Terminal organization of the corticospinal projection from the arm/hand region of the rostral primary motor cortex (M1r or old M1) to the cervical enlargement (C5-T1) in rhesus monkey.

High-resolution anterograde tracers and stereology were used to study the terminal organization of the corticospinal projection (CSP) from the rostral portion of the primary motor cortex (M1r) to spinal levels C5-T1. Most of this projection (90%) terminated contralaterally within laminae V-IX, with the densest distribution in lamina VII. Moderate bouton numbers occurred in laminae VI, VIII, and IX with few in lamina V. Within lamina VII, labeling occurred over the distal-related dorsolateral subsectors and proximal-related ventromedial subsectors. Within motoneuron lamina IX, most terminations occurred in the proximal-related dorsomedial quadrant, followed by the distal-related dorsolateral quadrant. Segmentally, the contralateral lamina VII CSP gradually declined from C5-T1 but was consistently distributed at C5-C7 in lamina IX. The ipsilateral CSP ended in axial-related lamina VIII and adjacent ventromedial region of lamina VII. These findings demonstrate the M1r CSP influences distal and proximal/axial-related spinal targets. Thus, the M1r CSP represents a transitional CSP, positioned between the caudal M1 (M1c) CSP, which is 98% contralateral and optimally organized to mediate distal upper extremity movements (Morecraft et al., 2013), and dorsolateral premotor (LPMCd) CSP being 79% contralateral and optimally organized to mediate proximal/axial movements (Morecraft et al., 2019). This distal to proximal CSP gradient corresponds to the clinical deficits accompanying caudal to rostral motor cortex injury. The lamina IX CSP is considered in the light of anatomical and neurophysiological evidence which suggests M1c gives rise to the major proportion of the cortico-motoneuronal (CM) projection, while there is a limited M1r CM projection.

Feasibility of probe washing after stereotactic needle biopsy as a novel technique for developing cell lines and xenografts of H3 K27-altered diffuse midline gliomas.

H3 K27-altered diffuse midline gliomas (DMGs) are frequently biopsied to obtain tissue diagnosis, inform clinical decision-making, and determine clinical trial eligibility. Tissue yield from biopsies is typically low, leaving little material available for research. To advance understanding of disease biology and promote preclinical testing of novel therapeutics, collecting viable cellular material from treatment-naive tumors is of paramount importance. Here, the authors report the feasibility of a practicable technique for creating DMG cell lines and patient-derived xenografts (PDXs) without the need for additional biopsy specimens. Tumor cells are obtained by probe washing immediately after completion of biopsy. Wash fluid is collected, and viable cells are expanded in vitro. Cultured cells are used to establish PDX rodent models. A total of 5 patient samples were collected by this technique. Viable tumor cells were obtained from 3 of the 5 samples, and cell lines suitable for experiments were obtained within 6-8 months. Orthotopic implantation and flank engraftment was successful in 1 of the 3 established cell lines. Animals harboring intracranial tumors were euthanized due to disease burden 6-7 months after stereotactic injection. Flank tumors formed within 4-5 months and were serially passaged. Molecular and tissue analyses confirmed retention of H3 K27M expression and loss of H3 K27me3 in all cell lines and PDXs.

Overcoming translational barriers in H3K27-altered diffuse midline glioma: Increasing the drug-tumor residence time.

Background: H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. Methods: We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Results: Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. Conclusions: These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.

STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma.

BACKGROUND: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. METHODS: We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. RESULTS: Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. CONCLUSIONS: STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

Lack of somatotopy among corticospinal tract fibers passing through the primate craniovertebral junction and cervical spinal cord: pathoanatomical substrate of central cord syndrome and cruciate paralysis.

