Localization of the corticofugal projection in the corona radiata (CR) and internal capsule (IC) can assist in evaluating a patient's residual motor capacity following subtotal brain damage and predicting their potential for functional restitution. To advance our understanding of the organization of the corticofugal projection in this critical brain region, we studied the trajectories of the projection arising from six different cortical arm representations in rhesus monkeys. They included the arm representation of the primary (M1), ventral lateral pre- (LPMCv), dorsolateral pre- (LPMCd), supplementary (M2), rostral cingulate (M3) and caudal cingulate (M4) motor cortices. In the CR, each pathway was segregated as medial motor area fibres arched over the caudate and lateral motor area fibres arched over the putamen. In the IC, the individual corticofugal pathways were found to be widespread, topographically organized and partially overlapping. At superior levels of the IC, the corticofugal projection from the arm representation of M3 coursed through the middle and posterior portion of the anterior limb (ICa). The projection from M2 passed through the posterior portion of the ICa and the genu (ICg). The projection from LPMCv travelled through the genu and anterior portion of the posterior limb (ICp). The projection from LPMCd occupied the anterior portion of the ICp. The projection from M4 descended through the mid-portion of the ICp. Fibres from M1 also travelled in the ICp, positioned immediately posterior to the M4 projection. As each fibre system progressed inferiorly within the IC, all fibres shifted posteriorly to occupy the ICp. Within the ICp, the projections from M3, M2, LPMCv, LPMCd, M4 and M1 maintained their anterior to posterior orientation, respectively. M2, LPMCd and LPMCv fibres overlapped extensively, as did fibres from M4 and M1. Our data suggest that CR and superior capsular lesions may correlate with more favourable levels of functional recovery due to the widespread nature of arm representation. In contrast, the extensive overlap and comparatively condensed organization of arm representation at inferior capsular levels suggest that lesions seated inferiorly are likely to correlate with poorer levels of recovery of upper limb movement. Based on the relative density of corticospinal neurones associated with the motor areas studied, our findings also suggest that motor deficit severity is likely to increase as a lesion occupies progressively more posterior regions of the IC.
A modified "Klüver" or dexterity board was developed to assess fine control of hand and digit movements by nonhuman primates during the acquisition of small food pellets from wells of different diameter. The primary advantages of the new device over those used previously include standardized positioning of target food pellets and controlled testing of each hand without the need for restraints, thereby allowing the monkey to move freely about the cage. Three-dimensional video analysis of hand motion was used to provide measures of reaching accuracy and grip aperture, as well as temporal measures of reach duration and food-pellet manipulation. We also present a validated performance score based on these measures, which serves as an indicator of successful food-pellet retrieval. Tests in three monkeys show that the performance score is an effective measure with which to study fine motor control associated with learning and handedness. We also show that the device and performance scores are effective for differentiating the effects of localized injury to motor areas of the cerebral cortex.
The corticobulbar projection to musculotopically defined subsectors of the facial nucleus was studied from the face representation of the primary (M1), supplementary (M2), rostral cingulate (M3), caudal cingulate (M4) and ventral lateral pre- (LPMCv) motor cortices in the rhesus monkey. We also investigated the corticofacial projection from the face/arm transitional region of the dorsal lateral premotor cortex (LPMCd). The corticobulbar projection was defined by injecting anterograde tracers into the face representation of each motor cortex. In the same animals, the musculotopic organization of the facial nucleus was defined by injecting fluorescent retrograde tracers into individual muscles of the upper and lower face. The facial nucleus received input from all face representations. M1 and LPMCv gave rise to the heaviest projection with progressively diminished intensity occurring in the M2, M3, M4 and LPMCd projections, respectively. Injections in all cortical face representations labelled terminals in all nuclear subdivisions (dorsal, intermediate, medial and lateral). However, significant differences occurred in the proportion of labelled boutons found within each functionally characterized subdivision. M1, LPMCv, LPMCd and M4 projected primarily to the contralateral lateral subnucleus, which innervated the perioral musculature. M2 projected bilaterally to the medial subnucleus, which supplied the auricular musculature. M3 projected bilaterally to the dorsal and intermediate subnuclei, which innervated the frontalis and orbicularis oculi muscles, respectively. Our results indicate that the various cortical face representations may mediate different elements of facial expression. Corticofacial afferents from M1, M4, LPMCv and LPMCd innervate primarily the contralateral lower facial muscles. Bilateral innervation of the upper face is supplied by M2 and M3. The widespread origin of these projections indicates selective vulnerability of corticofacial control following subtotal brain injury. The finding that all face representations innervate all nuclear subdivisions, to some degree, suggests that each motor area may participate in motor recovery in the event that one or more of these motor areas are spared following subtotal brain injury. Finally, the fact that a component of the corticofacial projection innervating both upper and lower facial musculature arises from the limbic proisocortices (M3 and M4) and frontal isocortices (M1, M2, LPMCv and LPMCd) suggests a potential anatomical substrate that may contribute to the clinical dissociation of emotional and volitional facial movement.
In this article, a “bedside to bench and back” approach for developing tissue engineered medical products (TEMPs) for clinical applications is reviewed. The driving force behind this approach is unmet clinical needs. Preclinical research, both in vitro and in vivo using small and large animal models, will help find solutions to key research questions. In clinical research, ethical issues regarding the use of cells and tissues, their sources, donor consent, as well as clinical trials are important considerations. Regulatory issues, at both institutional and government levels, must be addressed prior to the translation of TEMPs to clinical practice. TEMPs are regulated as drugs, biologics, devices, or combination products by the US Food and Drug Administration (FDA). Depending on the mode of regulation, applications for TEMP introduction must be filed with the FDA to demonstrate safety and effectiveness in premarket clinical studies, followed by 510(k) premarket clearance or premarket approval (for medical devices), biologics license application approval (for biologics), or New Drug Application approval (for drugs). A case study on nerve cuffs is presented to illustrate the regulatory process. Finally, perspectives on commercialization such as finding a company partner and funding issues, as well as physician culture change, are presented.
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