PLoS ONE
September 24, 2012
Milan Scheidegger, Martin Walter, Mick Lehmann et al.
282 citations
Ketamine, an NMDA receptor antagonist that modulates glutamate signaling, rapidly reduces functional connectivity between the default mode network (DMN) and the dorsal nexus, a dorsal medial prefrontal cortex region linked to depression. In a randomized, placebo-controlled, double-blind, crossover resting-state fMRI study in healthy subjects, ketamine decreased connectivity from the DMN's posterior cingulate cortex hub to the dorsal nexus, pregenual anterior cingulate, and medioprefrontal cortex. This subacute modulation at 24 hours overlaps with ketamine's peak antidepressant efficacy in treatment-resistant depression, suggesting that targeting glutamatergic system-driven network dysconnectivity may underlie successful depression treatment.
Human Brain Mapping
February 25, 2016
Milan Scheidegger, A Henning, Martin Walter et al.
78 citations
Ketamine, an NMDA receptor antagonist, reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation in 23 healthy subjects. Reduced amygdala reactivity to negative pictures correlated with resting-state connectivity to the pregenual anterior cingulate cortex. The intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. These findings suggest that modulation of glutamate-responsive circuits, associated with a shift in emotional bias and reduced amygdalo-hippocampal reactivity, may represent an early mechanism to restore disrupted neurobehavioral homeostasis in major depressive disorder.
Social Cognitive and Affective Neuroscience
April 13, 2016
Mick Lehmann, Erich Seifritz, A Henning et al.
58 citations
Distraction and rumination are distinct ways people respond to negative thoughts and feelings. Rumination involves elevated self-focus, linked to increased resting state functional connectivity and decreased reactivity within the default mode network. The NMDA receptor antagonist ketamine reduces functional connectivity in this network, but its effects on brain responses during stimulus perception were unknown. In healthy subjects given a single ketamine dose, blood oxygenation level-dependent (BOLD) reactivity to negative emotional pictures increased specifically in the pregenual anterior cingulate cortex, not in a posterior control region. The increase was greater in subjects with low ability to use distraction during negative experiences. Ketamine may attenuate pathological increased self-focus during negative experiences.
The International Journal of Neuropsychopharmacology
August 10, 2022
Anne Weigand, Matti Gärtner, Milan Scheidegger et al.
22 citations
Activity in the pregenual anterior cingulate cortex (pgACC) during emotional stimulation can predict how well a single intravenous infusion of ketamine will relieve depression symptoms in people with major depressive disorder. In 24 patients, pgACC activity was linked to an increase in glutamate in the same brain region 24 hours after the infusion, and this glutamate increase was associated with greater symptom improvement. The findings suggest pgACC activity may serve as a neuroimaging biomarker for early treatment response to ketamine.
European Archives of Psychiatry and Clinical Neuroscience
January 12, 2022
Matti Gärtner, Anne Weigand, Milan Scheidegger et al.
13 citations
Ketamine's rapid antidepressant effects involve the glutamatergic system. A multimodal imaging study of 23 healthy volunteers used resting state fMRI and proton magnetic resonance spectroscopy to examine links between metabolic and functional brain changes during intravenous ketamine infusion. The pregenual anterior cingulate cortex (pgACC) was the focus. Functional connectivity changed 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. Stronger pgACC activation during ketamine was linked to lower glutamine concentration, and reduced connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine.
The World Journal of Biological Psychiatry
January 5, 2022
Matti Gärtner, Mischa de Rover, Lena Václavů et al.
11 citations
In patients with Major Depressive Disorder, increased blood flow in the thalamus one day after a single low-dose ketamine infusion is linked to greater improvement in depressive symptoms. Lower thalamus blood flow before treatment predicts both a larger increase in flow after ketamine and stronger symptom reduction. The study used arterial spin labelling, a brain imaging technique that directly measures cerebral blood flow, avoiding the ambiguity of standard BOLD imaging. These findings suggest that measuring regional blood flow could help guide ketamine treatment decisions.