OBJECTIVE: In some cases of incomplete cervical spinal cord injury (iSCI) there is marked paresis and dysfunction of upper-extremity movement but not lower-extremity movement. A continued explanation of such symptoms is a somatotopic organization of corticospinal tract (CST) fibers passing through the decussation at the craniovertebral junction (CVJ) and lateral CST (LCST). In central cord syndrome, it has been suggested that injury to the core of the cervical cord may include selective damage to medially located arm/hand LCST fibers, without compromising laterally located leg fibers. Because such somatotopic organization in the primate CST might contribute to the disproportionate motor deficits after some forms of iSCI, the authors made a systematic investigation of CST organization in the CVJ and LCST using modern neuroanatomical techniques. METHODS: High-resolution anterograde tracers were used in 11 rhesus macaque monkeys to define the course of the corticospinal projection (CSP) through the CVJ and LCST from the arm/hand, shoulder, and leg areas of the primary motor cortex (M1). This approach labels CST fibers of all sizes, large and small, arising in these areas. The CSP from the dorsolateral and ventrolateral premotor cortex and supplementary motor area were also studied. A stereological approach was adapted to quantify labeled fiber distribution in 8 cases. RESULTS: There was no evidence for somatotopic organization of CST fibers passing through the CVJ or contralateral LCST. Fiber labeling from each cortical representation was widespread throughout the CST at the CVJ and LCST and overlapped extensively with fibers from other representations. This study demonstrated no significant difference between medial versus lateral subsectors of the LCST in terms of number of fibers labeled from the M1 arm/hand area. CONCLUSIONS: This investigation firmly rejects the concept of somatotopy among CST fibers passing through the CVJ and LCST, in contrast with the somatotopy in the cortex, corona radiata, and internal capsule. All CST fibers in the CVJ and LCST would thus appear to be equally susceptible to focal or diffuse injury, regardless of their cortical origin. The disproportionate impairment of arm/hand movement after iSCI must therefore be due to other factors, including greater dependence of hand/arm movements on the CST compared with the lower limb. The dispersed and intermingled nature of frontomotor fibers may be important in motor recovery after cervical iSCI.

Greater Reduction in Contralesional Hand Use After Frontoparietal Than Frontal Motor Cortex Lesions in Macaca mulatta.

We previously reported that rhesus monkeys recover spontaneous use of the more impaired (contralesional) hand following neurosurgical lesions to the arm/hand representations of primary motor cortex (M1) and lateral premotor cortex (LPMC) (F2 lesion) when tested for reduced use (RU) in a fine motor task allowing use of either hand. Recovery occurred without constraint of the less impaired hand and with occasional forced use of the more impaired hand, which was the preferred hand for use in fine motor tasks before the lesion. Here, we compared recovery of five F2 lesion cases in the same RU test to recovery after unilateral lesions of M1, LPMC, S1 and anterior portion of parietal cortex (F2P2 lesion - four cases). Average and highest %use of the contralesional hand in the RU task in F2 cases were twice that in F2P2 cases (p < 0.05). Recovery in the RU task was closely associated with volume and percentage of lesion to caudal (new) M1 (M1c) in both F2 and F2P2 lesion cases. One F2P2 case, with the largest M1c lesion and a large rostral somatosensory cortex (S1r) lesion developed severe contralesional hand non-use despite exhibiting some recovery of fine motor function initially. We conclude that the degree of reduced use of the contralesional hand is primarily related to the volume of M1c injury and that severe non-use requires extensive injury to M1c and S1r. Thus, assessing peri-Rolandic injury extent in stroke patients may have prognostic value for predicting susceptibility to RU and non-use in rehabilitation.

Changes in ipsilesional hand motor function differ after unilateral injury to frontal versus frontoparietal cortices in Macaca mulatta.

We tested the hypothesis that injury to frontoparietal sensorimotor areas causes greater initial impairments in performance and poorer recovery of ipsilesional dexterous hand/finger movements than lesions limited to frontal motor areas in rhesus monkeys. Reaching and grasping/manipulation of small targets with the ipsilesional hand were assessed for 6-12 months post-injury using two motor tests. Initial post-lesion motor skill and long-term recovery of motor skill were compared in two groups of monkeys: (1) F2 group-five cases with lesions of arm areas of primary motor cortex (M1) and lateral premotor cortex (LPMC) and (2) F2P2 group-five cases with F2 lesions + lesions of arm areas of primary somatosensory cortex and the anterior portion of area 5. Initial post-lesion reach and manipulation skills were similar to or better than pre-lesion skills in most F2 lesion cases in a difficult fine motor task but worse than pre-lesion skill in most F2P2 lesion cases in all tasks. Subsequently, reaching and manipulation skills improved over the post-lesion period to higher than pre-lesion skills in both groups, but improvements were greater in the F2 lesion group, perhaps due to additional task practice and greater ipsilesional limb use for daily activities. Poorer and slower post-lesion improvement of ipsilesional upper limb motor skill in the F2P2 cases may be due to impaired somatosensory processing. The persistent ipsilesional upper limb motor deficits frequently observed in humans after stroke are probably caused by greater subcortical white and gray matter damage than in the localized surgical injuries studied here.

Terminal organization of the corticospinal projection from the lateral premotor cortex to the cervical enlargement (C5-T1) in rhesus monkey.

