Highlights
• Bilateral neural interactions, excitatory and inhibitory, are present across the motor network during unimanual movements.
• An increase in task difficulty requires more efficient communication between hemispheres.
• Anatomical properties of transcallosal fiber tracts enable essential interhemispheric information exchange.
• Left (pre)motor areas play a key role in complex motor tasks.
Abstract: Motor control is a fundamental challenge for the central nervous system. In this review, we show that unimanual movements involve bi-hemispheric activation patterns that resemble the bilateral neural activation typically observed for bimanual movements. For unimanual movements, the activation patterns in the ipsilateral hemisphere arguably entail processes that serve to suppress interhemispheric cross-talk through transcallosal tracts. Improper suppression may cause involuntary muscle co-activation and as such it comes as no surprise that these processes depend on the motor task. Identifying the detailed contributions of local and global excitatory and inhibitory cortical processes to this suppression calls for integrating findings from various behavioral paradigms and imaging modalities. Doing so systematically highlights that lateralized activity in left (pre)motor cortex modulates with task complexity, independently of the type of task and the end-effector involved. Despite this lateralization, however, our review supports the idea of bi-hemispheric cortical activation being a fundamental mode of upper extremity motor control.
Keywords: UnimanualInterhemisphericMotor cortexMotor coordinationCorpus callosumBilateral activationElectroencephalography (EEG)Magnetoencephalography (MEG)Transcranial magnetic stimulation (TMS)Functional magnetic resonance imaging (fMRI)Structural MRI
4. Discussion
The question whether unimanual movements have a bilateral neural representation comes with quite some history. For many years it has been considered textbook knowledge that movement execution with one hand is characterized by largely – if not entirely – contralateral activation in the brain. This idea dates back to the nineteenth century and is based on early studies on animal brains and/or human pathology using invasive electrical stimulation (Jackson et al., 1870; Schiff, 1859). Gustav Fritsch together with Eduard Hitzig (1870) and, independently, David Ferrier (1873) stimulated the cortex surface of different (anesthetized) mammals and evoked movements in different parts of the contralateral side of the body. These studies allowed researchers to identify ordered motor maps within this contralateral hemisphere, in particular by Clinton Woolsey and Wilder Penfield in non-human mammals and in humans, respectively (Penfield and Boldrey, 1937; Woolsey and Fairman, 1946). In fact, Penfield and Boldrey (1937) identified the human motor homunculus just anterior to central sulcus (M1), i.e. the representation of body parts in brain areas containing an ensemble of neurons that, when activated, result in motor output. Especially in finely controlled limb muscles (fingers, hands, arms, legs), but also in the tongue, are these areas relatively large. These seminal studies were followed by studies on the SMA, where muscle activation on the contralateral side of the body could be evoked through electrical stimulation, much like stimulation of M1 (Woolsey, 1952).
4.1. Crossed and uncrossed fibers
By now, pyramidal tracts are the best-studied efferent pathways of the cortical motor system (Davidoff, 1990; Nyberg‐Hansen and Rinvik, 1963; Woolsey et al., 1972). Most of these tracts are bilaterally symmetrical and the bulk of fibers cross over to the opposite side at the pyramidal decussation – figures vary between about 70%–90% that undergo this crossing but the majority of studies tend towards higher percentages though this depends on the end-effector under study. For example, primates’ hand and finger muscles seem to have more uncrossed fibers (Al Masri, 2011; Hong et al., 2010; Nathan et al., 1990)). The remaining fibers (∼10-30 %) do not cross before they reach the spinal cord (Carson, 2005). The presence of these non-crossing fibers underlies the appealing idea that the ipsilateral hemisphere is involved in movements not only at the contralateral side of the body, but also at the ipsilateral side as extensively outlined here. An example for a possible model including ipsilateral control, i.e. an alternative to the combination of interhemispheric excitation and intrahemispheric inhibition, is shown in Fig. 1, panel A. Interestingly, in a very recent paper Bundy and Leuthardt (2019) discussed the functional role of the ipsilateral hemisphere in motor control. They argued that the descending pathways primarily elicit movements and speculated about how the interaction through the CC may facilitate unimanual movements. And, they concluded that a balance between the excitatory and inhibitory function of interhemispheric interactions is mandatory for proper motor function. Our systematic review confirms these suggestions but also highlights that the story is not that simple. Our reading of the literature has identified three key findings that seem to underlie the hypothesized excitatory and inhibitory bilateral neural interactions, namely (a) the increase in task complexity of the unimanual task under investigation requires more efficient communication between hemispheres, (b) the anatomical properties of transcallosal fiber tracts enable this interhemispheric information exchange, and (c) the left (pre)motor areas play a key role when performing more complex motor tasks, irrespective of whether the left or right hand is being used.