Translational psychiatry
October 14, 2024
Marvin S Meiering, David Weigner, Matti Gärtner et al.
4 citations
In healthy adults, a single dose of ketamine reduced activity in the hippocampus and the default mode network (DMN) and increased connections between frontal and limbic brain regions while participants viewed emotional faces. These effects occurred both during the infusion and 24 hours later. Pretreatment with lamotrigine, which blocks glutamate release, prevented the increase in brain connectivity and the delayed reduction in DMN activity, but did not affect the acute drop in hippocampal and DMN activity. The findings suggest that ketamine's acute changes in brain connectivity and its sustained effects on DMN activity depend on glutamate transmission, whereas its immediate suppression of limbic and DMN activity does not.
Translational psychiatry
June 18, 2024
Matti Gärtner, Anne Weigand, Marvin Sören Meiering et al.
1 citation
Ketamine reduces spontaneous brain activity in three subregions of the anterior cingulate cortex (ACC) during administration in healthy people. Lamotrigine, which inhibits glutamate release, attenuates this effect only in the ventral ACC subregions, suggesting glutamate involvement there. ACC activity returns to baseline 24 hours later, though group differences persist between the lamotrigine and ketamine groups. Trait negative emotionality is closely linked to activity changes in the subgenual ACC after ketamine. These findings clarify how ketamine affects different ACC subregions and may relate to its antidepressant mechanisms.
May 29, 2019
Michael Lifshitz, Matthew D. Sacchet, Julia M. Huntenburg et al.
1 citation
Major depressive disorder involves abnormal communication between large-scale brain networks. A randomized, active-controlled trial tested whether mindfulness-based therapy could alter resting-state functional connectivity in clinically depressed patients. A brief, clinically effective mindfulness intervention functionally decoupled top-down control regions from brain areas involved in sensory, affective, and attentional processing. These findings identify specific neural targets of mindfulness training, offering new insight into how this therapeutic approach works.
Journal of psychopharmacology (Oxford, England)
June 19, 2025
David Weigner, Marvin Sören Meiering, Anne Weigand et al.
Ketamine infusion significantly increased functional connectivity between the pregenual anterior cingulate cortex and the dorsomedial prefrontal cortex during a working memory task, and between the pregenual anterior cingulate cortex and the left insula during rest. These effects were absent when participants were pretreated with lamotrigine, a glutamate-release inhibitor. The findings suggest that ketamine's beneficial effects on brain communication, observed in psychiatric conditions linked to chronic stress, may depend on glutamate release.
Pharmacopsychiatry
September 1, 2011
Simone Grimm, Milan Scheidegger, A Henning et al.
Ketamine, a glutamatergic NMDA receptor antagonist with rapid antidepressant properties, was used to investigate the neurobiology of major depressive disorder. In a multimodal imaging study of 23 healthy subjects, a single ketamine infusion increased negative BOLD responses in brain regions involved in emotional processing, particularly limbic areas linked to emotional information and higher-order mental functions. During cognitive processing, ketamine affected negative BOLD responses in anterior but not posterior regions of the default-mode network. Strong correlations were found between glutamate, glutamine, GABA, and glutamine/glutamate ratios and these brain responses after ketamine administration, suggesting a link to glutamatergic neurotransmission.
Pharmacopsychiatry
September 1, 2011
Milan Scheidegger, A Henning, Martin Walter et al.
A subanaesthetic dose of ketamine alters brain activity during emotional processing and increases glutamate-glutamine cycling in the pregenual anterior cingulate cortex, a region linked to mood regulation. In 23 healthy subjects, ketamine infusion changed fMRI responses to emotional pictures, and these changes correlated with shifts in glutamine-to-glutamate ratios measured by spectroscopy. The findings suggest ketamine's rapid antidepressant effect may stem from enhanced glutamatergic neurotransmission.