4.1 Clinical assessment of LAH
In this longitudinal study, we assessed behavioral performances of the less-affected hand (LAH) in 28 patients at three sessions. LAH impairment was frequent one-month post-stroke, ranging from 16-61%, in line with previous studies. (Jones et al., 1989; Kitsos et al., 2013; Marque et al., 1997; Noskin et al., 2008; Semrau et al., 2017) At the chronic phase of stroke, the impairment of LAH was influenced by the type of the task. PPT and handgrip that require motor components remained impaired, while MST may be insensitive to movement time delays that require kinematic measures to be evidenced (Bustren, Sunnerhagen, & Alt Murphy, 2017; Metrot et al., 2013). Furthermore, baseline LAH performances correlated with the outcome at follow-ups and may become a useful tool in future clinical trials.
4.2 Mechanisms of LAH impairment
Our findings showed that several tracts including the i-CST, c-ALIC, CC, and i-SLF, depending on the task, were associated with LAH impairment.
We found moderate to strong correlations between the three LAH scores and FA in the ipsilesional CST, while no correlation was observed with contralesional CST-CSR and CST-PLIC, suggesting that LAH impairment is driven by the ipsilesional CST. Furthermore, i-CST was a strong predictor of PPT and grip impairment. These findings suggest that LAH impairment requiring motor processing such as PPT and grip relates to the damaged uncrossed fibers of the ipsilesional CST (Fig. 1 & S4A). These fibers terminate in the ventromedial intermediate zone to propriospinal neurons connected to distal motoneurons through intersegment spinal interneurons and may be involved in the motor control of dexterous hand movements (Tohyama et al., 2017). Taken together, our results support the hypothesis that damaged uncrossed ipsilateral CST fibers contribute to the motor components of LAH impairment.
LAH scores were also correlated with FA in bilateral ALIC and ACR, and CC. LMMs showed that PPT and handgrip impairment was associated with c-ALIC. Although ACR has been linked to cognition and particularly to attention in adults with brain injury (Niogi et al., 2008), a part of ACR fibers originate in the SMA, descend through the ALIC (Morecraft et al., 2002), and then merge with the CST in the CP (Schmahmann & Pandya, 2006), which continues in the pons and medulla to decussate at the pyramid caudal end (Fries et al., 1993; Schmahmann & Pandya, 2006). The involvement of SMA in simple motor tasks is documented by stroke studies, with SMA lesions leading to mild motor deficits (Fries et al., 1993), and i-SMA fMRI-related activity supporting motor recovery (Favre et al., 2014; Grefkes et al., 2008). Therefore, motor control components of LAH impairment may also implicate the contralesional CST through the transcallosal fibers and c-ALIC fibers from premotor and/or prefrontal areas (Fig. 1 and S4.B).
We found that LAH scores correlated with CC FA, which predicted MST. A role of the CC is motor coordination of bimanual (Andres et al., 1999) and unilateral hand motor movements through the balance of excitatory and inhibitory interhemispheric interactions (Chettouf et al., 2020). The ipsi- and contralesional motor areas exert a reciprocal influence through transcallosal fibers (Leichnetz, 1986), as evidenced in tracer studies showing reciprocal transcallosal connections for both MI and SMA (Gould, Cusick, Pons, & Kaas, 1986). In nonhuman primates, SMA lesions impaired the LAH motor program through transcallosal connections to contralesional SMA (Brinkman, 1984). Of note, c-ALIC and CC predicted worse LAH performances when accounting for the effects of i-CST and i-SLF, suggesting that LAH impairment may be compounded by the imbalance between ipsilesional and contralesional motor regions.
Our results showed that LAH impairment correlated with decreased FA in bilateral SLF and that i-SLF predicted PPT and MST. These findings support the theory that LAH impairment relates to unilateral movement bilateral hemispheric control (Chettouf et al., 2020; Jones et al., 1989; Kitsos et al., 2013; Noskin et al., 2008). In this view, the damaged hemisphere would alter LAH movements. Indeed, unimanual motor tasks implicating visuomotor components yield bilateral activity in the frontoparietal network (Cavina-Pratesi et al., 2018; Cavina-Pratesi et al., 2010; Chettouf et al., 2020; Culham et al., 2003). In agreement with this literature, PPT and MST, which require visuomotor control in contrast to handgrip, were associated with the SLF, a key structure of the frontoparietal network connecting parietal, premotor, and motor frontal areas in both human (Makris et al., 2005; Thiebaut de Schotten et al., 2011; Wang et al., 2016) and nonhuman primates (Schmahmann & Pandya, 2006). Furthermore, our findings that SLF disruptions alter LAH with visuomotor processing are supported by previous works showing an essential role for the SLF in motor planning and kinematic components of movement execution (Budisavljevic et al., 2017),.
We found consistent correlations between LAH impairment and spatial and attentional cognitive deficits that may result from SLF, ACR or ALIC disruptions, depending on the cognitive domain. Interestingly, excluding patients with cognitive deficit did not significantly improve LAH performances, suggesting that cognitive impairment was not a major cause of LAH impairment in this study. Nevertheless, as patients with severe apraxia or neglect were excluded from our study, we may have underestimated the influence of cognitive impairment on LAH impairment related to apraxia and neglect (Sunderland et al., 1999).
4.3 The role of the lesion volume
Lesion volume correlated with LAH impairment and predicted PPT and MST, consistently with nonhuman macaque experiments (Darling et al., 2011). Surprisingly, few studies, if any, have explored the relationships between lesion volume and LAH impairment in humans. Our results showing that LAH tasks with visuomotor processing were compounded by lesion volume provide empirical support for the notion of mass action through redundancy in the visuomotor system (Glassman, 1987).
4.4 Limitations
The small sample size is the main limitation of this study. However, this is the first study exploring the microstructural white matter disruptions to understand the underlying mechanisms of LAH impairment following stroke. Also, the longitudinal design with repeated measures for both behavioral and FA measures, the homogeneity of our population in terms of age, absence of leukoaraïosis, and stroke severity and territory, and the high model accuracy suggest that the sample size was adequate for this study. Nevertheless, the small sample may explain why we did not observe any effect of the lesion side, in contrast with others (Varghese & Winstein, 2019). Moreover, this study was part of a randomized clinical trial assessing cell therapy, which might have influenced outcomes. To account for this limitation, all LMMs were adjusted for cell therapy.