David W. McNeal

Amygdala interconnections with the cingulate motor cortex in the rhesus monkey.

Amygdala interconnections with the cingulate motor cortices were investigated in the rhesus monkey. Using multiple tracing approaches, we found a robust projection from the lateral basal nucleus of the amygdala to Layers II, IIIa, and V of the rostral cingulate motor cortex (M3). A smaller source of amygdala input arose from the accessory basal, cortical, and lateral nuclei, which targeted only the rostral region of M3. We also found a light projection from the lateral basal nucleus to the same layers of the caudal cingulate motor cortex (M4). Experiments examining this projection to cingulate somatotopy using combined neural tracing strategies and stereology to estimate the total number of terminal‐like immunoreactive particles demonstrated that the amygdala projection terminates heavily in the face representation of M3 and moderately in its arm representation. Fewer terminal profiles were found in the leg representation of M3 and the face, arm, and leg representations of M4. Anterograde tracers placed directly into M3 and M4 revealed the amygdala connection to be reciprocal and documented corticofugal projections to the facial nucleus, surrounding pontine reticular formation, and spinal cord. Clinically, such pathways would be in a position to contribute to mediating movements in the face, neck, and upper extremity accompanying medial temporal lobe seizures that have historically characterized this syndrome. Alterations within or disruption of the amygdalo‐cingulate projection to the rostral part of M3 may also have an adverse effect on facial expression in patients presenting with neurological or neuropsychiatric abnormalities of medial temporal lobe involvement. Finally, the prominent amygdala projection to the face region of M3 may significantly influence the outcome of higher‐order facial expressions associated with social communication and emotional constructs such as fear, anger, happiness, and sadness. J. Comp. Neurol. 500:134–165, 2007.

Cytoarchitecture and Cortical Connections of the Anterior Cingulate and Adjacent Somatomotor Fields in the Rhesus Monkey

The cytoarchitecture and cortical connections of the anterior cingulate, medial and dorsal premotor, and precentral region are investigated using the Nissl and NeuN staining methods and the fluorescent retrograde tract tracing technique. There is a gradual stepwise laminar change in the cytoarchitectonic organization from the proisocortical anterior cingulate region, through the lower and upper banks of the cingulate sulcus, to the dorsolateral isocortical premotor and precentral motor regions of the frontal lobe. These changes are characterized by a gradational emphasis on the lower stratum layers (V and VI) in the proisocortical cingulate region to the upper stratum layers (II and III) in the premotor and precentral motor region. This is accompanied by a progressive widening of layers III and VI, a poorly delineated border between layers III and V and a sequential increase in the size of layer V neurons culminating in the presence of giant Betz cells in the precentral motor region. The overall patterns of corticocortical connections paralleled the sequential changes in cytoarchitectonic organization. The proisocortical areas have connections with cingulate motor, supplementary motor, premotor and precentral motor areas on the one hand and have widespread connections with the frontal, parietal, temporal and multimodal association cortex and limbic regions on the other. The dorsal premotor areas have connections with the proisocortical areas including cingulate motor areas and supplementary motor area on the one hand, and premotor and precentral motor cortex on the other. Additionally, this region has significant connections with posterior parietal cortex and limited connections with prefrontal, limbic and multimodal regions. The precentral motor cortex also has connections with the proisocortical areas and premotor areas. Its other connections are limited to the somatosensory regions of the parietal lobe. Since the isocortical motor areas on the dorsal convexity mediate voluntary motor function, their close connectional relationship with the cingulate areas form a pivotal limbic-motor interface that could provide critical sources of cognitive, emotional and motivational influence on complex motor function.

Selective long-term reorganization of the corticospinal projection from the supplementary motor cortex following recovery from lateral motor cortex injury.

Brain injury affecting the frontal motor cortex or its descending axons often causes contralateral upper extremity paresis. Although recovery is variable, the underlying mechanisms supporting favorable motor recovery remain unclear. Because the medial wall of the cerebral hemisphere is often spared following brain injury and recent functional neuroimaging studies in patients indicate a potential role for this brain region in the recovery process, we investigated the long‐term effects of isolated lateral frontal motor cortical injury on the corticospinal projection (CSP) from intact, ipsilesional supplementary motor cortex (M2). After injury to the arm region of the primary motor (M1) and lateral premotor (LPMC) cortices, upper extremity recovery is accompanied by terminal axon plasticity in the contralateral CSP but not the ipsilateral CSP from M2. Furthermore, significant contralateral plasticity occurs only in lamina VII and dorsally within lamina IX. Thus, selective intraspinal sprouting transpires in regions containing interneurons, flexor‐related motor neurons, and motor neurons supplying intrinsic hand muscles, which all play important roles in mediating reaching and digit movements. After recovery, subsequent injury of M2 leads to reemergence of hand motor deficits. Considering the importance of the CSP in humans and the common occurrence of lateral frontal cortex injury, these findings suggest that spared supplementary motor cortex may serve as an important therapeutic target that should be considered when designing acute and long‐term postinjury patient intervention strategies aimed to enhance the motor recovery process following lateral cortical trauma. J. Comp. Neurol. 518:586–621, 2010.

