MDD) is often accompanied by severe impairments in working memory (WM). Neuroimaging studies investigating the mechanisms underlying these impairments have produced conflicting results. It remains unclear whether MDD patients show hyper- or hypoactivity in WM-related brain regions and how potential aberrations in WM processing may contribute to the characteristic dysregulation of cognition–emotion interactions implicated in the maintenance of the disorder. In order to shed light on these questions and to overcome limitations of previous studies, we applied a multivoxel pattern classification approach to investigate brain activity in large samples of MDD patients (N = 57) and matched healthy controls (N = 61) during a WM task that incorporated positive, negative, and neutral stimuli. Results showed that patients can be distinguished from healthy controls with good classification accuracy based on functional activation patterns. ROI analyses based on the classification weight maps showed that during WM, patients had higher activity in the left DLPFC and the dorsal ACC. Furthermore, regions of the default-mode network (DMN) were less deactivated in patients. As no performance differences were observed, we conclude that patients required more effort, indexed by more activity in WM-related regions, to successfully perform the task. This increased effort might be related to difficulties in suppressing task-irrelevant information reflected by reduced deactivation of regions within the DMN. Effects were most pronounced for negative and neutral stimuli, thus pointing toward important implications of aberrations in WM processes in cognition–emotion interactions in MDD.

Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N-methyl-d-aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting-state fMRI (rsfMRI), we assessed amygdalo-hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting-state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate-responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo-hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941-1952, 2016. © 2016 Wiley Periodicals, Inc.

Cocaine addiction is a chronically relapsing disorder that is associated with harmful consequences. Relapses occur frequently and effective pharmacotherapies are currently sparse. Preclinical studies suggest that altered glutamatergic signaling is crucial for the maintenance of cocaine self-administration. However, the translational validity of these models is currently unknown. Therefore, we investigated potential differences of glutamate, glutamine and further metabolite levels in the pregenual anterior cingulate cortex (pgACC) and the right dorsolateral prefrontal cortex (rDLPFC) of chronic cocaine users and controls using the PRior knOwledge FITting 2.0 tool in combination with two-dimensional J-resolved single-voxel (1) H-magnetic resonance spectroscopy at 3T and voxel tissue composition and relaxation correction. Glutamate and glutamine levels did not differ between cocaine users and controls, but higher weekly cocaine use and higher cocaine hair concentrations were associated with lower glutamine/creatine ratios in the pgACC. Interestingly, cocaine users exhibited higher glucose/total creatine ratios than controls in the pgACC and higher choline/creatine ratios in the pgACC and rDLPFC. These results imply that cocaine use is associated with altered cortical glucose metabolism and membrane turnover. Finally, cocaine use over the past 6 months appears to decrease cortical glutamine levels indicating changes in glutamate cycling.

The transverse relaxation times TAn echo-time series protocol was applied to one, two, or three volumes of interest with different fraction of white and gray matter including a total number of 106 healthy volunteers and acquiring a total number of 128 spectra. The data were fitted with the 2D fitting tool ProFit2, which included individual line shape modeling for all metabolites and allowed the TThe TThe relaxation time T

Ketamine, an anesthetic and illicit party drug, is emerging as a fast-Acting antidepressant

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist currently used as treatment for narcolepsy but also as a drug of abuse. Non-medical GHB users have repeatedly reported prosexual effects including libido-enhancement and lowering of attractiveness standards for partner selection. Here, we examined the putative prosexual effects of oral GHB in healthy males in two experiments both employing randomized, placebo-controlled, double-blind, balanced, and cross-over study designs. In experiment I, subjective effects of 20 and 35mg/kg GHB vs. placebo were tested in 32 participants using the Sexual Arousal and Desire Inventory. In experiment II, brain reactivity towards erotic vs. neutral pictures was investigated in 15 participants using functional magnetic resonance imaging after 35mg/kg GHB vs. placebo. In experiment I, prosexual effects of GHB were shown by increased SADI ratings regarding physiological, evaluative, and motivational aspects of sexual arousal. In experiment II, erotic visual stimuli activated the bilateral insula, nucleus accumbens (NAcc), fusiform gyrus, thalamus, and left occipital pole under placebo. After GHB administration, even sexually neutral pictures of persons induced subjective sexual arousal and increased activation of the bilateral NAcc and right anterior cingulate cortex, which significantly correlated (left NAcc by trend). Moreover, a psychophysiological interaction analysis showed that GHB increased connectivity between NAcc and ventromedial prefrontal cortex during processing of visual erotic cues, i.e., in the condition in which subjective sexual arousal was highest. Our data show that GHB stimulates hedonic sexual functioning and lowers the threshold for erotic perception, which is related to increased susceptibility of mesolimbic reward pathways.

Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain.Metabotropic glutamate receptor subtype 5 binding was quantified with positron emission tomography in 22 young healthy men who completed two experimental blocks separated by 1 week. Two positron emission tomography examinations were conducted in randomized, crossover fashion with the highly selective radioligand, ¹¹C-ABP688, once after 9 hours (sleep control) and once after 33 hours (sleep deprivation) of controlled wakefulness. ¹¹C-ABP688 uptake was quantified in 13 volumes of interest with high mGluR5 expression and presumed involvement in sleep-wake regulation.Sleep deprivation induced a global increase in mGluR5 binding when compared with sleep control (p.006). In anterior cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala, this increase correlated significantly with the sleep deprivation-induced increase in subjective sleepiness.This molecular imaging study demonstrates that cerebral functional mGluR5 availability is increased after a single night without sleep. Given that mGluR5 density is reduced in MDD, further research is warranted to examine whether this mechanism is involved in the potent antidepressant effect of wake therapy.

Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

depression Milan Scheidegger, Martin Walter, Mick Lehmann, Coraline Metzger, Simone Grimm, Heinz Boeker, Peter Boesiger, Erich Seifritz, and Anke Henning Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, Clinic of Affective Disorders and General Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland, Department of Psychiatry, Otto-von-Guericke University, Magdeburg, Germany, Cluster Languages of Emotion, Freie Universitat Berlin, Berlin, Germany

PURPOSE: To calibrate a pre-emphasis to sufficiently compensate eddy currents for application of dynamic shim updating to fMRI without extension of scan times. METHODS: Eddy current effects induced into all shim terms up to third-order were characterized by spatiotemporal field monitoring, using a third-order field camera. Pre-emphasis settings were derived from the measurements and iteratively evaluated and refined. The calibrated pre-emphasis was applied to slice-wise dynamic shim updating in combination with a dynamic excitation frequency (F0) determination and a slice-wise B0 optimization routine for in vivo echo planar imaging and resting-state functional MRI. RESULTS: The described method for pre-emphasis calibration led to settling times of remaining eddy current effects below 2 ms, allowing for the application of dynamic shim updating to fMRI without extension of scan times or induction of eddy current related artifacts. A dynamic F0 determination compensates frequency shifts induced by the superposition of different shim fields, and therefore, prevents an image shift within the field of view. Hardware limitations necessitate the reduction of the maximum applicable B0 shim field amplitudes and restrict the shim performance. CONCLUSION: The proposed method enables accurate pre-emphasis calibration, and therefore, the application of dynamic shim updating to fMRI. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Distraction and rumination are distinct response styles that determine how an individual deals with negative thoughts and feelings. Rumination is accompanied by an elevated self-focus, which is associated with increased resting state functional connectivity and decreased reactivity within the default mode network. Interestingly, the NMDA receptor antagonist ketamine reduces functional connectivity in this network, while its effects on blood oxygenation level-dependent (BOLD) responses during stimulus perception are not known. Ketamine might lead to a more variable processing of the external world with an attenuated self-focus by reducing the resting state connectivity. Here, we used an emotional picture-viewing task in combination with functional magnetic resonance imaging to test the hypothesis that a single ketamine administration to healthy subjects increases BOLD reactivity to negative stimuli. We found a region specific increase in BOLD reactivity in the pregenual anterior cingulate cortex and not in a posterior control region after ketamine compared with placebo administration. Moreover, a linear regression revealed that the increase in BOLD reactivity was more pronounced for subjects with a low ability to apply distraction during negative experiences. Our results implicate that ketamine attenuates a potentially pathological increased self-focus during negative experiences., Social Cognitive and Affective Neuroscience, 11 (8), ISSN:1749-5016, ISSN:1749-5024

Cocaine addiction is a chronically relapsing disorder that is associated with harmful consequences. Relapses occur frequently and effective pharmacotherapies are currently sparse. Preclinical studies suggest that altered glutamatergic signaling is crucial for the maintenance of cocaine self-administration. However, the translational validity of these models is currently unknown. Therefore, we investigated potential differences of glutamate, glutamine and further metabolite levels in the pregenual anterior cingulate cortex (pgACC) and the right dorsolateral prefrontal cortex (rDLPFC) of chronic cocaine users and controls using the PRior knOwledge FITting 2.0 tool in combination with two-dimensional J-resolved single-voxel (1) H-magnetic resonance spectroscopy at 3T and voxel tissue composition and relaxation correction. Glutamate and glutamine levels did not differ between cocaine users and controls, but higher weekly cocaine use and higher cocaine hair concentrations were associated with lower glutamine/creatine ratios in the pgACC. Interestingly, cocaine users exhibited higher glucose/total creatine ratios than controls in the pgACC and higher choline/creatine ratios in the pgACC and rDLPFC. These results imply that cocaine use is associated with altered cortical glucose metabolism and membrane turnover. Finally, cocaine use over the past 6 months appears to decrease cortical glutamine levels indicating changes in glutamate cycling.