High-resolution tract tracing and stereology were used to study the terminal organization of the corticospinal projection (CSP) from the ventral (v) and dorsal (d) regions of the lateral premotor cortex (LPMC) to spinal levels C5-T1. The LPMCv CSP originated from the postarcuate sulcus region, was bilateral, sparse, and primarily targeted the dorsolateral and ventromedial sectors of contralateral lamina VII. The convexity/lateral part of LPMCv did not project below C2. Thus, very little LPMCv corticospinal output reaches the cervical enlargement. In contrast, the LPMCd CSP was 5× more prominent in terminal density. Bilateral terminal labeling occurred in the medial sectors of lamina VII and adjacent lamina VIII, where propriospinal neurons with long-range bilateral axon projections reside. Notably, lamina VIII also harbors axial motoneurons. Contralateral labeling occurred in the lateral sectors of lamina VII and the dorsomedial quadrant of lamina IX, noted for harboring proximal upper limb flexor motoneurons. Segmentally, the CSP to contralateral laminae VII and IX preferentially innervated C5-C7, which supplies shoulder, elbow, and wrist musculature. In contrast, terminations in axial-related lamina VIII were distributed bilaterally throughout all cervical enlargement levels, including C8 and T1. These findings demonstrate the LPMCd CSP is structured to influence axial and proximal upper limb movements, supporting Kuypers conceptual view of the LPMCd CSP being a major component of the medial motor control system. Thus, distal upper extremity control influenced by LPMC, including grasping and manipulation, must occur through indirect neural network connections such as corticocortical, subcortical, or intrinsic spinal circuits.

New Corticopontine Connections in the Primate Brain: Contralateral Projections From the Arm/Hand Area of the Precentral Motor Region.

The ipsilateral corticopontine projection (iCPP) represents a massive descending axon system terminating in the pontine nuclei (PN). In the primate, this projection is well known for its dominant influence on contralateral upper limb movements through the classical cerebrocerebellar circuity system. Although a much weaker contralateral corticopontine projection (cCPP) from motor cortex to the paramedian region has been reported in the non-human primate brain, we provide the first comprehensive description of the cCPP from the lateral motor cortex using high resolution anterograde tract tracing in Macaca mulatta. We found a relatively light cCPP from the hand/arm area of the primary motor cortex (M1), comparatively moderate cCPP from ventrolateral premotor cortex (LPMCv) and a more robust and widespread cCPP from the dorsolateral premotor cortex (LPMCd) that involved all nine contralateral PN. The M1 projection primarily targeted the dorsal pontine region, the LPMCv projection targeted the medial pontine region and LPMCd targeted both regions. These results show the first stage of the primate frontomotor cerebrocerebellar projection is bilateral, and may affect both ipsilateral and contralateral limbs. Clinically, the cCPP originating in the non-injured hemisphere may influence the recovery process of the more affected upper extremity following subtotal unilateral damage to the lateral cortical region. The cCPP may also contribute to the mild impairment of the upper limb contralateral to a unilateral cerebellar injury.

Hand Motor Recovery Following Extensive Frontoparietal Cortical Injury Is Accompanied by Upregulated Corticoreticular Projections in Monkey.

We tested the hypothesis that arm/hand motor recovery after injury of the lateral sensorimotor cortex is associated with upregulation of the corticoreticular projection (CRP) from the supplementary motor cortex (M2) to the gigantocellular reticular nucleus of the medulla (Gi). Three groups of rhesus monkeys of both genders were studied: five controls, four cases with lesions of the arm/hand area of the primary motor cortex (M1) and the lateral premotor cortex (LPMC; F2 lesion group), and five cases with lesions of the arm/hand area of M1, LPMC, S1, and anterior parietal cortex (F2P2 lesion group). CRP strength was assessed using high-resolution anterograde tracers injected into the arm/hand area of M2 and stereology to estimate of the number of synaptic boutons in the Gi. M2 projected bilaterally to the Gi, primarily targeting the medial Gi subsector and, to a lesser extent, lateral, dorsal, and ventral subsectors. Total CRP bouton numbers were similar in controls and F2 lesion cases but F2P2 lesion cases had twice as many boutons as the other two groups (p = 0.0002). Recovery of reaching and fine hand/digit function was strongly correlated with estimated numbers of CRP boutons in the F2P2 lesion cases. Because we previously showed that F2P2 lesion cases experience decreased strength of the M2 corticospinal projection (CSP), whereas F2 lesion monkeys experienced increased strength of the M2 CSP, these results suggest one mechanism underlying arm/hand motor recovery after F2P2 injury is upregulation of the M2 CRP. This M2-CRP response may influence an important reticulospinal tract contribution to upper-limb motor recovery following frontoparietal injury.SIGNIFICANCE STATEMENT We previously showed that after brain injury affecting the lateral motor cortex controlling arm/hand motor function, recovery is variable and closely associated with increased strength of corticospinal projection (CSP) from an uninjured medial cortical motor area. Hand motor recovery also varies after brain injury affecting the lateral sensorimotor cortex, but medial motor cortex CSP strength decreases and cannot account for recovery. Here we observed that motor recovery following sensorimotor cortex injury is closely associated with increased strength of the descending projection from an uninjured medial cortical motor area to a brainstem reticular nucleus involved in control of arm/hand function, suggesting an enhanced corticoreticular projection may compensate for injury to the sensorimotor cortex to enable recovery of arm/hand motor function.

