Behavioral recovery after a spinal deafferentation injury in monkeys does not correlate with extent of corticospinal sprouting.

A long held view in the spinal cord injury field is that corticospinal terminal sprouting is needed for new connections to form, that then mediate behavioral recovery. This makes sense, but tells us little about the relationship between corticospinal sprouting extent and recovery potential. The inference has been that more extensive axonal sprouting predicts greater recovery, though there is little evidence to support this. Here we addressed this by comparing behavioral data from monkeys that had received one of two established deafferentation spinal injury models in monkeys (Darian-Smith et al., 2014, Fisher et al., 2019, 2020). Both injuries cut similar afferent pools supplying the thumb, index and middle fingers of one hand but each resulted in a very different corticospinal tract (CST) sprouting response. Following a cervical dorsal root lesion, the somatosensory CST retracted significantly, while the motor CST stayed largely intact. In contrast, when a dorsal column lesion was combined with the DRL, somatosensory and motor CSTs sprouted dramatically within the cervical cord. How these two responses relate to the behavioral outcome was not clear. Here we analyzed the behavioral outcome for the two lesions, and provide a clear example that sprouting extent does not track with behavioral recovery.

Spinal cord injury transiently alters Meissner's corpuscle density in the digit pads of macaque monkeys.

Meissner's corpuscles (MCs) are cutaneous mechanoreceptors found in glabrous skin and are exquisitely sensitive to light touch. Along with other receptors, they provide continuous sensory feedback that informs the execution of fine manual behaviors. Following cervical spinal deafferentation injuries, hand use can be initially severely impaired, but substantial recovery occurs over many weeks, even when ~95% of the original input is permanently lost. While most SCI research focuses on central neural pathway responses, little is known about the role of peripheral receptors in facilitating recovery. We begin to address this by asking the following: (1) What is the normal pattern of MCs in the distal pads of all five digits in the macaque monkey (with hands similar to humans)? (2) What happens to these receptors 4-5 months following either a dorsal column lesion (DCL) or a combined dorsal root/dorsal column lesion (DRL/DCL), when functional recovery is largely complete? (3) What happens chronically, 12-14 months later? Our findings show that in normal monkeys, MCs are densest in the distal pads of the opposing thumb and index finger, with the greatest concentration on the thumb. This reflects a close functional relationship between receptor density and precision grip. At 4-5 months post-injury, there was a (~30%) loss of MCs on the deafferented digits of the injured hand compared with the contralateral side. However, 12-14 months after a DRL/DCL, receptor densities had returned to normal levels. Our findings indicate a complex peripheral response and highlight the importance of the periphery in shaping central changes.

Extensive somatosensory and motor corticospinal sprouting occurs following a central dorsal column lesion in monkeys.

The corticospinal tract (CST) forms the major descending pathway mediating voluntary hand movements in primates, and originates from ∼nine cortical subdivisions in the macaque. While the terminals of spared motor CST axons are known to sprout locally within the cord in response to spinal injury, little is known about the response of the other CST subcomponents. We previously reported that following a cervical dorsal root lesion (DRL), the primary somatosensory (S1) CST terminal projection retracts to 60% of its original terminal domain, while the primary motor (M1) projection remains robust (Darian-Smith et al., J. Neurosci., 2013). In contrast, when a dorsal column lesion (DCL) is added to the DRL, the S1 CST, in addition to the M1 CST, extends its terminal projections bilaterally and caudally, well beyond normal range (Darian-Smith et al., J. Neurosci., 2014). Are these dramatic responses linked entirely to the inclusion of a CNS injury (i.e., DCL), or do the two components summate or interact? We addressed this directly, by comparing data from monkeys that received a unilateral DCL alone, with those that received either a DRL or a combined DRL/DCL. Approximately 4 months post-lesion, the S1 hand region was mapped electrophysiologically, and anterograde tracers were injected bilaterally into the region deprived of normal input, to assess spinal terminal labeling. Using multifactorial analyses, we show that following a DCL alone (i.e., cuneate fasciculus lesion), the S1 and M1 CSTs also sprout significantly and bilaterally beyond normal range, with a termination pattern suggesting some interaction between the peripheral and central lesions.

Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys.

