CHAPTER

Pathways mediating functional recovery

18

Stuart N. Baker*,1, Boubker Zaaimi*, Karen M. Fisher*, Steve A. Edgley†, Demetris S. Soteropoulos* *Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK Department of Physiology, Development and Neuroscience, Cambridge University, Cambridge, UK 1 Corresponding author: Tel.: +44-191-2088206; Fax: +44-191-2085227, e-mail address: [email protected]

†

Abstract Following damage to the motor system (e.g., after stroke or spinal cord injury), recovery of upper limb function exploits the multiple pathways which allow motor commands to be sent to the spinal cord. Corticospinal fibers originate from premotor as well as primary motor cortex. While some corticospinal fibers make direct monosynaptic connections to motoneurons, there are also many connections to interneurons which allow control of motoneurons indirectly. Such interneurons may be placed within the cervical enlargement, or more rostrally (propriospinal interneurons). In addition, connections from cortex to the reticular formation in the brainstem allow motor commands to be sent over the reticulospinal tract to these spinal centers. In this review, we consider the relative roles of these different routes for the control of hand function, both in healthy primates and after recovery from lesion.

Keywords corticospinal, reticulospinal, propriospinal, hand, motor cortex, primate, pyramidal tract

The motor system is the archetypical example of parallel distributed processing. Key motor structures are dispersed at all levels of the neuraxis, ranging from the cortex to the brainstem, spinal cord, peripheral nerves, and muscles. The dispersed nature of the system leaves it highly vulnerable to damage—stroke, spinal cord injury, brachial plexus evulsion, and myopathy all lead to similar devastating consequences; there are many routes to disability. However, this distributed network also has the advantage that there are multiple options to reconfigure and restore movement. Flaccid paralysis immediately following a central nervous system injury is rapidly replaced ☆

Submitted to Progress in Brain Research for an issue following the symposium in Montreal “Sensorimotor Rehabilitation: At the Crossroads of Basic and Clinical Sciences,” May 2014.

Progress in Brain Research, Volume 218, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2014.12.010 © 2015 Elsevier B.V. All rights reserved.

389

390

CHAPTER 18 Pathways for recovery

by recovery. The new motor system which emerges may have only limited abilities, and there may be maladaptive changes leading to unhelpful motor patterns (e.g., spasticity), but few patients would choose to forego these changes and return to their state immediately postlesion. It is important to understand which subsystems contribute to recovery in different conditions, as this provides us with a rational basis to think of circuit-level therapeutic options. In this chapter, we review some recent work from our own and other laboratories on the response to lesions within the brain or spinal cord. For reasons briefly explained at the end of the review, we will focus mainly on studies in primates.

1 CORTICAL ACTIVATION The primate motor cortex has many subdivisions (Rizzolatti et al., 1998). Even the primary motor cortex (M1) can be separated into a rostral and caudal portion. Rostral M1 connects to the brainstem (Keizer and Kuypers, 1989) and projects corticospinal output to spinal interneuron circuits (Rathelot and Strick, 2006, 2009); sensory input may be dominated by deep proprioceptors (Strick and Preston, 1982; Tanji and Wise, 1981). By contrast, caudal M1 projects corticospinal connections directly to spinal motoneurons, as well as to interneurons. Sensory input may have a cutaneous bias, although both deep and cutaneous inputs reach the two subdivisions (Cheney and Fetz, 1984; Kozelj and Baker, 2014; Lemon and Porter, 1976; Rosen and Asanuma, 1972; Wong et al., 1978). The nonprimary motor cortex is grossly divided into medial and lateral parts. The medial division includes the supplementary and cingulate motor areas; the lateral encompasses dorsal and ventral premotor areas. Clinical studies in human patients (Ward et al., 2003) and experimental work in monkey (Nishimura et al., 2007) have used imaging methods to map the changes in activity across these areas following a focal lesion. Whereas in healthy subjects a unilateral movement evokes activity exclusively in the contralateral hemisphere, in the early stages of recovery there is extensive activity on both sides. Such bilateral activation may persist into the chronic phase, but this is typically associated with worse functional recovery. Individuals who succeed in refining activity back to mainly contralateral areas have better outcomes. Inactivation and mapping studies (Rouiller et al., 1998) suggest that the preference is to recruit undamaged tissue immediately adjacent to the lesion (and hence from the same cytoarchitectonic area). This leads to changes in the somatotopic map on the cortical surface (Nudo, 2013), which in rodents can even mean that the hindlimb representation begins to encode forelimb movements (Starkey et al., 2012).

2 THE CORTICOSPINAL TRACT: CONTRALATERAL EFFECTS The corticospinal tract is the dominant descending pathway in primates (Lemon, 2008); in old world primates, a portion of this tract makes monosynaptic connections to ventral horn motoneurons, which are thought to provide the neural substrate for

2 The corticospinal tract: contralateral effects

dexterous finger movements. The tract originates from a wide swathe of motor cortical divisions (Dum and Strick, 1991); in addition, around 40% of corticospinal fibers arise from the somatosensory regions of the parietal lobe (in man: Jane et al., 1967 and in monkey: Russell and Demyer, 1961). The majority of fibers cross the midline in the medulla and descend in the dorsolateral funiculus. However, approximately 10–15% of corticospinal fibers are uncrossed, and descend in the dorsolateral or ventromedial funiculus ipsilateral to the hemisphere of origin (Liu and Chambers, 1964; Ralston and Ralston, 1985). Furthermore, many contralaterally descending fibers recross the midline within the cervical enlargement, allowing them to influence spinal circuits on the ipsilateral side (Rosenzweig et al., 2009). These facts, together with the patterns of cortical activation seen following a lesion, lead to the obvious hypothesis that recovery is driven by exploiting the diverse nature of the corticospinal tract. It seems natural to assume, for example, that ipsilateral cortical activation will exert its effects via ipsilateral corticospinal fibers. However, the situation is probably not so straightforward. The first clue comes from the known connectivity of corticospinal fibers in healthy animals. It is not the case that all corticospinal fibers are created equal. The direct corticomotoneuronal (CM) connections so beloved of neurology textbooks arise almost exclusively from the caudal subdivision of M1 (Rathelot and Strick, 2006, 2009). The supplementary motor area does have some CM connections, but these are rare, weak, and slowly conducting compared with those from M1 (Firmin et al., 2014; Maier et al., 2002; Rouiller et al., 1996). After a lesion of M1, there is some sprouting of corticospinal terminals from SMA, which includes those to the motoneurons in lamina IX, especially to the more dorsal portion (McNeal et al., 2010); however, even this cannot replace the extensive lost direct connectivity to motoneurons. The first important point, therefore, is that loss of M1 removes irrevocably the major part of the CM connections. Given their role in fine finger movement, recovery after M1 lesion will always lack a key component of the normal motor repertoire. Even when fine finger movements recover, there are subtle deficits in muscle activity patterns (Nishimura et al., 2009). The majority of corticospinal terminations do not target motoneurons, but interneurons. The detailed location of the interneuronal targets varies depending on the cortical area of origin. The most dramatic difference is that those corticospinal fibers originating in the parietal lobe terminate in the dorsal horn, whereas the projections from frontal areas target intermediate and ventral spinal laminae (Ralston and Ralston, 1985). This is consistent with the presumed role for parietal corticospinal fibers in the control of sensory inflow, although very little information on this function exists (Fetz, 1968). From M1, corticospinal fibers project mainly to contralateral spinal lamina VII (Morecraft et al., 2013; Yoshino-Saito et al., 2010). This lamina is also the main contralateral target of projections from SMA (McNeal et al., 2010), and in cat lumbar cord contains interneurons which receive input from both group I and group II afferents, as well as the reticulospinal tract (Bannatyne et al., 2009). The overlap in terminations from M1 and a major premotor area suggests that it would be possible to regain control of these interneuronal circuits following a focal lesion by exploiting

391

392

CHAPTER 18 Pathways for recovery

homologous projections from other areas. This is supported by observations that after M1 lesion, there is extensive sprouting of corticospinal fibers from SMA, and a >50% increase in the number of terminals from SMA in lamina VII. This possibility is especially important, since a common clinical situation resulting in M1 lesion is middle cerebral artery infarct; SMA is supplied from the anterior cerebral artery (Kang and Kim, 2008), and is spared in this situation, enabling it to contribute to recovery.

