Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process... 2022 Barnden et al

[Andy]

Full title: Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process—Multi-Cohort Multi-Modal Evidence

Abstract

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them. We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed.

We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10−8, 5 × 10−7, 0.002), T2wSE (p =2 × 10−6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets. In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain’s primary regulatory nuclei.

We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

Open access, https://www.mdpi.com/2076-3425/12/12/1693

 

[SNT Gatchaman]

RAS = reticular activating system (also Wikipedia link)

The concluding paragraph is —

Because human myelination and the human brainstem RAS are so difficult to study, observation in a human population of factors that characterise RAS myelination and its correlation with cortical myelination is of novel importance. The novel anti-correlated brainstem-sensorimotor myelination reported here across three cohorts and six MRI modalities confirm a strong association between the two regions and suggest an important, as yet unreported, regulatory mechanism. We propose that the requirement for coherence in the RAS—intralaminar thalamus—inhibitory interneuron oscillator circuit may stimulate inhibitory interneurons to regulate sensorimotor myelination to yield circuit oscillatory coherence in the human population, and thereby produce the observed inverse myelination relationship. As more is learned about regional oligodendrocyte and myelination variability, consideration of this inverse brainstem–cortical relationship may provide important input to the creation of an integrated global myelination narrative.

 

[SNT Gatchaman]

The original basic T1 spin-echo finding was reported in Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in CFS (2018, Fukuda). It was using an "old-fashioned" MRI sequence — although it was possibly ideal to discriminate this observation. This new paper supports that prior finding by replicating with five more modern sequences.

This work was motivated by the incidental finding in a clinical T1wSE study of an anti-correlation between sensorimotor and brainstem MRI levels, which were a surrogate for myelin.

To confirm this novel relationship, we here refine the methodology of the original study and importantly, apply it to nine independent image-sets from three different cohorts and five MRI modalities.

The conventional spin-echo sequence is slow and has been replaced by fast FSE/TSE (fast or turbo spin-echo, depending on manufacturer). Acquisition time is reduced, meaning less time required for the patient to stay very still in the scanner, but the signal-to-noise ratio is reduced.

Strong results were detected in little-used spin-echo MRI which, because it is insensitive to patient-induced magnetic field inhomogeneities, has lower inter-subject variance and, therefore, enhanced statistical sensitivity to human brain tissue variability.

Spin-echo (T1wSE and T2wSE) sequences, although seldom used, will respond to myelin levels without the inter-subject variability of patient-induced magnetic field inhomogeneities that affect T2* and bedevil gradient echo images.

 

[SNT Gatchaman]

The concept of deriving details of macroscopic human myelin regulation from cross-sectional studies is quite new.

We wished to test the hypothesis that sensorimotor myelin levels in humans are regulated by the subcortical nuclei of the reticular activation system (RAS) in the brainstem in concert with the adjacent connected hypothalamus, amygdala and hippocampus.

Note they de-emphasise ME/CFS in this paper — they are simply looking at this inverse relationship, as present in HCs or patients. They report further on ME/CFS in the supplementary material, but this presumably repeats what was shown in the earlier paper. (The idea was that brainstem deficits were present in ME/CFS that were compensated for by upregulation in sensorimotor myelination.)

Datasets extended from 2006 - 2016 and used both 1.5T and 3T magnets.

... we confirmed the novel anti-correlation between subcortical (brainstem) and sensorimotor myelination reported in 2018. The inverse relationship was confirmed in two T1wSE, one T2wSE, MTC, T2SPACE and a relative WM volume image-set, all of which respond to myelin levels.

Lower myelination in the subcortical region was associated with increased myelination in sensorimotor white matter, and vice versa. This study is unique in that it reports unprecedented observations of a myelination relationship across human populations with good reproducibility.

While confirmation of anti-correlated subcortical versus sensorimotor myelination is the primary result of this paper, we propose this is a manifestation of an unreported regulatory process which maintains adequate subcortical–sensorimotor communication in humans. Below we discuss its implications for regulatory mechanisms.

We assume that there is little lifetime adaptive change in the myelination of the RAS but that the variation observed here reflects normal human variability. Possible drivers of reciprocal myelination are (i) a requirement to match the excitatory RAS-to-cortex conduction velocities to the positive feedback cortico-reticular conduction velocities, or (ii) the need for coherence in the circuits involving the RAS—intralaminar thalamus—inhibitory interneuron oscillators.

The neurology and radiology is getting a bit complex, but that's probably most of what we need for now.

Spoiler: Sidebar

if such compensation tries to be more exaggerated in some pathological states, that opens up possibilities to explain symptoms that might vary both spatially and temporally — as the compensation might be more or less effective given any number of variable system inputs.

But hey — let's just do FND / conversion disorder / hysteria.