Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation
Vincenzo Di Lazzaro, Antonio Oliviero, Paolo Profice, Manuela Pennisi, Fabio Pilato, Geremia Zito Marinosci, M. Dileone, Rossella Nicoletti, Patrizio Pasqualetti, P. Tonali
The Journal of Physiology March 1, 2003 DOI: 10.1113/jphysiol.2002.030486 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Sample size | 7 |
| Population | Normal human subjects |
| Intervention | Ketamine |
| Dose | 0.01, 0.02 and 0.04 mg kg−1 min−1, i.v. |
| Topics | Ketamine Esketamine |
| Keywords | Transcranial magnetic stimulation Nmda receptor Glutamatergic Motor cortex Glutamate receptor Anesthesia Antagonist Excitatory postsynaptic potential |
| Citations | 255 |
| Key findings | Subanesthetic doses of ketamine reduce resting and active motor thresholds and increase motor-evoked potential amplitudes to transcranial magnetic stimulation, indicating enhanced motor cortex excitability via increased non-NMDA glutamatergic transmission. |
Abstract
Subanaesthetic doses of the N ‐methyl‐ d ‐aspartate (NMDA) antagonist ketamine have been shown to determine a dual modulating effect on glutamatergic transmission in experimental animals, blocking NMDA receptor activity and enhancing non‐NMDA transmission through an increase in the release of endogenous glutamate. Little is known about the effects of ketamine on the excitability of the human central nervous system. The effects of subanaesthetic, graded incremental doses of ketamine (0.01, 0.02 and 0.04 mg kg −1 min −1 , i.v .) on the excitability of cortical networks of the human motor cortex were examined with a range of transcranial magnetic and electric stimulation protocols in seven normal subjects. Administration of ketamine at increasing doses produced a progressive reduction in the mean resting motor threshold (RMT) ( F (3, 18) = 22.33, P < 0.001 ) and active motor threshold (AMT) ( F (3, 18) = 12.17, P < 0.001 ). Before ketamine administration, mean RMT ± s.d . was 49 ± 3.3 % of maximum stimulator output and at the highest infusion level it was 42.6 ± 2.6 % ( P < 0.001 ). Before ketamine administration, AMT ± s.d . was 38 ± 3.3 % of maximum stimulator output and at the highest infusion level it was 33 ± 4.4 % ( P < 0.002 ). Ketamine also led to an increase in the amplitude of EMG responses evoked by magnetic stimulation at rest; this increase was a function of ketamine dosage ( F (3, 18) = 5.29, P = 0.009 ). In contrast to responses evoked by magnetic stimulation, responses evoked by electric stimulation were not modified by ketamine. The differential effect of ketamine on responses evoked by magnetic and electric stimulation demonstrates that subanaesthetic doses of ketamine enhance the recruitment of excitatory cortical networks in motor cortex. Transcranial magnetic stimulation produces a high‐frequency repetitive discharge of pyramidal neurones and for this reason probably depends mostly on short‐lasting AMPA transmission. An increase in this transmission might facilitate the repetitive discharge of pyramidal cells after transcranial magnetic stimulation which, in turn, results in larger motor responses and lower thresholds. We suggest that the enhancement of human motor cortex excitability to transcranial magnetic stimulation is the effect of an increase in glutamatergic transmission at non‐NMDA receptors similar to that described in experimental studies.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| S(+)-ketamine Effect on Experimental Pain and Cardiac Output Healthy adult volunteers (10 men and 10 women) | 2009 | Pharmacokinetic-pharmacodynamic modeling study in healthy volunteers | n = 20 |
| Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression Patients with treatment-resistant bipolar depression | 2012 | Population pharmacokinetic analysis | n = 9 |
Citations in the library
Cited by 10
- KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS Depression and Anxiety April 6, 2016
- Increased signal diversity/complexity of spontaneous EEG, but not evoked EEG responses, in ketamine-induced psychedelic state in humans. PLoS One November 23, 2020
- Ketamine as a Fast Acting Antidepressant: Current Knowledge and Open Questions CNS Neuroscience & Therapeutics April 12, 2013
- Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity. Progress in Neuro-Psychopharmacology and Biological Psychiatry July 5, 2025
- The role of frontal EEG in predicting clinical response of major depressive disorder to intranasal ketamine and esketamine. Journal of Affective Disorders November 22, 2025
and 5 more in the library
Cites 3
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983