3 THE CORTICOSPINAL TRACT: IPSILATERAL EFFECTS We may identify three separate sources of ipsilateral corticospinal fibers. Both dorsolateral and ventromedial funiculi contain axons which do not cross at the medulla; in addition, axons which descend in the contralateral dorsolateral funiculus may recross to the ipsilateral side at the segmental level via the spinal commissure. Ipsilaterally descending axons in the dorsolateral funiculus (
10% of the total projection from one hemisphere; Rosenzweig et al., 2009) give rise to no identifiable terminals on the side on which they descend, passing directly to the spinal commissure and the contralateral gray matter (Yoshino-Saito et al., 2010). We might classify these simply as errors of axonal guidance in development; the error is corrected at the segmental level, and the target laminae appear the same as if the axon had crossed at the medulla. One report claimed that the ventromedial funiculus does not contain CST axons below the C7 segment (Ralston and Ralston, 1985), which would suggest a limited possible role in upper limb control, especially of the hand. However, later studies were able to identify such axons in more caudal segments (Rosenzweig et al., 2009; Yoshino-Saito et al., 2010), although they make up only
2% of the projection from one hemisphere (Rosenzweig et al., 2009). These axons terminate largely in lamina VIII. The major source of ipsilateral corticospinal terminals does not come from ipsilaterally descending fibers, but from axon collaterals from the contralateral tract, which cross the midline via the spinal commissure. These also target mainly lamina VIII (Morecraft et al., 2013; Yoshino-Saito et al., 2010). In cat lumbar cord, lamina VIII is the location of commissural interneurons, which project terminals to the contralateral cord (Bannatyne et al., 2003). Our recent work demonstrated the existence of a system of commissural interneurons also in the cervical enlargement of primates (Fig. 1; Soteropoulos et al., 2013). A projection to lamina VIII would thus be consistent with an action mainly on the side contralateral to the originating hemisphere, although probably integrating the descending command with proprioceptive and efference copy information pertaining to the opposite limb and available to the commissural interneurons by dint of their location. The available anatomical evidence is thus that the ipsilateral corticospinal tract does not represent a parallel pathway to the contralateral corticospinal tract. This conclusion is also supported by our electrophysiological studies, which focussed on hand and forearm muscles (Soteropoulos et al., 2011). Stimulation of the

FIGURE 1 Evidence for the existence of a system of commissural interneurons in the primate cervical spinal cord. (A1) Intracellular recording from a motoneuron, showing antidromic spike in response to stimulation of the ulnar nerve at the wrist, identifying it as projecting to intrinsic hand muscles. (A2) Excitatory postsynaptic potential (EPSP) in response to stimulation of the contralateral cord (100 mA), at the location indicated in the inset to (A1). A different motoneuron, which was identified as projecting to forearm extensor muscles, showed no response to a single stimulus to the contralateral cord (B1), but an inhibitory postsynaptic potential (IPSP) after triple-shock stimulation (B2). (C) An example of a motoneuron which gave an EPSP followed by an IPSP after contralateral cord stimulation (note the undershoot below the baseline level, marked by the dotted line). (D) Proportions of motoneurons with projections to different muscle categories which responded to contralateral cord stimulation with either monosynaptic or polysynaptic synaptic potentials. (E1) Response of a motoneuron to stimulation of the median nerve at the wrist, showing both antidromic and orthodromic spikes, identifying the projection target as intrinsic hand muscles. This motoneuron gave a weak IPSP following one stimulus to the contralateral median nerve (E2), but a robust EPSP following triple-shock stimulation (E3). (F1) Response of a different motoneuron to stimulation of the median nerve in the arm, identifying the projection target as forearm flexor muscles. This cell gave a weak IPSP following a single stimulus to the contralateral ulnar nerve (F2), which grew with three shocks (F3). (G) proportions of motoneurons with different projection targets which responded to contralateral nerve stimulation with either EPSPs or IPSPs. Adapted from Soteropoulos et al. (2013).

394

CHAPTER 18 Pathways for recovery

ipsilateral pyramidal tract very rarely produced mono- or disynaptic potentials in identified motoneurons in anesthetized animals (Fig. 2A–C). Stimulating either the whole tract in the medulla (Fig. 2E) or delivering more focal stimuli to sites within ipsilateral M1 (Fig. 2D) also failed to facilitate muscle activity in awake animals. Finally, apparent modulation in discharge of ipsilateral identified pyramidal tract neurons with ipsilateral limb movements appeared to be related to concomitant modulation in contralateral muscles, rather than genuinely reflecting coding for ipsilateral movements. Following long trains of stimuli (36 shocks, 333 Hz) to M1, ipsilateral muscles are facilitated (Montgomery et al., 2013); however, such stimuli could plausibly spread trans-synaptically either to contralateral cortex or brainstem centers (see below). There is thus no current evidence that the corticospinal tract plays a substantive role in motor coordination on the side ipsilateral to the hemisphere originating the fibers. The contribution of ipsilateral corticospinal connections to motor control remains unclear, but is unlikely to be involved in direct control of muscle activity on the side ipsilateral to the hemisphere originating the fibers. This is the situation in the healthy nervous system, but does recovery from lesion lead to a major reconfiguration of the role of the ipsilateral CST? After spinal hemisection, Rosenzweig et al. (2010) reported extensive sprouting of CST fibers in the cord caudal to and on the same side as the lesion. This included fibers from both hemispheres, either descending ipsilaterally or contralaterally in the unlesioned spinal hemicord and then crossing the midline via the spinal commissure below the lesion. Likewise, after a combined dorsal root and dorsal column lesion, Darian-Smith et al. (2014) reported extensive bilateral CST sprouting. However, all studies to date reveal that the pattern of termination of the ipsilateral CST after corticospinal lesion is little changed compared with control animals, and there remains a predominance of connections to lamina VIII. Once again, the electrophysiology seems to support the anatomical findings here. We made unilateral lesions of the pyramidal tract, and allowed animals to recover for around 6 months before searching for synaptic potentials evoked in motoneurons from stimulation of the ipsilateral (unlesioned) tract. Such effects remained rare and weak, similar to the finding in control animals (Fig. 2F; Zaaimi et al., 2012). At the present moment, there is thus no evidence that the ipsilateral corticospinal tract makes a significant positive contribution to functional recovery in primates. We note that the situation is quite different in rodents, where the ipsilateral CST plays a clear role in recovery following contralateral CST lesion (Brus-Ramer et al., 2007). This presumably reflects the very different nature of the CST in rodents compared to primates (see below).

