Introduction

Exercise plays a significant and multifaceted role in brain function, promoting neuroplasticity and enhancing cognitive abilities, among other benefits¹. These studies have shown that exercise increases cerebral blood flow (CBF)^1,2. These studies, however, have predominantly relied on measuring CBF in large arteries rather than at the tissue or regional levels^r2. Here, the aim was to use ASL MRI to assess gray matter (GM) CBF before, during, and after exercise in healthy volunteers. The objective was to determine whether ASL could capture dynamic changes in GM CBF as the targeted muscles (right wrist extensors) fatigued during a long-lasting maximal isometric effort.
The motivation stemmed from the implication of fatigue in neurological diseases³. Muscle fatigue, characterized as a reduction in the capacity of a muscle or group of muscles to generate force, can be influenced by a range of physiological and neurological factors as well as factors like exercise intensity, duration, and fitness level. Notably, fatigue is frequently cited as a symptom in neurological conditions such as Multiple Sclerosis (MS) and Parkinson's³. As MRI has become integral in the diagnosis and research of these diseases, the availability of an MRI-based method capable of providing a reliable and sensitive measurement of CBF stands to offer valuable insights into the complex interplay between CBF and other structural and functional factors associated with these conditions. These insights could significantly advance the development of more effective treatments and preventive measures.

Methods

A custom-made MRI-compatible 3D-printed device was constructed to secure the forearm in a standardized position (radial styloid process at the end of the supporting block, Figure-1). Isometric wrist extension force was applied laterally at a standardized location (1cm proximal to the middle metacarpophalangeal joint) and was measured through an MRI-compatible force transducer. Force data were collected via an MRI compatible dynamometer (MP3X; Biopac, USA).
Background suppressed pCASL⁴ images were acquired on 7 healthy young volunteers (age=21±2 years, 2 men) on a 3T Siemens Prisma system with: TE=14ms, TR=4500ms, labeling duration=1900ms, post-labeling duration=1900ms. Each condition: baseline, followed by exercise, and then rest, was acquired with 28 control/label pairs. : A T1w (MPRAGE) 1x1x1mm³ was also acquired for coregistration and tissue segmentation purposes.
For each participant, the CBF was computed using SPM12 routines and in-house developed software as previously described⁵, and included partial-volume correction (PVC) of the mean CBF for each condition⁵. Voxelwise paired t-tests were run to test for regional changes in CBF across conditions at both the single-particiapnt and group levels. The time-course of CBF data from regions that showed significant difference in CBF between exercise and baseline/rest conditions were compared with Force time-course measures obtained from the transducer. MatLab code was written to measure CBF in ROIs that showed significant change in CBF between exercise and baseline/rest conditions. Only voxels that survived the preset threshold (α=0.05, p=0.001, cluster level=80 voxels) were included.

Results

Figure-2 shows the time-course of CBF and Force in the primary motor cortex (PMC) for one of the participants; data from all participants showed a similar pattern in that there was: (1) an increase in CBF with exercise; (2) a gradual decrease in CBF during "rest"; (3) a lag in the onset of the CBF decrease to the baseline level and the decline in force. For the same participant, regions where CBF was significantly higher during exercise compared with baseline CBF are shown in Figure-3.
At the group level: The correlation between CBF and time at baseline and during exercise was found to be negligible (R² < 0.004, p > 0.7). Force exhibited a pronounced hyperbolic decline (R² = 0.877, p = 0.0001). During the "rest" period, CBF showed a discernible negative slope (R² = 0.48, p = 0.001). The primary motor control (PMC), the supplementary (Suppl), Putamen, and Anterior Cerebellum were the ROIs that showed significant change in CBF with exercise; results from these ROIs are summarized in Figure-4, with Figure-5 showing the T-maps from the paired T-test analysis.

Discussion

This study marks the first instance of using ASL MRI to assess dynamic changes in tissue CBF associated with maximum-effort isometric muscle contraction. The regional, tissue-level results appear to align with patterns observed in major arteries using Doppler and Xe-clearance techniques¹, confirming there is an initial increase in CBF followed by a gradual return to baseline levels¹. All participants exhibited a delay in the onset of CBF decrease back to baseline compared to the onset of fatigue. However, there were variations in this overall pattern among individuals, suggesting that other factors may influence the CBF response to fatigue⁶.

Acknowledgements

Authors are grateful to Samira Bouyagoub for helping with the experimental set-up and data collection, and Daniel Brooks for his assistance with 3D printing.

References

¹Ogoh S. and Ainslie P. N., J Appl Physiol 107 (2009); ²Mast I.H. et al., NeuroImage 250 (2022); ³Kluger et al., Neurology 80(4) (2013); ⁴Alsop D.C., et al., Mag Res Med, 73(1), (2015); ⁵Asllani I, et al., Mag Res Med 60(6), 2008. ⁶Smith K.J. and Ainslie P.N., Experimental Physiol., (2017).