Volumetric Effects of Motor Cortex Injury on Recovery of Dexterous Movements

Due to the heterogeneous nature of most brain injuries, the contributions of gray and white matter involvement to motor deficits and recovery potential remain obscure. We tested the hypothesis that duration of hand motor impairment and recovery of skilled arm and hand motor function depends on the volume of gray and white matter damage of the frontal lobe. Lesions of the primary motor cortex (M1), M1 + lateral premotor cortex (LPMC), M1 + LPMC + supplementary motor cortex (M2) or multifocal lesions affecting motor areas and medial prefrontal cortex were evaluated in rhesus monkeys. Fine hand motor function was quantitatively assessed pre-lesion and for 3-12 months post-lesion using two motor tests. White and gray matter lesion volumes were determined using histological and quantitative methods. Regression analyses showed that duration of fine hand motor impairment was strongly correlated (R(2)>0.8) with the volume of gray and white matter lesions, with white matter lesion volume being the primary predictor of impairment duration. Level of recovery of fine hand motor skill was also well correlated (R(2)>0.5) with gray and white matter lesion volume. In some monkeys post-lesion skill exceeded pre-lesion skill in one or both motor tasks demonstrating that continued post-injury task practice can improve motor performance after localized loss of frontal motor cortex. These findings will assist in interpreting acute motor deficits, predicting the time course and expected level of functional recovery, and designing therapeutic strategies in patients with localized frontal lobe injury or neurosurgical resection.

Terminal distribution of the corticospinal projection from the hand/arm region of the primary motor cortex to the cervical enlargement in rhesus monkey.

To further our understanding of the corticospinal projection (CSP) from the hand/arm representation of the primary motor cortex (M1), high‐resolution anterograde tracing methodology and stereology were used to investigate the terminal distribution of this connection at spinal levels C5 to T1. The highest number of labeled terminal boutons occurred contralaterally (98%) with few ipsilaterally (2%). Contralaterally, labeled boutons were located within laminae I–X, with the densest distribution found in lamina VII and, to a lesser extent, laminae IX and VI. Fewer terminals were found in other contralateral laminae. Within lamina VII, terminal boutons were most prominent in the dorsomedial, dorsolateral, and ventrolateral subsectors. Within lamina IX, the heaviest terminal labeling was distributed dorsally. Ipsilaterally, boutons were found in laminae V–X. The most pronounced distribution occurred in the dorsomedial and ventromedial sectors of lamina VII and fewer labeled boutons were located in other ipsilateral laminae. Segmentally, contralateral lamina VII labeling was highest at levels C5–C7. In contrast, lamina IX labeling was highest at C7–T1 and more widely dispersed among the quadrants at C8–T1. Our findings suggest dominant contralateral influence of the M1 hand/arm CSP, a contralateral innervation pattern in lamina VII supporting Kuypers (1982) conceptual framework of a “lateral motor system,” and a projection to lamina IX indicating significant influence on motoneurons innervating flexors acting on the shoulder and elbow rostrally (C5–C7), along with flexors, extensors, abductors and adductors acting on the digits, hand and wrist caudally (C8–T1). J. Comp. Neurol. 521:4205–4235, 2013.

Localization of arm representation in the cerebral peduncle of the non-human primate

Motor deficit severity and the potential for recovery in patients with brain injury depend on the integrity of descending corticofugal projections. Clinical assessment of these conditions following subtotal brain trauma requires a comprehensive understanding of the anatomical structures involved in the lesion as well as those structures that are spared. To assist in this endeavor, we investigated motor fiber organization in the crus cerebri of the cerebral peduncle (ccCP) in the rhesus monkey. Fibers originating from the arm representations of the primary (M1), supplementary (M2), rostral cingulate (M3), caudal cingulate (M4), dorsolateral pre‐ (LPMCd) and ventrolateral pre‐ (LPMCv) motor cortices were studied. The projections from the frontal and cingulate motor cortices formed descending longitudinal bundles that occupied the medial three‐fifths of the ccCP at superior and middle levels. Although considerable overlap characterized these corticofugal projections, a general topography was discernable. Fibers from M1 and M4 occupied the central subsector of the ccCP, and fibers from M3 resided medially. The main distribution of LPMCd, LPMCv, and M2 fibers occupied the centromedial region and overlapped extensively. Progressing inferiorly, all fiber bundles in the central and centromedial sectors gradually extended medially, and overlap increased. A common location of fiber passage occurred at the midbrain‐pontine isthmus where all of the fiber bundles overlapped. Our findings indicate that the widespread distribution of corticofugal motor projections may account for the favorable levels of motor recovery that accompany subtotal midbrain injury. At superior and mid‐levels of the ccCP anteromedial lesions may disrupt projections from M3, whereas anterolateral lesions may disrupt projections from M1 and M4. Fibers from M2, LPMCv, and LPMCd may be compromised to some degree in both situations. The compact and commixed nature of motor fiber organization at inferior levels and the midbrain‐pontine isthmus suggests a vulnerable region of passage for comprehensive disruption of frontal and cingulate corticofugal projection fibers. J. Comp. Neurol. 504:149–167, 2007.