4 THE RETICULOSPINAL TRACT The reticular formation is a collection of brainstem nuclei, which give rise to the reticulospinal tract (Sakai et al., 2009). This tract is known to be of importance in the control of swimming in fish (Grillner et al., 1997), and in the control of locomotion

4 The reticulospinal tract

FIGURE 2 Absence of effects from ipsilateral corticospinal tract in primate. (A) Intracellular recording from a motoneuron identified as projecting to forearm flexor muscles, following stimulation of either the ipsilateral or contralateral pyramidal tract (PT) at the medulla. While a clear monosynaptic response is seen following contralateral PT stimulation, there is no response after ipsilateral PT. This remains the case after triple-shock stimuli (B), intended to enhance (Continued)

395

396

CHAPTER 18 Pathways for recovery

(Drew et al., 1986; Mori et al., 2001), reaching (Schepens and Drew, 2004, 2006), and posture (Deliagina et al., 2008; Schepens et al., 2008) in cat. In primates, the reticulospinal tract projects widely within the spinal cord (Kuypers et al., 1962; Matsuyama et al., 1997, 1999), contacting interneurons which are also activated by the corticospinal tract (Riddle and Baker, 2010). Stimulation within the reticular formation produces both facilitation and suppression of ipsilateral and contralateral muscles acting around the wrist, elbow, and shoulder (Davidson and Buford, 2004, 2006), as well as more distal intrinsic hand muscles (Soteropoulos et al., 2012). A single fiber may diverge to multiple muscles (Davidson et al., 2007; Peterson et al., 1979). Connections to motoneurons innervating forelimb muscles can be mono- or disynaptic (Riddle et al., 2009). Although typically considered to control gross movements such as locomotion and to coordinate posture, in the primate there also appears to be a role in hand function. Reticulospinal axons connect to motoneurons and interneurons controlling the hand (Fig. 3A–E; Riddle et al., 2009; Riddle and Baker, 2010), and reticular neurons modulate their discharge during a fine independent finger movement task (Fig. 3F–I; Soteropoulos et al., 2012). In monkeys which had recovered from a unilateral lesion of the pyramidal tract, we recorded the amplitude and incidence of synaptic inputs to identified motoneurons. There were marked changes compared with controls, as illustrated in Fig. 4. To compute these bar graphs, we found the product of the incidence of effects with their mean amplitude; this provides an overall measure of input strength (original data are available in Zaaimi et al., 2012). Inputs to forearm flexor and intrinsic hand muscles were significantly increased, in some cases substantially so. By contrast, inputs to extensors showed no change. Previous work has shown a similar imbalance in strengthening of other pathways in response to lesions. Belhaj-saif and Cheney (2000) reported data consistent with FIGURE 2—Cont’d disynaptic transmission. (C) EPSP amplitude in response to contralateral and ipsilateral PT stimulation. Over 62 motoneurons, only two gave responses to ipsilateral PT, and these were smaller than all contralateral responses. (D) Averages of rectified EMG from ipsilateral and contralateral muscles recorded in an awake behaving monkey following stimulation of sites within the primary motor cortex. Traces are averaged over 23 different cortical sites (intensity ranged from 10 to 30 mA). While clear responses are seen in contralateral muscles, none are apparent in ipsilateral muscles. (E) Averages of rectified EMG from ipsilateral and contralateral muscles following stimulation of the PT at the medulla, using a strong intensity (500 mA) which just did not spread to the opposite side. Robust contralateral responses can be seen; onset latencies marked by arrowheads have been transposed to the ipsilateral traces, making it apparent that no deflections are apparent at appropriate latencies. (F) Changes in effects from the ipsilateral PT in motoneurons projecting to different muscle targets after monkeys had recovered from a unilateral PT lesion. Ordinates display the product of mean amplitude (measured over observed effects) with incidence (the proportion of tested cells which showed an effect). Negligible effects in control animals were not significantly different in animals which had recovered from PT lesion. Ordinate scale for each plot is chosen to be the same as Fig. 4.

4 The reticulospinal tract

FIGURE 3 Evidence that the primate reticular formation plays a role in hand function. (A1) Intracellular recording from a motoneuron, showing antidromic spike identifying project target as forearm flexor muscles. (A2) This cell received a small EPSP from the medial longitudinal fasciculus (MLF), which carries mainly reticulospinal fibers. (A3) The EPSP grew with three (Continued)

397

398

CHAPTER 18 Pathways for recovery

greater increases in rubrospinal output to flexors than extensors after a unilateral corticospinal tract lesion (see reanalysis in Zaaimi et al., 2012). McNeal et al. (2010) reported that corticospinal axon sprouting from the SMA following M1 and lateral premotor lesion was greater in the dorsal than ventral motor nuclei, which is consistent with increased strengthening to flexor rather than extensor motoneuron pools given the known locations within the cord ( Jenny and Inukai, 1983). It therefore appears that this is a general finding, across multiple systems; the reason why flexors should be preferentially strengthened is unknown. Imbalanced recovery between forearm flexors and extensors is a very common finding in stroke survivors, with the flexors often overactive and spastic, but the extensors weak (Kamper et al., 2003). Such patients cannot pick up an everyday object because they cannot open the hand; if an object is placed within their grasp, they maintain an effective grip. We suggest that imbalanced changes in subcortical connections form the neural substrate for imbalanced function, placing a limitation on the extent of recovery.

FIGURE 3—Cont’d shocks, suggesting a disynaptic pathway. (A4) This cell also received a large monosynaptic EPSP from the contralateral PT. (B1) Recording a different motoneuron, with antidromic spike identifying projection target as an intrinsic hand muscle. (B2) and (B3) This cell received a large monosynaptic EPSP from the MLF, which was larger than that from the PT (B4). (C) and (D) Peri-stimulus time histograms of the discharge of an interneuron in the intermediate zone of the cervical spinal cord, recorded extracellularly in an awake monkey, in response to stimulation of the PT (C) or MLF (D). Significant responses to both stimuli are seen (gray shading). White box marks the “dead time,” during which stimulus artifact prevented detection of spiking; inset to (C) shows overlain unit waveforms. (E) Proportions of interneurons which received input from PT or MLF alone, or convergent input from both pathways. Different displays show the results considering all neurons; only units which were recorded at spinal sites where stimulation produced responses in the hand; only units whose discharge facilitated during reaching, or during grasping. (F) Task arrangement for studying isolated finger movements. The head-fixed monkey wore a sleeve, with solid supports for both upper arm and forearm; the index finger was attached to a lever, and the animal trained to make flexion/extension movements to track a cursor on a screen. (G) Peri-stimulus time histogram (PSTH) and dot-raster display of the discharge of a single unit from the reticular formation, recorded during this task, together with averaged lever displacement signals. The unit modulated strongly, when the animal performed either the flexion or extension version of the task. (H) Baseline firing rate of populations of neurons from the reticular formation and the hand representation of primary motor cortex (M1). Rates were significantly higher for the reticular formation. (I) Distribution of rate modulation during the isolated finger movement task (defined as the difference between minimum and maximum rate in PSTHs compiled as in panel G). Results are shown separately for flexion and extension trials. There was no significant difference in rate modulation between M1 and the reticular formation. Panels (A and B): modified from Riddle et al. (2009). Panels (C–E): modified from Riddle and Baker (2010). Panels (F–I): modified from Soteropoulos et al. (2012).

5 Spinal systems for control of the hand

FIGURE 4 Changes in reticulospinal connections after recovery from pyramidal tract lesion. Plots show the size of mono- and disynaptic inputs to motoneurons identified as projecting to three muscle groups, following stimulation of the ipsilateral medial longitudinal fasciculus (MLF), which carries mainly reticulospinal fibers. Bars are shown for control animals (n ¼ 6) and after recovery from a complete unilateral lesion of the pyramidal tract. Significant changes were seen in motoneurons projecting to forearm flexor and intrinsic hand muscles, but not in those innervating forearm extensors. Plotting conventions are as in Fig. 2F. From Zaaimi et al. (2012).

