Neural Plasticity
January 1, 2016
Chuan-Chih Yang, Alfonso Barrós‐loscertales, Daniel Pinazo et al.
284 citations
Forty days of mindfulness meditation training in 13 novice meditators altered functional connectivity in brain networks linked to self-referential thought and emotion regulation. During meditation, internal consistency increased in the precuneus and temporoparietal junction but decreased in frontal regions, and connectivity between the dorsal anterior cingulate cortex and anterior insula was reduced. After training, resting-state connectivity between the pregenual anterior cingulate and dorsomedial prefrontal cortex decreased. Participants also reported significantly reduced depression and anxiety scores. These results suggest that meditation may produce antidepressant effects through neuroplastic changes in brain networks underlying affective disorders.
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.
Translational psychiatry
July 27, 2024
Rubén Herzog, Florentine Marie Barbey, Md Nurul Islam et al.
13 citations
Ketamine increases redundancy in brain dynamics—copies of the same information retrievable from three or more electrodes—most notably in the alpha frequency band, as measured by portable low-density EEG. In a double-blind crossover trial with 30 male adults, racemic ketamine compared to saline infusion produced greater redundancy during resting state, linked to dissociative shifts in consciousness. During an auditory oddball task, the effect was stronger for predictable standard stimuli than for deviant ones. Associations between ketamine's high-order interactions and experiences of derealization were observed, suggesting these measures capture pharmacological alterations in consciousness.
Neuroscience and biobehavioral reviews
July 1, 2024
Mina Kheirkhah, Allison C Nugent, Alicia A Livinski et al.
13 citations
Music and ketamine each influence therapeutic outcomes, yet their combined use is rarely studied. This scoping review maps existing research on administering music alongside ketamine or esketamine in humans. Studies include healthy volunteers and patients of various ages, using different doses and treatment processes, with music played at varying times relative to drug administration. Research on music during ketamine anesthesia is included, as anesthesia drove early ketamine use. Recreational ketamine studies are excluded. The review is limited to English-language articles with no year restriction. It is the first comprehensive overview of music and ketamine/esketamine interplay, offering guidance for future study design.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Mina Kheirkhah, Wallace C Duncan, Qiaoping Yuan et al.
6 citations
People with treatment-resistant depression show higher REM density in the first REM period and shorter REM latency than healthy volunteers, while total night REM density does not differ. Ketamine treatment reduces REM density in the first REM period but does not change total night REM density or REM latency. Baseline REM density in the first REM period moderately predicts whether a person will respond to ketamine, with higher levels indicating greater likelihood of response. This marker could help identify individuals most likely to benefit from ketamine therapy.
The international journal of neuropsychopharmacology
June 1, 2024
Thomas Liebe, Lena Vera Danyeli, Zümrüt Duygu Sen et al.
5 citations
Ketamine, an NMDA antagonist used as a rapid-acting antidepressant, disrupts the functional connectivity between the locus coeruleus (LC) and the thalamus, which is linked to a reduction in behavioral alertness. In a placebo-controlled, cross-over study with 35 healthy male participants (average age 25.1 years), ultra-high field 7T functional MRI revealed that acute disruption of the LC alertness network by ketamine correlates with decreased alertness. These findings highlight ketamine's effects beyond the glutamatergic system, suggesting a new mechanism involving noradrenergic pathways that may contribute to its antidepressant properties.
Journal of psychiatric research
April 1, 2024
Lena Vera Danyeli, Zümrüt Duygu Sen, Lejla Colic et al.
3 citations
In healthy men, a thinner posterior cingulate cortex (PCC) is linked to a stronger feeling of disembodiment after a low dose of ketamine, a drug that can rapidly relieve depression. The study measured cortical thickness in two brain regions—the PCC and the pregenual anterior cingulate cortex (pgACC)—and found that only PCC thickness correlated with the altered sense of self (disembodiment). No such link appeared for the pgACC. These results suggest the PCC plays a key role in ketamine's effects on self-experience, a feature shared with other fast-acting antidepressants that also produce psychedelic-like effects.
JAMA network open
June 1, 2026
Martin Walter, Christine Zu Eulenburg, Ani Damyanova et al.
1 citation
A novel oral prolonged-release ketamine tablet, KET01, produced minimal dissociative and cardiovascular side effects compared to intranasal esketamine, which caused significant dissociation. In a phase 2 trial for treatment-resistant depression, the primary endpoint at 21 days was not met; the difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score for 240 mg/day KET01 versus placebo was -1.82 points, not statistically significant. However, early reductions in depression scores were observed at 7 hours and at days 4 and 7. The antidepressant properties and tolerability support further development of KET01 for at-home use.
