M Scheidegger

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug 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.

Increased Metabotropic Glutamate Receptor Subtype 5 Availability in Human Brain After One Night Without Sleep

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans

Significance Major depressive disorder is a significant contributor to the global burden of disease, affecting 350 million people according to an estimation of the World Health Organization. Today, no valid biomarkers of depression, which could predict the efficacy of a certain treatment in a certain group of patients, exist. Sleep deprivation is an effective and rapid-acting antidepressive treatment. However, the biomechanism of this effect is largely unknown. This study shows the effects of sleep deprivation on human brain functional connectivity alterations via the dorsal nexus, an area which is crucial in major depressive disorder. Here, we offer a neurobiological explanation for the known antidepressive action of sleep deprivation. 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.

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

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 11C-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.

Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

Significance Social cognition critically impacts the development, progression, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. By applying a multimodal brain imaging strategy, the present study demonstrated the importance of the serotonin 2A/1A receptor system in the modulation of social exclusion processing. Understanding the biochemical underpinnings of the social rejection experience is important for increasing our knowledge about social/emotional processing and the related neural responses. The identification of relevant neural responses is in turn crucial for the efficacious management of disorders influenced by social factors. Our findings may help to diminish a knowledge gap that currently restrains the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders. 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.

Effects of ketamine on cognition-emotion interaction in the brain.

Cognition-emotion interaction in the brain can be investigated by incorporating stimuli with emotional content into cognitive tasks. Emotional stimuli in the context of a working memory (WM) task yield increased activation in WM-related lateral prefrontal regions, whereas cognitive effort enhances deactivation in emotion-related cortical midline regions. N-methyl-d-aspartate glutamate receptors (NMDA-Rs) are critically involved in WM, and NMDA-R antagonists, such as ketamine, accordingly affect WM but also have a profound impact on emotional processing, as underscored by the rapid reduction of depressive symptoms after administration of a single dose of ketamine. The effect of ketamine on both cognitive and emotional processing therefore makes it a useful tool to further explore cognition-emotion interaction in the brain. Twenty-three healthy subjects were administered ketamine to investigate whether its effects on WM performance and brain reactivity depend on emotional content or emotional valence of stimuli. Furthermore, we aimed at investigating how ketamine affects the integration of emotion and WM processes in emotion-related cortical midline regions and WM-related lateral prefrontal regions. Results show that ketamine modulates cognition-emotion interaction in the brain by inducing lateralized and valence-specific effects in emotion-related cortical midline regions, WM-related lateral prefrontal regions and insula. In emotion-related cortical midline regions ketamine abolishes enhancement of deactivation normally observed during cognitive effort, while in the right DLPFC and the left insula the previously described pattern of increased activation due to emotional content is abrogated exclusively for negative stimuli. Our data therefore shows a specific effect of ketamine on cognition-emotion interaction in the brain and indicates that its effect on amelioration of negative biases in MDD patients might be related to less interference of cognitive processing by negative emotional content.

Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation

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.

Glutamatergic and neurometabolic alterations in chronic cocaine users measured with 1H-magnetic resonance spectroscopy

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 1H‐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.

Fast iterative pre-emphasis calibration method enabling third-order dynamic shim updated fMRI

To calibrate a pre‐emphasis to sufficiently compensate eddy currents for application of dynamic shim updating to fMRI without extension of scan times.

Neural underpinnings of prosexual effects induced by gamma-hydroxybutyrate in healthy male humans

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.