5 SPINAL SYSTEMS FOR CONTROL OF THE HAND As made clear above, the majority of terminals from both corticospinal and reticulospinal tracts contact spinal interneurons, rather than monosynaptically activating motoneurons. It is tempting to see such interneurons as mere “relays” from descending motor command to the final common path of all motor output (Sherrington, 1906). However, these interneuron circuits have complex patterns of peripheral inputs and intrinsic connections, allowing them to perform substantial processing in their own right (Bannatyne et al., 2009; Jankowska, 2001; Kozelj and Baker, 2014; Williams et al., 2010). Recent work from Tadashi Isa’s group has revealed an important role for propriospinal interneurons located in spinal segments C3/C4 in the control of fine finger movements. In cat, this interneuron system is known to receive input from corticospinal, rubrospinal, and reticulospinal pathways, and makes monosynaptic connections to motoneurons in the cervical enlargement innervating the forelimb (Illert et al., 1977, 1978, 1981). Lesions of this system selectively impair visually directed reaching movements, but do not affect grasp (Alstermark et al., 1981). In monkey, the function of these cells appears to be different and related to control of the hand itself (Isa et al., 2007). After a corticospinal tract lesion at the C5 level, monkeys show impaired function on a precision grip task. However, with training they can achieve good recovery of independent finger movements, although these have subtle abnormalities in muscle activation compared with the unlesioned state

399

400

CHAPTER 18 Pathways for recovery

(Sasaki et al., 2004). By contrast if the corticospinal tract lesion is made at the C2 level, removing corticospinal input to the C3/C4 propriospinal neurons, precision grip does not recover (Alstermark et al., 2011). Importantly, the role in precision grip is not simply something which develops as part of the recovery process after loss of the CM connections. When the C3/C4 propriospinal system is rapidly, selectively and reversibly inactivated using genetic methods, the animals show an acute deficit in precision grip, even though their CM system is intact (Kinoshita et al., 2012). C3/ C4 neurons modulate their activity during a reach and grasp task (Niwa et al., 2004). The C3/C4 propriospinal neurons have proven a particularly tractable system to study the role of spinal interneurons, as their anatomic separation from the segmental location of forelimb motoneurons has allowed elegant dissection of their contribution. By contrast, less is known of the contribution of segmental interneurons to hand function. The available neural recordings show that intermediate zone interneurons modulate their discharge during both precision grip (Takei and Seki, 2010) and the grasp phase of reach-to-grasp movements (Riddle and Baker, 2010). Relevant in this context is the recent discovery of a class of genetically identified interneurons in the mouse spinal cord, the “dI3” neurons (Bui et al., 2013). These receive cutaneous input from the forepaw, and connect monosynaptically to motoneurons to mediate a short-latency cutaneous reflex. Mice where dI3 neurons were constitutively silenced were unable to grasp the bars of their cage, suggesting that they form a spinal substrate for rodent grasp. It is uncertain whether a direct analogue of dI3 neurons exists within the primate spinal cord, although a short-latency (presumed spinal) cutaneous excitatory reflex is present in human hand muscles (E1 reflex; Jenner and Stephens, 1982). It is thus quite possible that some of the neurons which modulate with grasp recorded in monkey by Takei and Seki (2010) and Riddle and Baker (2010) are the primate equivalent of mice dI3 cells. If so, a critical question would be how these neurons are controlled by descending pathways. Whereas primate spinal neurons firing during grasp receive both CST and RST inputs (Riddle and Baker, 2010), the inputs to mouse dI3 neurons from descending pathways are not known.

6 DIFFERENT TYPES OF HAND FUNCTION It is often assumed that the hand is controlled almost exclusively by the corticospinal tract; the origin for this view is the seminal work of Lawrence and Kuypers (Lawrence and Kuypers, 1968a,b, represented in Lemon et al., 2012). However, careful reading of that work does not support the idea of solely corticospinal control of the hand. Rather, Lawrence and Kuypers showed that monkeys with bilateral corticospinal tract lesions had enduring deficits in independent control of the digits. Some hand function did return after these lesions, but it allowed only whole-hand grasping, without the ability to adjust individual digits. This reduced function seemed to rely mainly on the rubrospinal tract, as placing a second lesion within that pathway left the animal unable to grasp food. Nevertheless, these animals were still able to climb,

6 Different types of hand function

grasping the bars of their cages sufficiently strongly to support their body weight (Lawrence and Kuypers, 1968b, see video 16 in Lemon et al., 2012). The reticulospinal tract is the only major pathway left to support such use of the hand. In humans, the rubrospinal tract is vestigial or absent (Nathan and Smith, 1955; Onodera and Hicks, 2010), so that the reticulospinal tract is likely to play an even greater role in recovery of hand function in man. The pattern of collateralization of corticospinal and reticulospinal axons within the spinal cord is consistent with different capabilities for hand control. Corticospinal axons contact just a few motor nuclei, allowing activation of limited groups of muscles (Buys et al., 1986; Shinoda et al., 1979). By contrast, reticulospinal neurons branch extensively and send collaterals to multiple motoneuron pools (Peterson et al., 1975). This prevents them generating fine, fractionated activity in small groups of muscles, which is required for independent control of the digits, but whole-hand grasp involving concurrent flexion of all fingers is possible. This is the type of hand function seen in a stroke survivor, where the ability to generate independent digit movements is much impaired (Lang and Schieber, 2003, 2004). Further support for the notion of different types of hand function, controlled by different neural substrates, comes from the study of Muir and Lemon (1983). Monkeys were trained to perform both a precision grip and a power grip (Fig. 4A and B, respectively), and recordings were made from M1 units identified as CM cells by spike triggered averaging. Figure 4 shows an example cell from their recordings, which had a postspike facilitation in the first dorsal interosseous muscle, providing evidence of a direct monosynaptic connection to motoneurons innervating this muscle. The facilitated muscle was more active during the power grip than during precision grip, yet the CM cell only modulated its discharge during the precision grip. This suggests that the CM system is especially concerned with hand function requiring fractionated digit use. The studies of Lawrence and Kuypers initially led to the suggestion that CM connections were directed mainly to distal muscles involved in hand control (Lawrence and Kuypers, 1968a). This is not the case, and a wide range of somatic motoneurons throughout the body receive direct cortical input (de Noordhout et al., 1999). However, there is a gradient in the strength of these connections. Following a 200 mA stimulus to the contralateral pyramidal tract, the mean excitatory postsynaptic input to motoneurons innervating forearm muscles is 2.0 mV, compared with 3.5 mV to motoneurons innervating muscles intrinsic to the hand (Fritz et al., 1985). This may represent a bias of the corticospinal tract to control more distal muscles. Interestingly, in our recordings we also found a trend for stronger monosynaptic input from the reticulospinal tract to motoneurons innervating intrinsic hand compared with forearm muscles (Fig. 4; Riddle et al., 2009; Zaaimi et al., 2012), suggesting that this may be a difference in the balance between central and reflex control, rather than a feature specific to the corticospinal tract. Figure 5 shows that corticospinal neurons appear to be active preferentially during fine independent control of the hand; this implies that mainly subcortical systems are involved in generating the power grip. However, this does not appear to be a

401

402

CHAPTER 18 Pathways for recovery

FIGURE 5 Cortico-motoneuronal cells preferentially modulate their discharge with fine finger movements. A single pyramidal tract neuron (PTN) was recorded in monkey primary motor cortex and identified as a cortico-motoneuronal cell projecting to the first dorsal interosseous muscle by spike-triggered averaging. A peri-event time histogram is shown during performance of a precision grip with light and heavy springs acting as the resistance (A) and a power grip (B). The PTN fired more strongly for the precision grip task, even though activity in the muscle target was stronger for the power grip (right traces). From Muir and Lemon (1983).

double dissociation; the available evidence is that spinal cord interneurons and reticular formation cells are also involved in fine finger movements (Kinoshita et al., 2012; Riddle and Baker, 2010; Soteropoulos et al., 2012; Takei and Seki, 2010; Fig. 3F–I). In agreement with this, cortical area F5 seems to encode a repertoire of different grasps, each requiring fractionated use of the hand (Murata et al., 1997; Umilta et al., 2007). F5 originates cortico-cortical connections to M1, which presumably provide access to CM cells (Shimazu et al., 2004), but in addition F5 sends its own corticospinal projections to spinal interneurons, and has corticoreticular connections (Borra et al., 2010). We therefore suggest that fine hand control arises from a combination of a lessselective input from reticulospinal cells and spinal cord interneurons (which receive both corticospinal and reticulospinal input) with a better fractionated command generated by CM cells. In this model, during functional recovery subcortical systems may already be active appropriately in response to a motor commands to generate a fine hand movement, but may have insufficient synaptic drive to raise motoneurons above firing threshold. The major adaptation which occurs during recovery is then the strengthening of subcortical pathways, allowing them to generate overt output (Zaaimi et al., 2012), although this lacks fractionation.

