Ketamine induces widespread changes in cortical-subcortical spectral connectivity in humans
Poster No:
1924
Submission Type:
Abstract Submission
Authors:
Ethan Solomon1, Tony Liu2, Isaac Kauvar2, Sam Vesuna1, Adelaida Chibukhchyan2, Lisa Yamada2, Adam Fogarty2, Pavithra Mukunda1, Kishandra Patron2, Eun Young Choi3, Paul Nuyujukian2, Carolyn Rodriguez1, Vivek Buch3, Karl Deisseroth2
Institutions:
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 2Department of Bioengineering, Stanford University, Stanford, CA, 3Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA
First Author:
Ethan Solomon
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Co-Author(s):
Sam Vesuna
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Pavithra Mukunda
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Carolyn Rodriguez
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Stanford, CA
Introduction:
The NMDA receptor antagonist ketamine induces profound changes in sensory experience and cognition, including dissociation, alterations in spatial awareness, perceptual disturbances, and amnesia. As a psychotomimetic and model of NMDA receptor hypofunction, ketamine may reflect brain changes that are relevant to schizophrenia, though its marked antidepressant effect also suggests relevance to mood disorders (Pribish et al., 2020). Prior work in animals – and non-invasive neuroimaging in humans – found that ketamine affects the physiology of cortical-subcortical networks, particularly involving the neural oscillations which organize activity within the thalamus, basal ganglia, and hippocampus (Dawson et al., 2013; Niesters et al., 2012; Rivolta et al., 2015). However, it is not known whether ketamine exerts similar effects in humans. Here we recorded intracranial electroencephalography (iEEG) from neurosurgical patients while giving IV ketamine to assess for changes in the oscillatory activity of subcortical structures and patterns of cortical-subcortical connectivity.
Methods:
We recruited 19 neurosurgical patients with indwelling electrodes and recorded neural activity while they received IV infusions of ketamine (0.5mg/kg) over a 40-minute interval. Implants included grid, strip, and stereo-EEG depth electrodes with robust sampling of diverse neocortical regions and subcortical areas (amygdala, hippocampus, thalamus, basal ganglia). iEEG signals were analyzed using oscillation-detection algorithms (Donoghue et al., 2020) to understand the neural power and connectivity response to ketamine across the theta (3-8Hz), alpha (9-13Hz), beta (15-25Hz), and gamma (30-55Hz) bands. Cortical-subcortical connectivity was assessed using phase-based metrics and subjected to network topographical analyses, comparing between pre-ketamine rest and the active ketamine infusion period.
Results:
Relative to pre-infusion baseline, ketamine significantly increased the occurrence of hippocampal theta oscillations (t-test, T(17)=4.78, p<0.001) and decreased beta (T(17)=-4.27, p<0.001), but caused no significant change in the rate of alpha or gamma oscillations (Figure 1). Amygdala, temporal pole, and basal ganglia also showed theta oscillatory increases, but other neocortical regions did not. Basal ganglia exhibited the largest decreases in the occurrence of beta oscillations relative to all other brain regions (T(11)=-4.43, p=0.001). Gamma oscillations were significantly increased in prefrontal cortices, thalamus, and basal ganglia (p<0.05, FDR-corrected). In the theta band, inter-regional synchronization (weighted phase-lag index) was broadly increased between the cortex and medial temporal lobe (z=5.3, p<0.01, nonparametric), demonstrating that the hippocampus and nearby structures serve as a hub of ketamine-induced theta connectivity (Figure 2). Inter-regional gamma connectivity also increased, but with a markedly different network structure centering around hubs of connectivity in the orbitofrontal and anterior cingulate cortices (p<0.05, nonparametric). Mirroring spectral power effects, basal ganglia were significantly decoupled in the beta band from widespread prefrontal, parietal, and lateral temporal cortices.
Conclusions:
Ketamine induces widespread changes in the oscillatory activity of cortical and subcortical structures in humans, altering patterns of cortical-subcortical spectral connectivity. These changes center around anatomic hubs that segregate by frequency band; the medial temporal lobe complex emerges as a hub of enhanced theta activity and cortical connectivity, while gamma-band increases are found in prefrontal and cingulate cortices. Significant beta decoupling is found in interactions between basal ganglia and neocortex. These findings suggest ketamine may exert its dissociative and cognitive effects through alterations in the fundamental rhythms that organize cortical-subcortical information processing.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 2
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
EEG/MEG Modeling and Analysis
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Subcortical Structures
Novel Imaging Acquisition Methods:
EEG 1
Keywords:
Basal Ganglia
ELECTROCORTICOGRAPHY
Electroencephaolography (EEG)
ELECTROPHYSIOLOGY
Psychiatric Disorders
Schizophrenia
Sub-Cortical
Systems
1|2Indicates the priority used for review
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2. Donoghue, T., Haller, M., Peterson, E. J., Varma, P., Sebastian, P., Gao, R., Noto, T., Lara, A. H., Wallis, J. D., Knight, R. T., Shestyuk, A., & Voytek, B. (2020). Parameterizing neural power spectra into periodic and aperiodic components. Nature Neuroscience, 23(12), 1655–1665.
3. Niesters, M., Khalili-Mahani, N., Martini, C., Aarts, L., Van Gerven, J., Van Buchem, M. A., Dahan, A., & Rombouts, S. (2012). Effect of Subanesthetic Ketamine on Intrinsic Functional Brain Connectivity: A Placebo-controlled Functional Magnetic Resonance Imaging Study in Healthy Male Volunteers. Anesthesiology, 117(4), 868–877.
4. Pribish, A., Wood, N., & Kalava, A. (2020). A Review of Nonanesthetic Uses of Ketamine. Anesthesiology Research and Practice, 2020(1), 5798285.
5. Rivolta, D., Heidegger, T., Scheller, B., Sauer, A., Schaum, M., Birkner, K., Singer, W., Wibral, M., & Uhlhaas, P. J. (2015). Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical–Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings. Schizophrenia Bulletin, 41(5), 1105–1114.