The aging motor system as a model for plastic changes of GABA-mediated intracortical inhibition and their behavioral relevance

Abstract

Since GABAA-mediated intracortical inhibition has been shown to underlie plastic changes throughout the lifespan from development to aging, here, the aging motor system was used as a model to analyze the interdependence of plastic alterations within the inhibitory motorcortical network and level of behavioral performance. Double-pulse transcranial magnetic stimulation (dpTMS) was used to examine inhibition by means of short-interval intracortical inhibition (SICI) of the contralateral primary motor cortex in a sample of 64 healthy right-handed human subjects covering a wide range of the adult lifespan (age range 20-88 years, mean 47.6 ± 20.7, 34 female). SICI was evaluated during resting state and in an event-related condition during movement preparation in a visually triggered simple reaction time task. In a subgroup (N = 23), manual motor performance was tested with tasks of graded dexterous demand. Weak resting-state inhibition was associated with an overall lower manual motor performance. Better event-related modulation of inhibition correlated with better performance in more demanding tasks, in which fast alternating activation of cortical representations are necessary. Declining resting-state inhibition was associated with weakened event-related modulation of inhibition. Therefore, reduced resting-state inhibition might lead to a subsequent loss of modulatory capacity, possibly reflecting malfunctioning precision in GABAAergic neurotransmission; the consequence is an inevitable decline in motor function.

Figure 1.

A, Observed resting-state SICI reduction over lifetime (linear regression line ± 95% CI region). B, Predicted resting-state SICI reduction over lifetime (best linear unbiased predictors ± 95% prediction intervals). SICI is presented as conditioned MEP amplitude/unconditioned MEP amplitude × 100 (log transformed). Red dashed horizontal line indicates 100% SICI (unconditioned = conditioned MEP amplitude on the log scale).

Figure 2.

A, Observed SICI_move modulation from early to late movement preparation (average ± 95% CI) averaged over the whole sample (N = 64). Time zones of movement preparation ranged from early (−5), indicating ∼35% of individual reaction time, to late (0), indicating ∼95% of individual reaction time in approximately equal steps. B, Observed SICI_move modulation (average ± 95% CI) depicted for three example age groups: dark blue, young (20–40 years of age); blue, middle-aged (40–60 years of age); light blue, old (60–90 years of age). C, Predicted age-related decrement in SICI_move modulation (best linear unbiased predictors for linear slope ± SE) during movement preparation. SICI is presented as conditioned MEP amplitude/unconditioned MEP amplitude × 100 (log transformed). Dashed horizontal line indicates 100% SICI (unconditioned= conditioned MEP amplitude on the log scale).

Figure 3.

Predicted linear slope of SICI_move modulation declines over lifetime indicating a loss of modulatory capacity in the GABA_A-mediated intracortical inhibition as a function of age.

Figure 4.

Association between resting-state SICI level and SICI_move modulation during movement preparation. The more disinhibited at rest, the weaker the modulation of event-related inhibition.

Figure 5.

Correlations between behavioral parameters and resting-state inhibition (top row), and event-related modulation of inhibition (bottom row). Overall, stronger resting-state inhibition correlated with overall better manual performance. Stronger event-related modulation of inhibition, expressed as linear slope, was associated with better performance in tasks with higher dexterous demands, i.e., higher motor processing load such as 2FT and CRT.