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Evolutionally, development of the direct connection from the motor cortex to spinal motoneurons [corticomotoneuronal (CM) pathway] parallels the ability of hand dexterity. Damage to the corticofugal fibers in higher primates resulted in deficit of fractionated digit movements. Based on such observations, it was generally believed that the CM pathway plays a critical role in the control of hand dexterity. On the other hand, a number of “phylogenetically older” indirect pathways from the motor cortex to motoneurons still exist in primates. The indirect pathways are mediated by intercalated neurons such as segmental interneurons (sINs), propriospinal neurons (PNs) reticulospinal neurons (RSNs), or rubrospinal neurons (RuSNs). However, their contribution to hand dexterity remains elusive. Lesion of the brainstem pyramid sparing the transmission through the RuSNs and RSNs, resulted in permanent deficit of fractionated digit movements in macaque monkeys. On the other hand, in our recent study, after lesion of the dorsolateral funiculus (DLF) at the C5 segment, which removed the lateral corticospinal tract (l-CST) including the CM pathway and the transmission through sINs and RuSNs but spared the processing through the PNs and RSNs, fractionated digit movements recovered within several weeks. These results suggest that the PNs can be involved in the recovery of fractionated digit movements, but the RSNs and RuSNs have less capacity in this regard. However, on closer inspection, it was found that the activation pattern of hand and arm muscles considerably changed after the C5 lesion, suggesting limitation of PNs for the compensation of hand dexterity. Altogether, it is suggested that PNs, RSNs RuSNs, and the CM pathway (plus sINs) make a different contribution to the hand dexterity and appearance of motor deficit of the hand dexterity caused by damage to the corticofugal fibers and potential of recovery varies depending on the rostrocaudal level of the lesion.
Keywords: corticospinal tract, propriospinal neuron, precision grip, macaque monkeyA generally accepted concept on the neuronal mechanism of hand dexterity is that the direct corticomotoneuronal (CM) connection, which first appears in the higher primates during evolution, plays a major role in the control of hand dexterity such as the potential to control fractionated digit movements as represented by precision grip (1–4). This concept is primarily derived from (1) parallel development of the fractionated digit movements and the CM pathway (5–8), and (2) observation of human patients and lesion studies in non-human primates (9–12); stroke that affects the corticofugal fibers severely affects the fractionated digit movements in patients, and lesion of the pyramidal tract at the brainstem level permanently impairs the hand dexterity in monkeys. In addition, some of the CM cells were shown to be specifically activated during the precision grip, but not during the power grip, even though their target muscles were similarly activated (13).
On the other hand, the corticofugal fibers issue collaterals to targets at various rostrocaudal levels besides spinal motoneurons (14, 15). Thus, the direct CM pathway is not the exclusive route to spinal motoneurons, instead there are several indirect routes, which could mediate the cortical command to hand and arm motoneurons located in the lower cervical segments (C6-Th1). First, the neurons in the magnocellular red nucleus (16, 17) and the ponto-medullary reticular formation (18–21) mediate the cortical command to motoneurons via the rubrospinal tract (RuST) and reticulospinal tract (RST), respectively. In addition, it was recently determined that the propriospinal neurons (PNs) in the mid-cervical segments and segmental interneurons (sINs) in the cervical enlargement (C6-Th1) could relay the cortical inputs to motoneurons (22, 23). Moreover, the existence of the pathway from the ipsilateral cortex to spinal motoneurons, mediated by reticulospinal neurons (RSNs), has been shown in cats (24). To date, these indirect pathways have been considered not to contribute to the control of fractionated digit movements because a major advantage of the direct CM pathway was actually to bypass the indirect routes, which were considered to have too widespread connections with distal motoneurons to mediate the command for independent digit movements (25). However, recently, it has been clarified that the PNs are involved in the control of dexterous digit movements in the normal state (26, 27) and also in the recovery of precision grip after lesion of the direct CM connection. In this manuscript, the current views on the role of these indirect pathways in the control of hand dexterity in the normal state and during functional recovery after damage to the corticospinal tract will be discussed.