Fassen wir Geist und Natur nicht als Dichotomie sondern im Sinne von Peirce als Kontinuität auf, dann lässt die genauere Betrachtung des Körpers semiotische Leibphänomene als Zeichen einer Sprache erkennen, deren Grammatik es – im Sinne einer «Bioarchäologie» – zu entschlüsseln gilt. Hierfür stellen die Neurowissenschaften mit modernen Visualisierungstechniken geeignete epistemische Hilfsmittel bereit: Sie machen körperliche Vorgänge des Informationsaustausches sichtbar und heben die semiotisch wenig erschlossene Ebene komplexer neuronaler Zeichentransformationen ans Licht. Um eine Integration der physiologischen und psychologischen Perspektive bemüht sich das transdisziplinäre Projekt der «Neuropsychoanalyse». Sie hebt die Relevanz natürlicher Verarbeitungsmechanismen des Körpers für die subjektiv geprägten Zeichentransformationen des mentalen Erlebens hervor und weicht eine semiotisch allzu undurchlässige Grenzziehung zwischen Psycho- und Neurodynamik etwas auf. Die Hirntätigkeit als potenziell erkenntnisleitenden Zeichenprozess zu verstehen, darf aber nicht in einer unreflektierten Bezugnahme auf neuronale Zeichensysteme münden, wenn die Neuropsychoanalyse mehr als nur eine medienwirksame Neurokarikatur psychodynamischer Konzepte erreichen will.

Long lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug seeking behavior and extinction learning. Accordingly blocking mGluR5s attenuated self administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with (11)C ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction related brain areas. Drug use was assessed by self report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20) compared with non smokers (n=11). In terms of effect sizes lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50 21) insula (d=1.47 20) and putamen (d=1.46 18). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.Molecular Psychiatry advance online publication 30 April 2013; doi:10.1038/mp.2013.51.

In many patients with major depressive disorder, sleep deprivation, or wake therapy, induces an immediate but often transient antidepressant response. It is known from brain imaging studies that changes in anterior cingulate and dorsolateral prefrontal cortex activity correlate with a relief of depression symptoms. Recently, resting-state functional magnetic resonance imaging revealed that brain network connectivity via the dorsal nexus (DN), a cortical area in the dorsomedial prefrontal cortex, is dramatically increased in depressed patients. To investigate whether an alteration in DN connectivity could provide a biomarker of therapy response and to determine brain mechanisms of action underlying sleep deprivations antidepressant effects, we examined its influence on resting state default mode network and DN connectivity in healthy humans. Our findings show that sleep deprivation reduced functional connectivity between posterior cingulate cortex and bilateral anterior cingulate cortex (Brodmann area 32), and enhanced connectivity between DN and distinct areas in right dorsolateral prefrontal cortex (Brodmann area 10). These findings are consistent with resolution of dysfunctional brain network connectivity changes observed in depression and suggest changes in prefrontal connectivity with the DN as a brain mechanism of antidepressant therapy action.

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression. ISSN:1932-6203

Converging evidence suggests that a single sub-anesthetic dose of ketamine can produce strong and rapid antidepressant effects in patients that do not respond to standard treatment. Despite a considerable amount of research investigating ketamine's mechanisms of action, the exact neuronal targets conveying the antidepressant effects have not been identified yet. Preclinical studies suggest that molecular changes induced by ketamine bring forward large-scale network reconfigurations that might relate to ketamine's antidepressant properties. In this prospective two-site study we measured resting state fMRI in 24 depressed patients prior to, and 24 h after a single sub-anesthetic dose of ketamine. We analyzed functional connectivity (FC) at baseline and after ketamine and focused our analysis on baseline FC and FC changes directly linked to symptom reduction in order to identify neuronal targets that predict individual clinical responses to ketamine. Our results show that FC increases after ketamine between right lateral prefrontal cortex (PFC) and subgenual anterior cingulate cortex (sgACC) are positively linked to treatment response. Furthermore, low baseline FC between these regions predicts treatment outcome. We conclude that PFC-sgACC connectivity may represent a promising biomarker with both predictive and explanatory power.