7 Ipsilateral motor output

7 IPSILATERAL MOTOR OUTPUT As described above, many studies have shown that following recovery from lesion, motor cortical areas ipsilateral to the affected limb become active. In addition, there is often a causal ipsilateral output from the contralesional cortex: transcranial magnetic stimulation (TMS) over the unaffected hemisphere can yield responses in the ipsilateral limb. Although these ipsilateral responses to noninvasive cortical stimulation can be seen in healthy subjects, these are at a higher threshold and weaker than those seen in stroke survivors (Alagona et al., 2001). It is commonly assumed that ipsilateral motor evoked potentials must be mediated by the ipsilateral corticospinal tract running from the contralesional cortex but, as detailed above, the available evidence is that this is unlikely to make a substantial contribution. The most likely pathway to mediate such effects is a cortico-reticulospinal route. This has also been proposed to mediate ipsilateral responses to TMS in healthy subjects, since these responses depend on head rotation (Tazoe and Perez, 2014; Ziemann et al., 1999) and reticulospinal cells are known to receive input from neck proprioceptors, which could thus bias their excitability to a corticoreticular input volley. A similar conclusion on the most likely pathway mediating ipsilateral cortical outputs in cat was reached by Edgley et al. (2004). We have recently shown that neurons in the reticular formation, including identified reticulospinal cells, show robust short-latency responses to TMS delivered over both ipsilateral and contralateral M1 (Fig. 6; Fisher et al., 2012). Stroke survivors show considerable heterogeneity in the extent to which they exhibit ipsilateral responses to TMS from the contralesional hemisphere, and this correlates negatively with the extent of functional recovery: ipsilateral effects are strongest in patients with poorly recovered hand and arm function (Turton et al., 1996). This is understandable if we see ipsilateral TMS responses in the affected limb as a surrogate marker for the involvement of cortico-reticulospinal pathways in the recovery process. Patients with only limited damage to contralateral corticospinal tract will recover by recruiting primary and premotor cortical areas adjacent to the lesion, and will benefit from the increased fractionation of movement which the corticospinal tract can produce. By contrast, patients where the lesion leads to more substantial contralateral corticospinal loss have no alternative but to rely on cortico-reticulospinal outputs, with their attendant less fractionated output. Such patients will show ipsilateral responses to TMS in the affected limb. An increased reliance on reticulospinal pathways may also partially underlie the bilateral changes in motor control which are commonly seen in stroke survivors, since reticulospinal fibers branch extensively to innervate the spinal cord bilaterally (Davidson et al., 2007; Peterson et al., 1975). One common observation is of mirror movements, whereby involuntary movements occur contralateral to the limb voluntarily activated. Although these can occur in healthy subjects, especially children, they are more common in stroke survivors (Nelles et al., 1998). Mirror movements could be characterized as an unwanted “spill over” of a unilateral command to bilateral spinal circuits reflecting the divergent cortico-reticulospinal anatomy.

403

404

CHAPTER 18 Pathways for recovery

FIGURE 6 Neurons in the primate reticular formation respond to transcranial magnetic brain stimulation delivered to the primary motor cortex. Each display shows at the top dot rasters of neural responses to single stimuli at different intensities (denoted as a percentage of maximal stimulator output). Underneath are peri-stimulus time histograms of the responses to 100% stimulus intensity and inset overlaid waveforms of the unit spike. The cell in (A) responded with a single spike at short latency for intensities above 60%. The cell in (B) responded at longer latency with a burst of spikes, which grew stronger at higher intensities; at 100%, this was joined by an earlier response at short latency. The early response is likely to be caused by corticoreticular connections, whereas the later response is most likely caused by activation of auditory and vestibular afferents caused by the loud click sound when the magnetic coil discharges. From Fisher et al. (2012).

In addition, whereas the limb ipsilateral to the cortical lesion used to be referred to as “unaffected,” there is increasing recognition that it may show subtle motor deficits compared with healthy controls. Such deficits become especially apparent when the patient tries to coordinate the two sides. It may be that the intact corticospinal tract suddenly finds itself controlling a limb subject to an unwanted efference copy of the command sent to the other side. Even if this is insufficient to generate overt mirroring in a given patient, it could exert a subliminal disruptive influence. The situation might be analogous to the runners in a “three-legged race,” who are neurologically intact but must learn to control a leg shackled to that of their partner. Most participants in such events reach the finish line, but movement is clumsy and requires a high level of conscious concentration for success.

9 Conclusions

8 DIFFERENCES BETWEEN RODENT AND PRIMATE MODELS In the field of neuroprotection, there has been considerable concern recently about the failure to translate treatments which are successful in rodents to human patients (O’Collins et al., 2006). Some have suggested that the translational pipeline could be improved by more extensive use of primate model systems before moving to clinical trials, as these better model the complex vascular and neural response of humans (Cook et al., 2012; Courtine et al., 2007). In the field of recovery and rehabilitation after brain or spinal cord injury, it remains common to use rodents both to test candidate therapy, and to elucidate basic principles of recovery. While this has the advantage of rapid, low cost, and hence potentially high-throughput experimental paradigms, it is important not to lose sight of the substantial differences between primate and rodent motor systems. The rodent corticospinal tract passes within the dorsal columns, and hence spinal cord injury models must necessarily damage corticospinal and ascending sensory fibers together. By contrast, in human patients sensory (dorsal column) and corticospinal (dorsolateral funiculus) damage can be separated. This is likely to be important, since it is known that sensory systems play an important role in recovery, especially in hand function (Darian-Smith and Ciferri, 2005). The spinal terminations of the rodent corticospinal tract focus mainly on the more dorsal lamina IV and V (Casale et al., 1988; Liang et al., 1991), in contrast to the ventral focus on lamina VI–IX in monkey (Kuypers, 1981). Another important difference is that in rat the ipsilateral corticospinal tract is a substantive pathway, capable of influencing motor output. Following unilateral corticospinal lesion, the ipsilateral tract makes an important contribution to functional recovery (Biernaskie et al., 2005); this may be enhanced by measures designed to boost ipsilateral corticospinal activity (Brus-Ramer et al., 2007; Carmel et al., 2014). Finally, rodents lack CM connections (Alstermark et al., 2004; Yang and Lemon, 2003) and the associated fine independent finger movements. Grasp is likely to rely predominantly on spinal interneuronal circuits, since ablating a specific class of interneurons prevents useful paw grasp (Bui et al., 2013). These spinal interneuronal circuits most likely show important differences from those in primates: for example, the C3/C4 propriospinal system, of such demonstrable importance to both monkey or cat motor function, does not receive monosynaptic input from the corticospinal tract in rat (Alstermark et al., 2004; Isa et al., 2007), such that propriospinal interneurons must be driven mainly by reticulospinal pathways (Alstermark et al., 2004; Filli et al., 2014). For these reasons, while the rodent remains a useful model for several aspects of motor control, many of the principles described in this review cannot be readily taken across to work in rodent.

9 CONCLUSIONS These are exciting times in the field of neurorehabilitation. After many decades of concentration on cortical pathways for motor control, we are starting to understand how spinal and brainstem systems might contribute to primate movements. These

405

406

CHAPTER 18 Pathways for recovery

neural circuits might function at a more “basic” level in the healthy animal than their more elevated cortical masters, but they become of pivotal importance in the race to recover function after a brain or spinal cord lesion. Discovering more about the biology of the entire primate motor system, both cortical and subcortical, will doubtless suggest novel therapeutic avenues to enhance functional recovery. Around 100,000 people within the UK alone have a stroke leading to disability every year. Using primate species which appropriately model man, and with a readiness to translate basic neuroscience to clinical reality, there is a real prospect of tangible benefit for these patients over the next 10–20 years.