Frontiers in Psychiatry
September 2, 2025
Mina Kheirkhah, Nastasia McDonald, Julia Aepfelbacher et al.
1 citation
Adding mindfulness, music, and a light-occluding eye mask during ketamine infusion for depression did not improve antidepressant effects compared to ketamine alone, but it enriched the subjective experience. Participants in the combined sensory intervention group reported deeper engagement, a stronger sense of connection to reality, increased focus, moments of relief from sadness, and feelings of awe and spiritual insight. However, four individuals in that group reported discomfort. The findings suggest that while the sensory interventions make the experience more meaningful for many, they may cause discomfort for a few, and making them optional could avoid this.
Research square
March 21, 2024
Agustin Ibanez, Rubén Herzog, Florentine Barbey et al.
1 citation
Ketamine increases redundancy in brain dynamics, particularly in the alpha frequency band, and this effect is more pronounced during resting state and associated with dissociative experiences. In a double-blinded cross-over design with 30 male adults, racemic ketamine was compared to saline infusion. Higher-order interactions (HOI) computed from EEG data showed that ketamine boosted redundancy, especially for predictable stimuli in an auditory oddball task. These findings suggest that ketamine-induced shifts toward dissociation correlate with increased redundancy in neural signal interactions, highlighting the potential of complexity measures with portable EEG for monitoring pharmacological changes in consciousness.
Brain, behavior, and immunity
July 5, 2026
Bruno Pedraz-Petrozzi, Marta Marszalek-Grabska, Emilia Fornal et al.
In adults with treatment-resistant depression receiving six intravenous ketamine infusions over three weeks, higher baseline levels of the neuroprotective metabolite kynurenic acid (KYNA) in the kynurenine pathway were associated with greater symptom improvement by day 18. KYNA remained stable over time and did not track with symptom changes, suggesting it acts as a trait-like marker rather than a state-dependent one. Early shifts toward the neurotoxic branch of the pathway (kynurenine and 3-hydroxykynurenine) were linked to reductions in hopelessness and suicidality scores after the first infusion. These exploratory findings indicate that a kynurenine pathway profile biased toward neuroprotective metabolites may inform future biomarker studies of ketamine response, but require validation in larger samples.
Frontiers in psychiatry
January 1, 2025
Leonard Marx, Zümrüt Duygu Sen, Lena Vera Danyeli et al.
Ketamine's rapid antidepressant effects are thought to involve glutamate signaling and brain-derived neurotrophic factor (BDNF), but how these two factors interact is unclear. In a randomized, placebo-controlled crossover study with 35 healthy men, researchers measured glutamate levels in the pregenual anterior cingulate cortex using 7 Tesla magnetic resonance spectroscopy and plasma BDNF levels before and after infusions of S-ketamine or placebo. A significant interaction emerged between treatment condition and changes in glutamate on BDNF level changes, with a trend-level positive correlation between glutamate and BDNF changes only in the ketamine group. These findings offer initial in vivo evidence that ketamine's influence on BDNF is tied to its glutamatergic action.
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.
Zümrüt Duygu Sen, Nitin Sharma, Lena Vera Danyeli et al.
preprint
Ketamine causes temporary dissociative experiences alongside its rapid therapeutic effects. This study examined whether pleasant and unpleasant dissociations can be predicted by functional connectivity of the posteromedial cortex (PMC) in 35 male participants during ultrahigh-field MRI. Pleasant dissociation (oceanic boundlessness) was predicted by PMC connections with control network regions at baseline and during infusion, and additionally with default mode network regions during infusion. Unpleasant dissociation (anxious ego dissolution) could not be predicted by PMC connectivity. The findings suggest distinct brain mechanisms for pleasant versus unpleasant dissociations, and that PMC connectivity changes may be a shared neural feature of dissociation from both ketamine and psychedelics.
arXiv Preprint Archive
November 20, 2021
Dongmei Shi, Meng Li, Martin Walter et al.
The brain's functional connectivity patterns can be modeled using ensemble theory from statistical physics. In this framework, dynamic functional connectivity patterns (microstates) are linearly combined to produce static functional connectivity (the macrostate). Applying this model to the effect of ketamine on the brain, the authors show that the maximum work principle indicates the brain's capacity to do work declines significantly after ketamine injection compared to a control condition. Additionally, a quantum mechanical operator for the brain is identified, and a Hilbert space spanned by its eigenvectors is constructed, suggesting that quantum mechanics may provide new tools for studying brain systems.