Cortisol inhibits neuroplasticity induction in human motor cortex

Abstract

We investigated whether plasticity of human motor cortex (M1) is influenced by time of day, and whether changes in circulating levels of cortisol contribute to this effect. Neuroplasticity was induced using paired associative stimulation (PAS), involving electrical stimulation of left median nerve, paired with transcranial magnetic stimulation over the right M1 25 ms later (90 pairs at 0.05 Hz). Surface EMG was recorded from the left abductor pollicis brevis (APB) and first dorsal interosseous muscle. Cortisol levels were assessed from saliva. Time-of-day modulation of PAS effectiveness was assessed in 25 subjects who were tested twice, at 8:00 A.M. and 8:00 P.M. on separate days. In a second double-blind study, 17 subjects were tested with PAS at 8:00 P.M. on two occasions after administration of oral hydrocortisone (24 mg) or placebo. The motor-evoked potential (MEP) in resting APB increased significantly after PAS in the evening (when endogenous cortisol levels were low), but not in the morning. Oral hydrocortisone prevented facilitation of the APB MEP after PAS, and in the drug study, mean salivary cortisol levels were negatively associated with PAS effectiveness. The GABA(B)-mediated cortical silent period for APB was longer in the morning than in the evening, and was lengthened by PAS and oral hydrocortisone. We conclude that neuroplasticity in human M1 and GABA(B)-dependent intracortical inhibitory systems are influenced by time of day and modified by circulating levels of cortisol.

Figure 1.

A, B, Schematic diagram of the testing protocol indicating the approximate relative timings for assessment of neurophysiological parameters before and after PAS in experiment 1 (A) and experiment 2 (B). The gray bars indicate when saliva samples were collected. Measurements of APB MEP amplitude were made at two time points: pre-PAS and post-PAS. Ingestion, Oral dose of hydrocortisone or placebo.

Figure 2.

A, B, Group (mean ± SEM) MEP amplitude for APB (A) and FDI (B) before (pre-PAS) and after (post-PAS) paired associative stimulation. Data are from morning experiments (am) on the left, and evening (pm) experiments on the right. APB MEP amplitude was significantly larger post-PAS than pre-PAS in the evening session (*p < 0.001), but not in the morning. APB MEP amplitude post-PAS was significantly greater in the evening than in the morning (^#p < 0.001). FDI MEP amplitude (B) was not affected by PAS or time of day.

Figure 3.

Group (mean ± SEM) data of cortical silent period duration before (pre-PAS) and after (post-PAS) paired associative stimulation. Data from morning experiments (am) are on the left, and evening (pm) experiments are on the right. Cortical silent period duration was significantly longer in the morning (*p = 0.006) than in the evening. There was a significant increase in cortical silent period duration after PAS in both the morning and evening sessions (^#p = 0.002).

Figure 4.

Influence of PAS and time of day on SICI. Group (mean ± SEM) SICI data from 20 subjects assessed in the morning (am; circles) and evening (pm; triangles), before (pre-PAS; filled symbols) and after (post-PAS; open symbols) paired associative stimulation. SICI was assessed with paired-pulse TMS using four different conditioning TMS intensities (60–90% AMT), with an interstimulus interval of 3 ms. SICI was quantified as percentage of MEP amplitude obtained in conditioned trials compared with test-alone trials. SICI was unchanged after PAS both in the A.M. and P.M.. The overall level of SICI did not differ between A.M. and P.M. sessions.

Figure 5.

A, B, Group (mean ± SEM) MEP amplitude for APB (A) and FDI (B) before (pre-PAS) and after (post-PAS) paired associative stimulation. Data from the hydrocortisone (cortisol) administration session are on the left, and data from the placebo session are on the right. APB MEP amplitude was significantly larger post-PAS than pre-PAS in the placebo session (*p = 0.007), but not in the cortisol session. APB MEP amplitude post-PAS was significantly greater in the placebo than in the cortisol session (^#p = 0.039). FDI MEP amplitude (B) was not affected by PAS or medication.

Figure 6.

Group (mean ± SEM) data of cortical silent period duration before (pre-PAS) and after (post-PAS) paired associative stimulation. Data from the hydrocortisone (cortisol) administration group are on the left, and data from the placebo group are on the right. Cortical silent period duration was significantly longer in the cortisol (*p < 0.001) than in the placebo group. There was a significant increase in cortical silent period duration after PAS in both sessions (^#p < 0.001).

Figure 7.

A–F, Salivary cortisol concentration (A, B) and the relationship between salivary cortisol concentration and APB MEP facilitation after PAS (C, D) and cortical silent period duration (E, F). Data from study 1 (endogenous cortisol) are on the left, and data from study 2 (hydrocortisone administration) are on the right. Pre-PAS salivary cortisol concentration in the morning was significantly greater than all other samples (A) (*p < 0.001). Post-PAS salivary cortisol concentration in the morning was significantly greater than both P.M. samples, but less than the pre-PAS A.M. sample (^#p < 0.001). B, Exogenous cortisol administration significantly elevated salivary cortisol concentration in the evening compared with placebo (*p < 0.001). C, Linear regression analysis revealed a nonsignificant relationship (r² = 0.04) between the log of average salivary cortisol concentration and APB MEP facilitation ratio (post-PAS MEP amplitude/pre-PAS MEP amplitude) in study 1 (endogenous cortisol). D, Linear regression analysis revealed a significant negative relationship (r² = 0.13, p = 0.039) between the log of average salivary cortisol concentration and APB MEP facilitation ratio in study 2 (hydrocortisone administration). E, Nonsignificant relationship (r² = 0.002) between the log of average salivary cortisol concentration and pre-PAS cortical silent period duration in study 1. F, Significant relationship (r² = 0.14, p = 0.028) between the log of average salivary cortisol concentration and pre-PAS cortical silent period duration in study 2.