REFERENCES Alagona, G., Delvaux, V., Gerard, P., De Pasqua, V., Pennisi, G., Delwaide, P.J., Nicoletti, F., Maertens de Noordhout, A., 2001. Ipsilateral motor responses to focal transcranial magnetic stimulation in healthy subjects and acute-stroke patients. Stroke 32, 1304–1309. Alstermark, B., Lundberg, A., Norrsell, U., Sybirska, E., 1981. Integration in descending motor pathways controlling the forelimb in the cat. 9. Differential behavioural defects after spinal cord lesions interrupting defined pathways from higher centres to motoneurones. Exp. Brain Res. 42, 299–318. Alstermark, B., Ogawa, J., Isa, T., 2004. Lack of monosynaptic corticomotoneuronal EPSPs in rats: disynaptic EPSPs mediated via reticulospinal neurons and polysynaptic EPSPs via segmental interneurons. J. Neurophysiol. 91, 1832–1839. Alstermark, B., Pettersson, L.G., Nishimura, Y., Yoshino-Saito, K., Tsuboi, F., Takahashi, M., Isa, T., 2011. Motor command for precision grip in the macaque monkey can be mediated by spinal interneurons. J. Neurophysiol. 106, 122–126. Bannatyne, B.A., Edgley, S.A., Hammar, I., Jankowska, E., Maxwell, D.J., 2003. Networks of inhibitory and excitatory commissural interneurons mediating crossed reticulospinal actions. Eur. J. Neurosci. 18, 2273–2284. Bannatyne, B.A., Liu, T.T., Hammar, I., Stecina, K., Jankowska, E., Maxwell, D.J., 2009. Excitatory and inhibitory intermediate zone interneurons in pathways from feline group I and II afferents: differences in axonal projections and input. J. Physiol. 587, 379–399. Belhaj-Saif, A., Cheney, P.D., 2000. Plasticity in the distribution of the red nucleus output to forearm muscles after unilateral lesions of the pyramidal tract. J. Neurophysiol. 83, 3147–3153. Biernaskie, J., Szymanska, A., Windle, V., Corbett, D., 2005. Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur. J. Neurosci. 21, 989–999. Borra, E., Belmalih, A., Gerbella, M., Rozzi, S., Luppino, G., 2010. Projections of the hand field of the macaque ventral premotor area F5 to the brainstem and spinal cord. J. Comp. Neurol. 518, 2570–2591. Brus-Ramer, M., Carmel, J.B., Chakrabarty, S., Martin, J.H., 2007. Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury. J. Neurosci. 27, 13793–13801. Bui, T.V., Akay, T., Loubani, O., Hnasko, T.S., Jessell, T.M., Brownstone, R.M., 2013. Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior. Neuron 78, 191–204.

References

Buys, E.J., Lemon, R.N., Mantel, G.W.H., Muir, R.B., 1986. Selective facilitation of different hand muscles by single corticospinal neurones in the conscious monkey. J. Physiol. 381, 529–549. Carmel, J.B., Kimura, H., Martin, J.H., 2014. Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J. Neurosci. 34, 462–466. Casale, E.J., Light, A.R., Rustioni, A., 1988. Direct projection of the corticospinal tract to the superficial laminae of the spinal cord in the rat. J. Comp. Neurol. 278, 275–286. Cheney, P.D., Fetz, E.E., 1984. Corticomotoneuronal cells contribute to long-latency stretch reflexes in the rhesus monkey. J. Physiol. 349, 249–272. Cook, D.J., Teves, L., Tymianski, M., 2012. A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci. Transl. Med. 4, 154ra133. Courtine, G., Bunge, M.B., Fawcett, J.W., Grossman, R.G., Kaas, J.H., Lemon, R., Maier, I., Martin, J., Nudo, R.J., Ramon-Cueto, A., Rouiller, E.M., Schnell, L., Wannier, T., Schwab, M.E., Edgerton, V.R., 2007. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? Nat. Med. 13, 561–566. Darian-Smith, C., Ciferri, M.M., 2005. Loss and recovery of voluntary hand movements in the macaque following a cervical dorsal rhizotomy. J. Comp. Neurol. 491, 27–45. Darian-Smith, C., Lilak, A., Garner, J., Irvine, K.A., 2014. Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys. J. Neurosci. 34, 12267–12279. Davidson, A.G., Buford, J.A., 2004. Motor outputs from the primate reticular formation to shoulder muscles as revealed by stimulus-triggered averaging. J. Neurophysiol. 92, 83–95. Davidson, A.G., Buford, J.A., 2006. Bilateral actions of the reticulospinal tract on arm and shoulder muscles in the monkey: stimulus triggered averaging. Exp. Brain Res. 173, 25–39. Davidson, A.G., Schieber, M.H., Buford, J.A., 2007. Bilateral spike-triggered average effects in arm and shoulder muscles from the monkey pontomedullary reticular formation. J. Neurosci. 27, 8053–8058. De Noordhout, A.M., Rapisarda, G., Bogacz, D., Gerard, P., De Pasqua, V., Pennisi, G., Delwaide, P.J., 1999. Corticomotoneuronal synaptic connections in normal man: an electrophysiological study. Brain 122 (Pt. 7), 1327–1340. Deliagina, T.G., Beloozerova, I.N., Zelenin, P.V., Orlovsky, G.N., 2008. Spinal and supraspinal postural networks. Brain Res. Rev. 57, 212–221. Drew, T., Dubuc, R., Rossignol, S., 1986. Discharge patterns of reticulospinal and other reticular neurons in chronic, unrestrained cats walking on a treadmill. J. Neurophysiol. 55, 375–401. Dum, R.P., Strick, P.L., 1991. The origin of corticospinal projections from the premotor areas in the frontal lobe. J. Neurosci. 11, 667–689. Edgley, S.A., Jankowska, E., Hammar, I., 2004. Ipsilateral actions of feline corticospinal tract neurons on limb motoneurons. J. Neurosci. 24, 7804–7813. Fetz, E.E., 1968. Pyramidal tract effects on interneurons in the cat lumbar dorsal horn. J. Neurophysiol. 31, 69–80. Filli, L., Engmann, A.K., Zorner, B., Weinmann, O., Moraitis, T., Gullo, M., Kasper, H., Schneider, R., Schwab, M.E., 2014. Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury. J. Neurosci. 34, 13399–13410.

407

408

CHAPTER 18 Pathways for recovery

Firmin, L., Field, P., Maier, M.A., Kraskov, A., Kirkwood, P.A., Nakajima, K., Lemon, R.N., Glickstein, M., 2014. Axon diameters and conduction velocities in the macaque pyramidal tract. J. Neurophysiol. 112, 1229–1240. Fisher, K.M., Zaaimi, B., Baker, S.N., 2012. Reticular formation responses to magnetic brain stimulation of primary motor cortex. J. Physiol. 590, 4045–4060. Fritz, N., Illert, M., Kolb, F.P., Lemon, R.N., Muir, R.B., Van Der Burg, J., Wiedemann, E., Yamaguchi, T., 1985. The cortico-motoneuronal input to hand and forearm motoneurones in the anaesthetized monkey. J. Physiol. 366, 20P. Grillner, S., Georgopoulos, A.P., Jordan, L.M. (Eds.), 1997. Selection and Initiation of Motor Behavior. MIT Press, Cambridge, MA. Illert, M., Lundberg, A., Tanaka, R., 1977. Integration in descending motor pathways controlling the forelimb in the cat. 3. Convergence on propriospinal neurons transmitting disynaptic excitation from the corticospinal tract and other descending tracts. Exp. Brain Res. 29, 323–346. Illert, M., Lundberg, A., Padel, Y., Tanaka, R., 1978. Integration in descending motor pathways controlling the forelimb in the cat. 5. Properties of and monosynaptic connections on C3-C4 propriospinal neurones. Exp. Brain Res. 33, 101–130. Illert, M., Jankowska, E., Lundberg, A., Odutola, A., 1981. Integration in descending motor pathways controlling the forelimb in the cat. 7. Effects from the reticular formation on C3-C4 propriospinal neurones. Exp. Brain Res. 42, 269–281. Isa, T., Ohki, Y., Alstermark, B., Pettersson, L.G., Sasaki, S., 2007. Direct and indirect corticomotoneuronal pathways and control of hand/arm movements. Physiology (Bethesda) 22, 145–152. Jane, J.A., Yashon, D., Demyer, W., Bucy, P.C., 1967. The contribution of the precentral gyrus to the pyramidal tract of man. J. Neurosurg. 26, 244–248. Jankowska, E., 2001. Spinal interneuronal systems: identification, multifunctional character and reconfigurations in mammals. J. Physiol. 533, 31–40. Jenner, J.R., Stephens, J.A., 1982. Cutaneous reflex responses and their central nervous pathways studied in man. J. Physiol. 333, 405–419. Jenny, A.B., Inukai, J., 1983. Principles of motor organization of the monkey cervical spinal cord. J. Neurosci. 3, 567–575. Kamper, D.G., Harvey, R.L., Suresh, S., Rymer, W.Z., 2003. Relative contributions of neural mechanisms versus muscle mechanics in promoting finger extension deficits following stroke. Muscle Nerve 28, 309–318. Kang, S.Y., Kim, J.S., 2008. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 70, 2386–2393. Keizer, K., Kuypers, H.G.J.M., 1989. Distribution of corticospinal neurons with collaterals to the lower brain stem reticular formation in monkey (Macaca fascicularis). Exp. Brain Res. 74, 311–318. Kinoshita, M., Matsui, R., Kato, S., Hasegawa, T., Kasahara, H., Isa, K., Watakabe, A., Yamamori, T., Nishimura, Y., Alstermark, B., Watanabe, D., Kobayashi, K., Isa, T., 2012. Genetic dissection of the circuit for hand dexterity in primates. Nature 487, 235–238. Kozelj, S., Baker, S.N., 2014. Different phase delays of peripheral input to primate motor cortex and spinal cord promote cancellation at physiological tremor frequencies. J. Neurophysiol. 111, 2001–2016. Kuypers, H.G.J.M. (Ed.), 1981. Anatomy of the Descending Pathways. American Physiological Society, Bethesda, MD.