In this section, first, we will review the anatomy and physiology of several indirect routes from the motor cortex to spinal motoneurons (Figure (Figure1). 1 ). The direct CM pathway is primarily originated from the primary motor cortex (M1), especially in the region along the bank of the central sulcus [new M1; (28)]. On the other hand, the whole M1 (both the bank and convexity regions) and other sensorimotor cortices such as premotor (PM), supplementary (SMA), cingulate (CMA), primary somatosensory (S1) areas send descending axons to the subcortical centers and intermediate zone of the spinal cord and might contribute to the indirect pathways (15, 29–33).
Direct and indirect pathways from the sensorimotor cortices to hand motoneurons, and sites of lesion in the studies cited in this review. Connection from the midline-crossing axons from the contralateral corticospinal tract and commissural interneurons (coINs) was not clarified before (marked as “?” in this figure). Connection from the RuSNs to the PNs and sINs, and that from the RSNs to PNs were demonstrated in cats, but not in primates yet.
The RuST originates from the magnocellular subdivision of the red nucleus in the ventral midbrain. The magnocellular red nucleus markedly develops in the reptile, birds, and lower mammals, but becomes less evident in higher primates including humans (34). In the cat, the direct connection of the RuST with spinal motoneurons is limited to those innervating the most distal muscles (35) but the rubrospinal neurons (RuSNs) have been shown to be connected mainly to spinal interneurons and modulate the spinal reflexes (36). In primates, the RuST makes direct connection with motoneurons of wrist muscles and control dynamic phase of movements (16). Cortical input to the magnocellular red nucleus is mainly originated from the M1 (17).
The RST is originated from the medial ponto-medullary reticular formation and is a phylogenetically old descending motor pathway. It has long been considered to control the movements of proximal muscles such as head, trunk, and proximal limbs rather than distal muscles in cats (37, 38). However, recent studies have shown that these pathways are also involved in the control of hand movements in primates. Davidson and Buford studied the stimulus triggered and spike-triggered averaging of EMG activity following activation of the medial ponto-medullary reticular neurons in awake monkeys and showed short latency excitation in shoulder and arm muscles (18, 19). Baker and colleagues showed that electrical stimulation of the medial ponto-medullary reticular formation evoked mono- or oligosynaptic excitation in motoneurons innervating distal muscles and spinal interneurons in the lower cervical segments in macaque monkeys (20, 39). They also showed a group of reticular neurons that exhibited activity closely related to slow finger movements (40). Cortical inputs to these reticular neurons have been studied by neuroanatomical techniques (29, 41). These results suggested the possible contribution of RSNs in primates to the control of hand movements (42).
The propriospinal relay of cortical commands for the control of hand and arm movements has been extensively studied by Lundberg and colleagues in cats, which lack the direct CM connection (43–46). Electrical stimulation of the brainstem pyramid induced disynaptic excitation in forelimb motoneurons in anesthetized cats (47). To clarify the segmental location of intercalated neurons mediating the disynaptic excitation, selective lesion of the lateral corticospinal tract (l-CST) was made by transecting the DLF at various rostrocaudal levels. It was found that substantial amount of excitation still remained after the l-CST lesion at the C5 level, whereas the excitation almost completely disappeared after the C2 lesion, which suggested the involvement of PNs in the C3-C4 segments (C3-C4 PNs) in the control of forelimb movements besides the sINs. Cell bodies of the PNs are mainly distributed in the lateral part of the laminae VI, VII, and VIII of the C3-C4 segments and their descending axons are located in the ventral part of the lateral funiculus and lateral part of the ventral funiculus. Function of the PNs and sINs was assessed by behavioral observation with the l-CST lesion at C5 or C2 segment (48). The cat with the l-CST lesion at C5 exhibited deficit in the grasping movements, whereas both reaching and grasping were impaired in those with the C2 lesion. Based on these findings, it has been proposed that PNs are mainly involved in the control of reaching, while grasping is primarily controlled by the sINs. In macaque monkeys, disynaptic pyramidal excitatory excitation via PNs was found in relatively small number of motoneurons and it was questioned whether there was significant transmission of corticospinal excitation of hand motoneurons through this route (49–51). However, it was shown that disynaptic excitation of motoneurons could be observed when glycinergic inhibition was reduced by intravenous administration of strychnine in anesthetized macaque monkeys (22) and the C3-C4 PNs which were antidromically activated from forelimb motor nuclei became orthodromically activated by the pyramidal stimulation after strychnine injection (23). These results suggested that cortical command could be mediated to motoneurons by the C3-C4 PNs, however, strong feedforward inhibition, which might be unique in primates, masked the pathway.
