Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation

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.

Altered paired associative stimulation‐induced plasticity in NMDAR encephalitis

“…However, ICF is not solely mediated by NMDAR, but also by GABA A receptors as indicated in studies with benzodiazepines4, 40, 41 as well as by non‐NMDA glutamate receptors 4, 42. In addition, ketamine, an NMDAR antagonist, showed no effects on ICF 16. PAS is known to be predominantly mediated via NMDAR, however, also other neurotransmitters with different dominance are likely involved.…”

“…This so‐called PAS8 is now a widely used protocol to noninvasively investigate rapid‐onset cortical plasticity in healthy subjects and neurological patients 9, 10, 11, 12. Importantly, it has been shown to predominantly reflect NMDAR function,8, 13, 14 whereas MEP and motor threshold (MT) are relatively independent from NMDAR function 4, 8, 13, 15, 16, 17…”

Transcranial Magnetic Stimulation to Investigate Motor Cortical Circuitry and Plasticity in Spinal Cord Injury

“…The inhibitory effect originates from the GABA A receptor mediated IPSP, which has a duration of around 20ms [72] this is supported by a decrease in ICF in the presence of benzodiazepines [73] The facilitatory component of ICF is most likely due to NMDA receptor mediated excitatory postsynaptic potentials [74] as seen by decreases in ICF by NMDA receptor antagonists [75,76]. Ketamine [77], a NMDA receptor antagonist, does not seem to change ICF contrary to other NMDA antagonists, suggesting ICF is mediated via NMDA and non-NMDA receptors [74]. ICF was tested in a case study of a 67 year old woman with C8-T1 ischemic myelopathy with CS and TS at 80% and 120% RMT, respectively, and using inter-pulse intervals of 10 and 15ms.…”

TRPV1 Channels Regulate Cortical Excitability in Humans

“…Paired-pulse TMS was used to assess short-interval cortical facilitation (SICF; believed to follow the activation of glutamatergic cortical interneurons) (Di Lazzaro et al, 2003), short-interval cortical inhibition/facilitation (SICI/ICF; mediated by intrinsic GABA A ergic or excitatory circuits) (Kujirai et al, 1993;Ziemann, 2004;Florian et al, 2008), and long-interval intracortical inhibition (LICI; mediated by local GABA B pathways) (Valls-Solé et al, 1992;Werhahn et al, 1999) of the right M1.…”