References

Kuypers, H.G., Fleming, W.R., Farinholt, J.W., 1962. Subcorticospinal projections in the rhesus monkey. J. Comp. Neurol. 118, 107–137. Lang, C.E., Schieber, M.H., 2003. Differential impairment of individuated finger movements in humans after damage to the motor cortex or the corticospinal tract. J. Neurophysiol. 90, 1160–1170. Lang, C.E., Schieber, M.H., 2004. Reduced muscle selectivity during individuated finger movements in humans after damage to the motor cortex or corticospinal tract. J. Neurophysiol. 91, 1722–1733. Lawrence, D.G., Kuypers, H.G.J.M., 1968a. The functional organization of the motor system in the monkey. I. The effects of bilateral pyramidal lesions. Brain 91, 1–14. Lawrence, D.G., Kuypers, H.G.J.M., 1968b. The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathway. Brain 91, 15–36. Lemon, R.N., 2008. Descending pathways in motor control. Annu. Rev. Neurosci. 31, 195–218. Lemon, R.N., Porter, R., 1976. Afferent input to movement-related precentral neurones in conscious monkeys. Proc. R. Soc. Lond. Ser. B 194, 313–339. Lemon, R.N., Landau, W., Tutssel, D., Lawrence, D.G., 2012. Lawrence and Kuypers (1968a, b) revisited: copies of the original filmed material from their classic papers in Brain. Brain 135, 2290–2295. Liang, F., Moret, M., Wiesendanger, M., Rouiller, E.M., 1991. Corticomotoneuronal connections in the rat: evidence from double-labeling of motoneurons and corticospinal axon arborizations. J. Comp. Neurol. 311, 356–366. Liu, C.N., Chambers, W.W., 1964. An experimental study of the cortico-spinal system in the monkey (Macaca Mulatta). the spinal pathways and preterminal distribution of degenerating fibers following discrete lesions of the pre- and postcentral gyri and bulbar pyramid. J. Comp. Neurol. 123, 257–283. Maier, M.A., Armand, J., Kirkwood, P.A., Yang, H.W., Davis, J.N., Lemon, R.N., 2002. Differences in the corticospinal projection from primary motor cortex and supplementary motor area to macaque upper limb motoneurons: an anatomical and electrophysiological study. Cereb. Cortex 12, 281–296. Matsuyama, K., Takakusaki, K., Nakajima, K., Mori, S., 1997. Multi-segmental innervation of single pontine reticulospinal axons in the cervico-thoracic region of the cat: anterograde PHA-L tracing study. J. Comp. Neurol. 377, 234–250. Matsuyama, K., Mori, F., Kuze, B., Mori, S., 1999. Morphology of single pontine reticulospinal axons in the lumbar enlargement of the cat: a study using the anterograde tracer PHA-L. J. Comp. Neurol. 410, 413–430. Mcneal, D.W., Darling, W.G., Ge, J., Stilwell-Morecraft, K.S., Solon, K.M., Hynes, S.M., Pizzimenti, M.A., Rotella, D.L., Vanadurongvan, T., Morecraft, R.J., 2010. Selective long-term reorganization of the corticospinal projection from the supplementary motor cortex following recovery from lateral motor cortex injury. J. Comp. Neurol. 518, 586–621. Montgomery, L.R., Herbert, W.J., Buford, J.A., 2013. Recruitment of ipsilateral and contralateral upper limb muscles following stimulation of the cortical motor areas in the monkey. Exp. Brain Res. 230, 153–164. Morecraft, R.J., Ge, J., Stilwell-Morecraft, K.S., Mcneal, D.W., Pizzimenti, M.A., Darling, W.G., 2013. Terminal distribution of the corticospinal projection from the hand/arm region of the

409

410

CHAPTER 18 Pathways for recovery

primary motor cortex to the cervical enlargement in rhesus monkey. J. Comp. Neurol. 521, 4205–4235. Mori, S., Matsuyama, K., Mori, F., Nakajima, K., 2001. Supraspinal sites that induce locomotion in the vertebrate central nervous system. Adv. Neurol. 87, 25–40. Muir, R.B., Lemon, R.N., 1983. Corticospinal neurons with a special role in precision grip. Brain Res. 261, 312–316. Murata, A., Fadiga, L., Fogassi, L., Gallese, V., Raos, V., Rizzolatti, G., 1997. Object representation in the ventral premotor cortex (area F5) of the monkey. J. Neurophysiol. 78, 2226–2230. Nathan, P.W., Smith, M.C., 1955. Long descending tracts in man. I. Review of present knowledge. Brain 78, 248–303. Nelles, G., Cramer, S.C., Schaechter, J.D., Kaplan, J.D., Finklestein, S.P., 1998. Quantitative assessment of mirror movements after stroke. Stroke 29, 1182–1187. Nishimura, Y., Onoe, H., Morichika, Y., Perfiliev, S., Tsukada, H., Isa, T., 2007. Timedependent central compensatory mechanisms of finger dexterity after spinal cord injury. Science 318, 1150–1155. Nishimura, Y., Morichika, Y., Isa, T., 2009. A subcortical oscillatory network contributes to recovery of hand dexterity after spinal cord injury. Brain 132, 709–721. Niwa, M., Fadok, J.P., Fetz, E.E., Perlmutter, S.I., 2004. C3-C4 interneurons in behaving monkey: activity related to reach-and-grasp and wrist movements. Soc. Neurosci. Abstr, 656.6. Nudo, R.J., 2013. Recovery after brain injury: mechanisms and principles. Front. Hum. Neurosci. 7, 887. O’Collins, V.E., Macleod, M.R., Donnan, G.A., Horky, L.L., Van Der Worp, B.H., Howells, D.W., 2006. 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467–477. Onodera, S., Hicks, T.P., 2010. Carbocyanine dye usage in demarcating boundaries of the aged human red nucleus. PLoS One 5, e14430. Peterson, B.W., Maunz, R.A., Pitts, N.G., Mackel, R.G., 1975. Patterns of projection and branching of reticulospinal neurons. Exp. Brain Res. 23, 333–351. Peterson, B.W., Pitts, N.G., Fukushima, K., 1979. Reticulospinal connections with limb and axial motoneurons. Exp. Brain Res. 36, 1–20. Ralston, D.D., Ralston, H.J., 1985. The terminations of corticospinal tract axons in the macaque monkey. J. Comp. Neurol. 242, 325–337. Rathelot, J.A., Strick, P.L., 2006. Muscle representation in the macaque motor cortex: an anatomical perspective. Proc. Natl. Acad. Sci. U.S.A 103, 8257–8262. Rathelot, J.A., Strick, P.L., 2009. Subdivisions of primary motor cortex based on corticomotoneuronal cells. Proc. Natl. Acad. Sci. U.S.A 106, 918–923. Riddle, C.N., Baker, S.N., 2010. Convergence of pyramidal and medial brain stem descending pathways onto macaque cervical spinal interneurons. J. Neurophysiol. 103, 2821–2832. Riddle, C.N., Edgley, S.A., Baker, S.N., 2009. Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract. J. Neurosci. 29, 4993–4999. Rizzolatti, G., Luppino, G., Matelli, M., 1998. The organization of the cortical motor system: new concepts. Electroencephalogr. Clin. Neurophysiol. 106, 283–296. Rosen, I., Asanuma, H., 1972. Peripheral afferent inputs to the forelimb area of the monkey motor cortex: input–output relations. Exp. Brain Res. 14, 257–273. Rosenzweig, E.S., Brock, J.H., Culbertson, M.D., Lu, P., Moseanko, R., Edgerton, V.R., Havton, L.A., Tuszynski, M.H., 2009. Extensive spinal decussation and bilateral