In Fig. 1, we also depict another alternative, namely possible inhibitory cortico-cortical projections from S1 to M1 within a hemisphere (panel C). We added this model because of culminating evidence for synchronized or fine-tuned interactions between the periphery and S1 via feedback afferent pathways (see, e.g., Baker (2007) and references therein). Discussing this and other related animal studies in more detail is, however, beyond the scope of the current review.
4.2. Bilateral interaction
When executing a unimanual movement the human motor network shows consistent bilateral activation. This finding has been confirmed with all neuroimaging modalities reviewed here. It hence seems likely that inhibitory and faciliatory processes are needed to suppress the outflow of activity in the ipsilateral hemisphere to avoid bimanual motor (co-) activation.
TMS studies have revealed both an increase and a decrease in IHI. These conflicting IHI patterns might be explained by differences in experimental settings, especially the type of conditioning stimuli. The intensity of the stimuli could be adjusted to compensate for the increased MEP amplitude induced at the stimulus side because of the unimanual movements (Nelson et al., 2009; Sattler et al., 2012) and may hence yield a reduced IHI. By contrast, when conditioning stimuli are not adjusted to compensate for the stimulus-induced increase in MEP amplitude, IHI may increase (Hinder et al., 2010a, b; Liang et al., 2014; Uehara et al., 2014; Vercauteren et al., 2008). According to Brocke et al. (2008) these inhibitory processes are accompanied by measurable changes in the local neurovascular signal. As we summarized, unimanual movements are associated with BOLD activation in the contralateral and deactivation in the ipsilateral sensorimotor cortices. It has been suggested that this deactivation in the ipsilateral hemisphere could be caused by transcallosal inhibition involving GABAergic interneurons (Matsumura et al., 1992), an idea that might deserve future exploration.
BOLD changes of bilateral premotor areas seem strongly correlated with each other, as well as with the changes in M1 contralateral to the moving hand. This agrees with EEG and MEG assessments that revealed a decrease in both alpha and beta power, and an increase in coherence between bilateral premotor and sensorimotor cortices when performing unimanual movements. This bilateral coupling becomes more pronounced with increasing task complexity. There, symmetry appears broken in that left PM is especially active during both left- and right-hand complex movements. This is particularly interesting in view of the so-called ‘motor dominance theory’ that suggests that the left hemisphere is more capable than the right one to support motor activity; it hence might always be involved in motor execution, be that with the right or the left hand (Callaert et al., 2011; Ziemann and Hallett, 2001).
4.3. Task dependency
The direction and location of both inhibition and facilitation appears to depend on the motor task that is performed. Overall, an experimentally induced increase in task complexity, in particularly an increase in motor timing requirements, seems to be accompanied with more (efficient) communication between hemispheres. For unimanual movements we envision the following scenario when task complexity increases: Inhibition of the ipsilateral hemisphere likely increases, while inhibition of the contralateral hemisphere likely reverses into facilitation when the motor task becomes more challenging. Several research groups forwarded the idea that activation patterns of complex motor control operate at a ‘high level’ (Donoghue and Sanes, 1994; Gerloff et al., 1998a; Hummel et al., 2003; Manganotti et al., 1998; Sadato et al., 1996), but this level remains ill defined. Hummel et al. (2003) suggested that a task-complexity related increase in ipsilateral activation is not caused by motor memory load but by processing increasingly difficult transitions between movements. Interestingly, however, task-dependent activations, both excitatory and inhibitory, are not restricted to bilateral M1s, but are also present in other parts of the motor network, in particular in SMA and PM (Andres and Gerloff, 1999). The role of SMA in the preparation and performance of sequential movements has been demonstrated by, e.g., Gerloff et al. (1997), where stimulation with rTMS over SMA induced errors in motor performance in the more complex sequences. And, the role of left PM has been discussed above.