The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al., 2013), CST projections originating from primary somatosensory (S1) and motor (M1) cortex responded quite differently to injury. Terminal projections from the S1 (areas 3b/1/2) shrank to <60% of the contralateral side, while M1 CST projections remained robust or expanded (>110%). Here, we asked what happens when a central lesion is added to the equation, to better simulate clinical injury. Monkeys (n = 6) received either a unilateral (1) dorsal root lesion (DRL), (2) or a combined DRL/dorsal column lesion (DRL/DCL), or (3) a DRL/DCL where the DCL was made 4 months following the initial DRL. Electrophysiological recordings were made in S1 4 months postlesion in the first two groups, and 6 weeks after the DCL in the third lesion group, to identify the reorganized region of D1-D3 (thumb, index finger, and middle finger) representation. Anterograde tracers were then injected bilaterally to assess spinal terminal labeling. Remarkably, in all DRL/DCL animals, terminal projections from the S1 and M1 extended bilaterally and caudally well beyond terminal territories in normal animals or following a DRL. These data were highly significant. Extensive sprouting from the S1 CST has not been reported previously, and these data raise important questions about S1 CST involvement in recovery following spinal injury.

Corticospinal sprouting occurs selectively following dorsal rhizotomy in the macaque monkey.

The corticospinal tract in the macaque and human forms the major descending pathway involved in volitional hand movements. Following a unilateral cervical dorsal root lesion, by which sensory input to the first three digits (D1-D3) is removed, monkeys are initially unable to perform a grasp retrieval task requiring sensory feedback. Over several months, however, they recover much of this capability. Past studies in our laboratory have identified a number of changes in the afferent circuitry that occur as function returns, but do changes to the efferent pathways also contribute to compensatory recovery? In this study we examined the role of the corticospinal tract in pathway reorganization following a unilateral cervical dorsal rhizotomy. Several months after animals received a lesion, the corticospinal pathways originating in the primary somatosensory and motor cortex were labeled, and terminal distribution patterns on the two sides of the cervical cord were compared. Tracers were injected only into the region of D1-D3 representation (identified electrophysiologically). We observed a strikingly different terminal labeling pattern post lesion for projections originating in the somatosensory versus motor cortex. The terminal territory from the somatosensory cortex was significantly smaller compared with the contralateral side (area mean = 0.30 vs. 0.55 mm2), indicating retraction or atrophy of terminals. In contrast, the terminal territory from the motor cortex did not shrink, and in three of four animals, aberrant terminal label was observed in the dorsal horn ipsilateral to the lesion, indicating sprouting. These differences suggest that cortical regions play a different role in post-injury recovery

Consistency of hand preference across low-level and high-level tasks in capuchin monkeys (Cebus apella).

Numerous studies investigating behavioral lateralization in capuchins have been published. Although some research groups have reported a population-level hand preference, other researchers have argued that capuchins do not show hand preference at the population level. As task complexity influences the expression of handedness in other primate species, the purpose of this study was to collect hand preference data across a variety of high- and low-level tasks to evaluate how task complexity influences the expression of hand preference in capuchins. We tested eleven captive brown capuchin monkeys (Cebus apella) to determine if they show consistent hand preferences across multiple high- and low-level tasks. Capuchins were expected to display high intertask consistency across the high-level tasks but not the low-level tasks. Although most individuals showed significant hand preferences for each task, only two of the high-level tasks that involved similar hand motions were significantly positively correlated, indicating consistency of hand preference across these tasks only. None of the tasks elicited a group-level hand preference. High-level tasks elicited a greater strength of hand preference than did low-level tasks. No sex differences were found for the direction or strength of hand preference for any task. These results contribute to the growing database of primate laterality and provide additional evidence that capuchins do not display group-level hand preferences.

Corpus callosum morphology in capuchin monkeys is influenced by sex and handedness.

Sex differences have been reported in both overall corpus callosum area and its regional subdivisions in humans. Some have suggested this reflects a unique adaptation in humans, as similar sex differences in corpus callosum morphology have not been reported in any other species of primate examined to date. Furthermore, an association between various measurements of corpus callosum morphology and handedness has been found in humans and chimpanzees. In the current study, we report measurements of corpus callosum cross-sectional area from midsagittal MR images collected in vivo from 14 adult capuchin monkeys, 9 of which were also characterized for hand preference on a coordinated bimanual task. Adult females were found to have a significantly larger corpus callosum: brain volume ratio, rostral body, posterior midbody, isthmus, and splenium than adult males. Left-handed individuals had a larger relative overall corpus callosum area than did right-handed individuals. Additionally, a significant sex and handedness interaction was found for anterior midbody, with right-handed males having a significantly smaller area than right-handed females. These results suggest that sex and handedness influences on corpus callosum morphology are not restricted to Homo sapiens.