References

termination of cervical corticospinal projections in rhesus monkeys. J. Comp. Neurol. 513, 151–163. Rosenzweig, E.S., Courtine, G., Jindrich, D.L., Brock, J.H., Ferguson, A.R., Strand, S.C., Nout, Y.S., Roy, R.R., Miller, D.M., Beattie, M.S., Havton, L.A., Bresnahan, J.C., Edgerton, V.R., Tuszynski, M.H., 2010. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat. Neurosci. 13, 1505–1510. Rouiller, E.M., Moret, V., Tanne, J., Boussaoud, D., 1996. Evidence for direct connections between the hand region of the supplementary motor area and cervical motoneurons in the macaque monkey. Eur. J. Neurosci. 8, 1055–1059. Rouiller, E.M., Yu, X.H., Moret, V., Tempini, A., Wiesendanger, M., Liang, F., 1998. Dexterity in adult monkeys following early lesion of the motor cortical hand area: the role of cortex adjacent to the lesion. Eur. J. Neurosci. 10, 729–740. Russell, J.R., Demyer, W., 1961. The quantitative corticoid origin of pyramidal axons of Macaca rhesus. With some remarks on the slow rate of axolysis. Neurology 11, 96–108. Sakai, S.T., Davidson, A.G., Buford, J.A., 2009. Reticulospinal neurons in the pontomedullary reticular formation of the monkey (Macaca fascicularis). Neuroscience 163, 1158–1170. Sasaki, S., Isa, T., Pettersson, L.G., Alstermark, B., Naito, K., Yoshimura, K., Seki, K., Ohki, Y., 2004. Dexterous finger movements in primate without monosynaptic corticomotoneuronal excitation. J. Neurophysiol. 92, 3142–3147. Schepens, B., Drew, T., 2004. Independent and convergent signals from the pontomedullary reticular formation contribute to the control of posture and movement during reaching in the cat. J. Neurophysiol. 92, 2217–2238. Schepens, B., Drew, T., 2006. Descending signals from the pontomedullary reticular formation are bilateral, asymmetric, and gated during reaching movements in the cat. J. Neurophysiol. 96, 2229–2252. Schepens, B., Stapley, P., Drew, T., 2008. Neurons in the pontomedullary reticular formation signal posture and movement both as an integrated behavior and independently. J. Neurophysiol. 100, 2235–2253. Sherrington, C.S., 1906. The Integrative Action of the Nervous System. Yale University Press, London. Shimazu, H., Maier, M.A., Cerri, G., Kirkwood, P.A., Lemon, R.N., 2004. Macaque ventral premotor cortex exerts powerful facilitation of motor cortex outputs to upper limb motoneurons. J. Neurosci. 24, 1200–1211. Shinoda, Y., Zarzecki, P., Asanuma, H., 1979. Spinal branching of pyramidal tract neurons in the monkey. Exp. Brain Res. 34, 59–72. Soteropoulos, D.S., Edgley, S.A., Baker, S.N., 2011. Lack of evidence for direct corticospinal contributions to control of the ipsilateral forelimb in monkey. J. Neurosci. 31, 11208–11219. Soteropoulos, D.S., Williams, E.R., Baker, S.N., 2012. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements. J. Physiol. 590, 4011–4027. Soteropoulos, D.S., Edgley, S.A., Baker, S.N., 2013. Spinal commissural connections to motoneurons controlling the primate hand and wrist. J. Neurosci. 33, 9614–9625. Starkey, M.L., Bleul, C., Zorner, B., Lindau, N.T., Mueggler, T., Rudin, M., Schwab, M.E., 2012. Back seat driving: hindlimb corticospinal neurons assume forelimb control following ischaemic stroke. Brain 135, 3265–3281.

411

412

CHAPTER 18 Pathways for recovery

Strick, P.L., Preston, J.B., 1982. Two representations of the hand in area 4 of a primate. II. Somatosensory input organization. J. Neurophysiol. 48, 150–159. Takei, T., Seki, K., 2010. Spinal interneurons facilitate coactivation of hand muscles during a precision grip task in monkeys. J. Neurosci. 30, 17041–17050. Tanji, J., Wise, S.P., 1981. Submodality distribution in sensorimotor cortex of the unanaesthetized monkey. J. Neurophysiol. 45, 467–481. Tazoe, T., Perez, M.A., 2014. Selective activation of ipsilateral motor pathways in intact humans. J. Neurosci. 34, 13924–13934. Turton, A., Wroe, S., Trepte, N., Fraser, C., Lemon, R.N., 1996. Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke. Electroencephalogr. Clin. Neurophysiol. 101, 316–328. Umilta, M.A., Brochier, T., Spinks, R.L., Lemon, R.N., 2007. Simultaneous recording of macaque premotor and primary motor cortex neuronal populations reveals different functional contributions to visuomotor grasp. J. Neurophysiol. 98, 488–501. Ward, N.S., Brown, M.M., Thompson, A.J., Frackowiak, R.S., 2003. Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 126, 2476–2496. Williams, E.R., Soteropoulos, D.S., Baker, S.N., 2010. Spinal interneuron circuits reduce approximately 10-Hz movement discontinuities by phase cancellation. Proc. Natl. Acad. Sci. U.S.A 107, 11098–11103. Wong, Y.C., Kwan, H.C., MacKay, W.A., Murphy, J.T., 1978. Spatial organization of precentral cortex in awake primates. I. Somatosensory inputs. J. Neurophysiol. 41, 1107–1118. Yang, H.W., Lemon, R.N., 2003. An electron microscopic examination of the corticospinal projection to the cervical spinal cord in the rat: lack of evidence for cortico-motoneuronal synapses. Exp. Brain Res. 149, 458–469. Yoshino-Saito, K., Nishimura, Y., Oishi, T., Isa, T., 2010. Quantitative inter-segmental and inter-laminar comparison of corticospinal projections from the forelimb area of the primary motor cortex of macaque monkeys. Neuroscience 171, 1164–1179. Zaaimi, B., Edgley, S.A., Soteropoulos, D.S., Baker, S.N., 2012. Changes in descending motor pathway connectivity after corticospinal tract lesion in macaque monkey. Brain 135, 2277–2289. Ziemann, U., Ishii, K., Borgheresi, A., Yaseen, Z., Battaglia, F., Hallett, M., Cincotta, M., Wassermann, E.M., 1999. Dissociation of the pathways mediating ipsilateral and contralateral motor-evoked potentials in human hand and arm muscles. J. Physiol. 518 (Pt. 3), 895–906.