In cats, it has been shown a population of sINs mainly located in laminae VI and VII of the forelimb segments (C6-Th1) were orthodromically activated from the CST and exert postspike effects on hand motoneurons (52). In primates, Fetz and colleagues developed a technique of single unit recording from cervical spinal cord in awake monkeys performing wrist flexion-extension task. They reported a group of sINs which showed increase or decrease in activity in relation to the wrist movements (53). Moreover, some of them were shown to exhibit postspike effects on EMG activity of wrist muscle with spike-triggered averaging (54). These results suggest that a population of sINs mediate commands for wrist flexion or extension to wrist motoneurons in monkeys (55). More recently, Takei and Seki (56, 57) showed that a group of premotor sINs, identified by the postspike effects on the EMG activity of hand muscles, modulated their activities during precision grip task. These lines of studies suggest that the sINs could mediate commands for fractionated digit movements to motoneurons. In both lines of studies, presence of the cortical input to these INs was not demonstrated, which needs to be assessed in future studies.
Contribution of the ipsilateral motor cortex to forelimb movements has been investigated in several studies [e.g., Ref. (58)]. In primates a recent study intensively investigated whether the ipsilateral motor cortex is involved in the control of forelimb movements by applying a variety of techniques and eventually concluded that there is no evidence that the ipsilateral motor cortex controls the movements (59). In normal primates, stimulation of the ipsilateral pyramid induced no effects on membrane potential of forelimb motoneurons (59). On the other hand, Jankowska and colleagues showed that stimulation of the ipsilateral brainstem pyramid induced oligosynaptic excitation in hindlimb motoneurons after administration of 4-aminopyridine to increase the excitability of the neural circuits in anesthetized cats. Subsequently they analyzed the pathway mediating the effect and showed that RSNs which descend through the contralateral spinal cord mediate the inputs from the ipsilateral brainstem pyramid to the motoneurons via the commissural interneurons (coINs) in the lumbar spinal cord (24). Thus, there might exist an oligosynaptic pathway from the ipsilateral motor cortex to forelimb motoneurons, which would be unmasked by pharmacological manipulation to enhance excitability of the pathway. On the other hand, reversible blockade of ipsilateral M1 caused no effects on precision grip movements in intact monkeys (60), however, the same manipulation was shown to impair the hand movements during early stage of recovery after C5 l-CST lesion (60), suggesting the potential of the ipsilateral motor cortex to control hand muscles during recovery from the spinal cord injury. Similar pharmacological manipulation as used by Jankowska and colleagues in cats should be tested in monkeys in future to investigate the pathway to resolve this discrepancy.
In this section, we will review the literature describing the recovery of hand and arm movements, especially of their dexterity, following lesion of the corticofugal fibers mainly in non-human primate models (Figure (Figure1). 1 ). As shown below, the potential of recovery of the dexterous digit movements is markedly different depending on the level of the lesion, which might be due to the available indirect pathways in each case. We will also discuss on the possible neural pathways which might be responsible for the recovery. Here we have to note that location of lesions made to assess the function of individual systems was different, e.g., in some cases by lesioning the input pathway and in other cases by lesioning the output pathway.
