Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Abstract

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Keywords: motor cortex; pre-supplementary motor area; substantia nigra; transcranial magnetic stimulation.

FIGURE 1

Flowchart illustrating the inclusion/exclusion criteria and participants in each group. Stage 1 screening includes medical history questionnaire, magnetic resonance imaging (MRI) safety screen, and transcranial magnetic stimulation (TMS) safety screen. Stage 2 screening includes neuropsychological assessment and transcranial ultrasound of the substantia nigra. Stage 3 screening is the neurological examination performed by a neurologist that specializes in movement disorders. ^aHistory of neurological damage and/or illness, history of diagnosed medicated mental/psychiatric disease or disorder, and/or self‐reported prior or current use of antipsychotic medications. ^bTested late in study and excluded due to oversupply of SN− participants. ^cParticipant disclosed disease/disorder that was not reported on medical history questionnaire, or neurologist identified potential undiagnosed neurological disease/disorder. Abbreviations: SN− group, normal area of substantia nigra echogenicity on the right and left side; SN+ group, abnormally large area of substantia nigra echogenicity on the right and/or left side.

FIGURE 2

Data from two representative participants. (a) and (b) Echomorphology of the mesencephalic brainstem in one participant with normal substantia nigra echogenicity (a) and one participant with abnormal substantia nigra echogenicity (i.e., hyperechogenicity; b). Solid white line represents the outer edge of the mesencephalic brainstem. The substantia nigra ipsilateral to the probe (the side at which the planimetric measurement is collected) is encircled with a dotted line. (c) Section of ¹H MRS spectrum obtained from the pre‐supplementary motor cortex from the participant shown in panel a. Spectrum was obtained at 3T (Philips Achieva TX, Best, the Netherlands) using an eight channel head coil and the PRESS sequence (TE = 32, TR = 2 s, 1024 data points, 32 transients, VOI 2 cm³). Spectrum shown transformed with no apodization. The placement of the VOI (yellow cube) over the dorsomedial aspect of the superior frontal gyrus, at the level of Brodmann's area 6, is also displayed along the coronal (top panel), transverse (middle panel), and sagittal (lower panel) planes.

FIGURE 3

Average EMG traces from the right first dorsal interosseous muscle in one participant. The EMG response (motor evoked potential or “MEP”) evoked by single‐ and paired‐pulse transcranial magnetic stimulation (TMS) over the left motor cortex are shown. (a) Averaged MEP evoked in relaxed muscle by single‐pulse TMS at an intensity of 130% of resting motor threshold. Vertical dashed lines are placed at the boundaries of the MEP. (b) Averaged MEP evoked by single‐pulse TMS (at the same intensity) during a weak voluntary contraction. Vertical dashed lines represent the duration of the silent period (i.e., stimulus onset to resumption of voluntary EMG). Note that the size of the MEP is much larger during the voluntary contraction than during relaxation. (c) Average amplitude of the test (unconditioned) and conditioned MEP for paired‐pulse TMS during relaxation. A subthreshold stimulus (70% resting motor threshold) was delivered 3 ms before a suprathreshold test stimulus. The averages of 10 EMG traces are shown.

FIGURE 4

Variables and planned regressions in the three multivariate regression models.

FIGURE 5

Single‐subject and group data showing short‐interval intracortical inhibition and intracortical facilitation within the primary motor cortex. (a) Group data (n = 22) for the average amplitude of the motor evoked potential (MEP) across the right and left hemisphere during paired‐pulse transcranial magnetic stimulation (TMS). The boundary of each box indicates the 25th and 75th percentile and the whiskers (error bars) indicate the 10th and 90th percentiles. The solid and dashed lines within each box indicate the median and mean values, respectively. Data illustrate the significant main effects of conditioning stimulus intensity (white boxes: 70% resting motor threshold; gray boxes: 90% resting motor threshold) and condition (test and 2, 3, 10, and 12 ms interstimulus intervals) on MEP amplitude. The significant main effects were observed in a three‐way repeated measures analysis of variance (ANOVA; within subject factors: Side, conditioning stimulus intensity, and condition). *Significant difference between test MEP and conditioned MEP at 2, 3, 10, and 12 ms interstimulus intervals (p ≤ .010). ^§Significant difference between the two intensities of conditioning stimulation within a given interstimulus interval (p ≤ .021). (b) Single subject data (n = 22) showing the relationship between intracortical facilitation within the right primary motor cortex and area of echogenicity in the right substantia nigra (p = .005, multivariate linear regression). Intracortical facilitation is the average across the 10 and 12 ms interstimulus intervals (expressed as a % of the test amplitude) when the intensity of the conditioning stimulation was set at 90% resting motor threshold.