4.4. Outlook
4.4.1. Multimodal approaches
As highlighted in the Introduction, the CC is the main gateway for interhemispheric communication. A positive correlation was reported between the callosal thickness of the CC and the hand performance of the (right) dominant hand, but not of the (left) non-dominant hand (Kurth et al., 2013; Sehm et al., 2016). According to the aforementioned motor dominance theory one might speculate that this pattern of results will also be observed with left-handed participants. One could then assume that the left hemisphere is more involved in the support of motor activity and that the thickness of the CC is mainly related to the passage from left to right M1.
Stronger structural connectivity (higher FA) is associated with the reduction of unwanted mirror movements. Likewise, age-related atrophy implies weaker structural connectivity yielding stronger functional connectivity and poorer performance (Fling et al., 2012; Langan et al., 2010; Sullivan et al., 2010).
Earlier work investigated whether the CC exerts an inhibitory or excitatory role in the interhemispheric communication and concluded that there is evidence in the literature for both outcomes, although most studies support the excitatory function of the CC in interhemispheric communication (Bloom and Hynd, 2005; Carson, 2005; van der Knaap and van der Ham, 2011). As likewise hypothesized in the introduction, if transcallosal pathways are primarily excitatory and if the motor network shows (almost) symmetric, bilateral activation patterns while moving unimanually, then this indicates some type of intrahemispheric inhibition mediated through intrahemispheric pathways probably involving the premotor areas (Daffertshofer et al., 2005; Stinear and Byblow, 2002).
Combining the findings of multimodal approaches to study unimanual movements may help indeed to better understand how the brain enables the fine-tuned motor coordination that we are capable of. Still, several questions concerning the control of unilateral hand movements remain unanswered. Based on this review, we suggest that future research should investigate the role of the left hemisphere in greater detail, in particular the left PM. There is some evidence that this area plays a key role in the control of unimanual movements, but more research is needed, specifically with both left- and right-handed participants, to confirm this.
Only a few studies linked structural and functional connectivity in one experiment while performing unimanual movements (cf. Supplementary Material S2, Table 5). This is unfortunate because – as we outlined here – unimanual movements are likely to rely on the interhemispheric cross-talk through transcallosal tracts. We do suggest to intensify the research that combines different modalities as this may be key to unravel all the factors involved in unimanual motor control.
4.4.2. Integrating other populations
Our main aim was to specify the determinants and functional role of the often reported, bilateral activation patterns in the cortex during normal unimanual motor control in healthy humans. For this review we only included non-invasive studies, since invasive approaches may alter the normally functioning brain and, by this, the normal control of unimanual behavior. Yet, there is much to learn by combining our finding with the plenitude of studies in non-human primates, let alone studies on impaired motor control as observed in, e.g., stroke patients. For instance, Grefkes and Ward (2014) identified that lesions in M1 can lead to proportional changes in ventral PM activity. In fact, they argued that inactivation of either ipsi- or contralateral M1 or contralateral ventral PM deteriorates hand function recovery post stroke (there experimentally induced macaque monkeys). Interestingly, studies on partly hemiparetic stroke patients revealed unimanual movement of the affected (contralesional) side to display clearly bilateral neural activity. While this may indicate the ‘emergence’ of ipsilateral control to compensate motor impairment post stroke, one has to realize that motor learning of the non-affected side can limit the recovery of the affected one (Boddington and Reynolds, 2017; Dodd et al., 2017), which arguably speaks for a (dis-)balance of interhemispheric excitation versus intrahemispheric inhibition (Grefkes and Ward, 2014; Koch et al., 2016), as advocated here.
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