Many classical lesion experiments were performed at the level of the brainstem pyramid [“pyramidotomy”; (9–12)]. In these studies, fractionated, independent digit movements were severely impaired. The deficit in the studies by Lawrence and Kuypers (11) was generally less severe compared with other studies. But still, recovery was observed only in movements of more proximal part of the arm and less fractionated movements of the hand. The authors hypothesized that the recovered movements must be controlled by the brainstem routes which were spared by the pyramidal lesion. To test the involvement of the brainstem pathways in recovery, they made additional lesion of the lateral brainstem pathway and ventromedial brainstem pathway either at the brainstem or in the spinal cord, respectively (12), and found that interruption of the lateral brainstem pathway (presumably the RuST) resulted in impairment of distal extremity and hand movements, while interruption of the ventromedial pathways (presumably RST) resulted in a severe impairment of movements in axial muscles and proximal extremities. Based on these findings, the recovery of hand movements following the pyramidotomy was supposed to be chiefly compensated by the RuST. In humans, Bucy et al. (61) reported the results of transection of the cerebral peduncle in patients with dyskinesia and showed recovery of limb movements, which was considered partly due to the spared corticospinal fibers but mainly due to the subcortical pathways.
On the other hand, more recently, Baker and colleagues investigated the role of the RST in the control of distal hand movements and showed that after recovery from lesion of the brainstem pyramid, “the lesioned animals had recovered to a high level of gross motor function as described previously (12).” but showed “no evidence of relatively independent finger movements” (62). The authors analyzed the amplitude of the EPSPs evoked by electrical stimulation of the medial ponto-medullary reticular formation in hand muscles became facilitated, which suggested plasticity in the RST for compensation of the impairment of the corticospinal inputs to the spinal circuits. Based on these findings, it is suggested that the RST is responsible for some recovery of hand movements after stroke but only for gross motor function of hand, not for fractionated digit movements.
Cortical activation during the course of recovery after the C5 lesion was investigated with positron emission tomography (PET) (60, 63). It was revealed that during the early period of recovery (1 month postoperative), activity of bilateral M1 hand areas were increased in comparison to the preoperative state, while at the late stage of the recovery (3–4 months postoperative), the activation of the contralesional M1 was enhanced and expanded, and bilateral PMv also increased the activation. Causal relationship of these areas to recovery was tested by reversible blockade of these cortical areas with microinjection of muscimol. It was found that contralesional M1 was involved in recovery during both early and late recovery stages, ipsilesional M1 only during the early stage and ipsilesional PMv only during the late stage. Thus, depending on the recovery stages, the contribution of different cortical areas to the recovery changed. How these areas are involved in the recovery, namely the pathway from these cortical areas to the hand motoneurons of the affected limb, remains unclear.
The effect of early rehabilitative training was investigated in the C5 l-CST lesion model (64). In one group of animals with the l-CST lesion, the affected forelimb was restrained for 1 month and the rehabilitative training was then initiated. The progress of recovery of hand dexterity in these animals was compared 3 months after initiation of the training with the animals in which the training was started immediately after the lesion. The recovery was much worse in the animals with late onset of training, which suggests that the early rehabilitative training is important for better recovery of motor function after the spinal cord injury.
The effects of hemisection at the lower cervical level (C5-C7) have been studied by several groups (65–69). These studies showed that initially the monkeys exhibited severe flaccid hemiparesis during the first month and remarkable recovery of grasping movements of the affected limb occurred during the following several months. However, the deficit in the hand dexterity remained. Galea and Darian-Smith (65) studied the possibility of regeneration of severed corticospinal axons, however they could not clearly show it, and suggested that the incomplete recovery must be achieved by optimization of signal transmission from the cortex to spinal cord via the reduced population of corticospinal and corticobulbospinal projection or effective use of the spinal circuitries. More recently, Rosenzweig et al. (68) showed extensive sprouting of midline-crossing axons from the corticospinal fibers descending in intact side of the spinal cord, which may underlie the recovery of hand movements (68).
In humans, Nathan and Smith (70) reported the cases of cordotomies for the treatment of pain from cancer. When the first large cordotomy was performed unilaterally to incise almost all the descending tracts on one side (or plus those in the ventral funiculus on the contralateral side), it caused severe paresis in the ipsilateral hindlimb, but the paresis regressed and limb movements showed good recovery. However, if the second cordotomy was carried out on the contralateral side, the recovery that had occurred was immediately removed and little re-recovery occurred. These results suggested the contralateral corticospinal tract, whose fibers must recross the cord should be responsible for the recovery, which is supported by the above mentioned observation in the non-human primate model.
