The neurophysiological effects of single-dose theophylline in patients with chronic stroke: A double-blind, placebo-controlled, randomized cross-over study

Abstract

Background: Reducing inhibitory neurotransmission with pharmacological agents is a potential approach for augmenting plasticity after stroke. Previous work in healthy subjects showed diminished intracortical inhibition after administration of theophylline.

Objective: We assessed the effect of single-dose theophylline on intracortical and interhemispheric inhibition in patients with chronic stroke, in a double-blind, placebo-controlled, cross-over study.

Methods: Eighteen subjects were randomly administered 300 mg of extended-release theophylline or placebo. Immediately and 5 hours following administration, transcranial magnetic stimulation was used to assess bihemispheric resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, and interhemispheric inhibition. Adverse effects on cardiovascular, neurological, and motor performance outcomes were also surveilled. Change between morning and afternoon sessions were compared across conditions. One week later, patients underwent the same assessments after crossing over to the opposite experimental condition. Subjects and investigators were blinded to the experimental condition during data acquisition and analysis.

Results: For both hemispheres, changes in intracortical or interhemispheric neurophysiology were comparable under theophylline and placebo conditions. Theophylline induced no adverse neurological, cardiovascular, or motor performance effects. For both conditions and hemipsheres, the baseline level of inhibition inversely correlated with its change between sessions: less baseline inhibition (i.e. disinhibition) was associated with a strengthening in inhibition over the day, and vice versa.

Conclusion: A single dose of theophylline is well-tolerated by patients with chronic stroke, but does not alter cortical excitability. The inverse relationship between baseline inhibition and its change suggests the existence of a homeostatic process. The lack of effect on cortical inhibition may be related to an insufficiently long exposure to theophylline, or to differential responsiveness of disinhibited neural circuitry in patients with stroke.

Keywords: Recovery of function; cerebral infarction; homeostasis; motor cortex; transcranial magnetic stimulation.

Fig. 1

Resting motor thresholds in the lesioned (A) and nonlesioned (B) hemispheres under placebo and theophylline conditions. Changes from morning (AM) to afternoon (PM) sessions were not significantly different between placebo and theophylline. Values are maximum stimulator output (MSO) mean±SD.

Fig. 2

Short-interval intracortical inhibition with a 1 ms ISI in the lesioned (A) and nonlesioned (B) hemispheres under placebo and theophylline conditions. Changes from morning (AM) to afternoon (PM) sessions were not significantly different between placebo and theophylline. Normalized MEP amplitudes are mean ± SD.

Fig. 3

Short-interval intracortical inhibition with a 2 ms ISI in the lesioned (A) and nonlesioned (B) hemispheres under placebo and theophylline conditions. Changes from morning (AM) to afternoon (PM) sessions were not significantly different between placebo and theophylline. Normalized MEP amplitudes are mean ±SD.

Fig. 4

Long-interval intracortical inhibition under placebo and theophylline conditions in the lesioned (A) and nonlesioned (B) hemispheres. Changes from morning (AM) to afternoon (PM) sessions were not significantly different between placebo and theophylline. Normalized MEP amplitudes are mean ± SD.

Fig. 5

Interhemispheric inhibition projecting onto the lesioned (A) and nonlesioned (B) hemispheres under placebo and theophylline conditions. Changes from morning (AM) to afternoon (PM) sessions were not significantly different between placebo and theophylline. Normalized MEP amplitudes are mean ± SD.

Fig. 6

Correlations between morning value of SICI_2ms and its delta between morning and afternoon, assessed by condition (placebo and theophylline) and hemisphere (lesioned and nonlesioned). All relationships were strongly inversely correlated and significant (p < 0.001) across conditions and hemispheres. This relationship indicates that subjects with higher morning values (i.e., baseline disinhibition) tend to become more inhibited by the afternoon, whereas subjects with lower morning values (i.e., strong baseline inhibition) tend to become less inhibited by the afternoon. A. Placebo, lesioned hemisphere. B. Placebo, nonlesioned hemisphere. C. Theophylline, lesioned hemisphere. D. Theophylline, nonlesioned hemisphere.

Fig. 7

Hand strength and dexterity under placebo and theophylline conditions. Changes from morning (AM) to afternoon (PM) in pinch strength in the paretic (A) and nonparetic (B) hands, time of 9-Hole Peg Test (9HPT) completion in the paretic (C) and nonparetic (D) hands, and errors (peg drops) on the 9HPT in the in the paretic (E) and nonparetic (F) hands did not significantly differ between placebo and theophylline. Values are mean ±SD.