Measurement of coordination of object manipulation in non-human primates

We present a modification of the automated movement assessment panel [Gash DM, Zhang Z, Umberger G, Mahood K, Smith M, Smith C, et al. An automated movement assessment panel for upper limb motor functions in rhesus monkeys and humans. J Neurosci Methods 1999;89:111-7] that incorporates a three-dimensional load cell to record forces applied by monkeys while manipulating food targets. The absolute force-time integral (total absolute impulse) is used to characterize the total of the applied forces over time as the food (carrot chip with a hole punched through the center) is manipulated and lifted from a flat surface (easiest task) and threaded over a straight rod (medium difficulty) or curved rod (highest difficulty). The total impulse can be measured even on unsuccessful attempts to acquire the food. Thus, it can be used to evaluate changes in performance even before successful acquisition occurs as in learning or recovery following a nervous system insult. We show from tests in three rhesus monkeys that the total absolute impulse measure is sensitive to task complexity, learning and lesion of frontal lobe motor areas (in one case) and that there is good reliability in day-to-day performance (even with long periods between performances) after the monkey has learned the task. Importantly, the task requires minimal training as the monkeys can be successful on even the most difficult of these tasks with one or two training sessions, yet performance improvements continue to occur over several testing sessions. Furthermore, the three levels of task difficulty permit analysis of a progression of ability.

Plasticity of cerebral functions.

Over the past two decades, results from neurophysiological studies in animal models and neuroimaging studies in human populations have converged along a common thread. Neuroplasticity in the remaining, intact tissue accompanies functional recovery after brain injury. Now, virtually every new therapeutic approach in postinjury rehabilitation relies on the fundamental principles of neuroplasticity for theoretical validity. In this chapter, the basic tenets of plasticity are outlined, and the neural substrates in the cerebral cortex that may subserve recovered functions are reviewed.

Volumetric effects of motor cortex injury on recovery of ipsilesional dexterous movements

Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post-injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3-12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating that larger lesions were associated with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage.

Frontal and frontoparietal injury differentially affect the ipsilateral corticospinal projection from the nonlesioned hemisphere in monkey (Macaca mulatta)

Upper extremity hemiplegia is a common consequence of unilateral cortical stroke. Understanding the role of the unaffected cerebral hemisphere in the motor recovery process has been encouraged, in part, by the presence of ipsilateral corticospinal projections (iCSP). We examined the neuroplastic response of the iCSP from the contralesional primary motor cortex (cM1) hand/arm area to spinal levels C5–T1 after spontaneous long‐term recovery from isolated frontal lobe injury and isolated frontoparietal injury. High‐resolution tract tracing, stereological, and behavioral methodologies were applied. Recovery from frontal motor injury resulted in enhanced numbers of terminal labeled boutons in the iCSP from cM1 compared with controls. Increases occurred in lamina VIII and the adjacent ventral sectors of lamina VII, which are involved in axial/proximal limb sensorimotor processing. Larger frontal lobe lesions were associated with greater numbers of terminal boutons than smaller frontal lobe lesions. In contrast, frontoparietal injury blocked this response; total bouton number was similar to controls, demonstrating that disruption of somatosensory input to one hemisphere has a suppressive effect on the iCSP from the nonlesioned hemisphere. However, compared with controls, elevated bouton numbers occurred in lamina VIII, at the expense of lamina VII bouton labeling. Lamina IX boutons were also elevated in two frontoparietal lesion cases with extensive cortical injury. Because laminae VIII and IX collectively harbor axial, proximal, and distal motoneurons, therapeutic intervention targeting the ipsilateral corticospinal linkage from cM1 may promote proximal, and possibly distal, upper‐limb motor recovery following frontal and frontoparietal injury. J. Comp. Neurol. 524:380–407, 2016.