Cholinergic brain structure and sensory-afferent modulation of motor cortex excitability

Introduction The basal forebrain provides important output within the cholinergic system. The cholinergic system may also influence the effects of paired associative stimulation (PAS), a plasticity inducing protocol involving paired median nerve and motor cortex stimulation, and short latency afferent inhibition (SAI) in which a median nerve sensory afferent stimulus induces short lasting conditioning effects on motor cortex excitability. The responses to either PAS or SAI can be variable. Here we hypothesized that the basal forebrain structural characteristics, or those of the thalamus as important sensory-afferent relay station with cholinergic input, relate to the functional influence of the cholinergic system measured using PAS or SAI. We therefore asked whether structural variability in these cholinergic brain areas could explain some of that functional variability observed with PAS or SAI. Material and methods Forty healthy volunteers (12 male; mean age 60, range 26–81) underwent a facilitatory PAS protocol with an inter-stimulus interval (ISI) of around 25 ms. An LTP-like facilitatory response was defined as an increase post-PAS of MEP amplitude of at least 10% relative to pre-PAS MEP size. SAI employed median nerve condition of motor cortex stimulation with inhibitory as well as facilitatory ISIs. We obtained T1 MPRAGE sequences on a 3T MRI scanner. MRI data were processed using Statistical Parametric Mapping and the CAT12 Toolbox (http://www.neuro.uni-jena.de/cat/) implemented in Matlab 2015a. Volumes of the basal forebrain were determined using a stereotactic atlas based on combined postmortem MRI and histological examination of cholinergic nuclei. As it is based on the histological examination of a single brain specimen and may not generalize across individuals, we also used volumes of right and left BFCS as obtained from the CAT12 toolbox. We used ANOVA models for group comparisons of responders and non-responders to PAS or SAI. Results Nineteen participants (48%) had an LTP-like response to PAS. Age, sex, or motor thresholds did not predict the PAS response. SAI had inhibitory effects in 80% of participants (n = 32). There was no association between the amount of PAS effects and the SAI response. Basal forebrain and right thalamus volumes were larger in SAI responders while volumes were similar in PAS responders and non-responders. Discussion The results suggest that a larger basal forebrain cholinergic output system, and a larger thalamus as sensory-afferent relay station that receives cholinergic input facilitate the short lasting modulation of motor cortex excitability in the SAI paradigm. This could be because of higher cholinergic tone. The cholinergic system may be less important in longer lasting modulation of motor cortex excitability in the PAS paradigm where an LTP-like response may involve more GABA-ergic neurotransmission