Sensorimotor cortex injury effects on recovery of contralesional dexterous movements in Macaca mulatta.

The effects of primary somatosensory cortex (S1) injury on recovery of contralateral upper limb reaching and grasping were studied by comparing the consequences of isolated lesions to the arm/hand region of primary motor cortex (M1) and lateral premotor cortex (LPMC) to lesions of these same areas plus anterior parietal cortex (S1 and rostral area PE). We used multiple linear regression to assess the effects of gray and white matter lesion volumes on deficits in reaching and fine motor performance during the first month after the lesion, and during recovery of function over 3, 6 and 12months post-injury in 13 monkeys. Subjects with frontoparietal lesions exhibited larger deficits and poorer recovery as predicted, including one subject with extensive peri-Rolandic injury developing learned nonuse after showing signs of recovery. Regression analyses showed that total white matter lesion volume was strongly associated with initial post-lesion deficits in motor performance and with recovery of skill in reaching and manipulation. Multiple regression analyses using percent damage to caudal M1 (M1c), rostral S1 (S1r), LPMC and area PE as predictor variables showed that S1r lesion volumes were closely related to delayed post-lesion recovery of upper limb function, as well as lower skill level of recovery. In contrast, M1c lesion volume was related primarily to initial post-lesion deficits in hand motor performance. Overall, these findings demonstrate that frontoparietal injury impairs hand motor function more so than frontal motor injury alone, and results in slower and poorer recovery than lesions limited to frontal motor cortex.

Recovery of precision grasping after motor cortex lesion does not require forced use of the impaired hand in Macaca mulatta.

We investigated recovery of precision grasping of small objects between the index finger and thumb of the impaired hand without forced use after surgically placed lesions to the hand/arm areas of M1 and M1 + lateral premotor cortex in two monkeys. The unilateral lesions were contralateral to the monkey's preferred hand, which was established in prelesion testing as the hand used most often to acquire raisins in a foraging board (FB) task in which the monkey was free to use either hand to acquire treats. The lesions initially produced a clear paresis of the contralesional hand and use of only the ipsilesional hand to acquire raisins in the FB task. However, beginning about 3 weeks after the lesion both monkeys spontaneously began using the impaired contralesional hand in the FB task and increased use of that hand over the next few tests. Moreover, the monkeys clearly used precision grasp to acquire the raisins in a similar manner to prelesion performances, although grasp durations were longer. Although the monkeys used the contralesional hand more often than the ipsilesional hand in some postlesion testing sessions, they did not recover to use the hand as often as in prelesion testing when the preferred hand was used almost exclusively. These findings suggest that recovery of fine hand/digit motor function after localized damage to the lateral frontal motor areas in rhesus monkeys does not require forced use of the impaired hand.

Cortical innervation of the hypoglossal nucleus in the non-human primate (Macaca mulatta).

The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate, and insular cortices in the rhesus monkey by using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula, and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, and moderate projections from LPMCv and rostral part of M2, with considerably fewer hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain.

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).

Laterality affects spontaneous recovery of contralateral hand motor function following motor cortex injury in rhesus monkeys.

The purpose of this study was to test whether brain laterality influences spontaneous recovery of hand motor function after controlled brain injuries to arm areas of M1 and lateral premotor cortex (LPMC) of the hemisphere contralateral to the preferred hand in rhesus monkeys. We hypothesized that monkeys with stronger hand preference would exhibit poorer recovery of skilled hand use after such brain injury. Degree of handedness was assessed using a standard dexterity board task in which subjects could use either hand to retrieve small food pellets. Fine hand/digit motor function was assessed using a modified dexterity board before and after the M1 and LPMC lesions in ten monkeys. We found a strong negative relationship between the degree of handedness and the recovery of manipulation skill, demonstrating that higher hand preference was associated with poorer recovery of hand fine motor function. We also observed that monkeys with larger lesions within M1 and LPMC had greater initial impairment of manipulation and poorer recovery of reaching skill. We conclude that monkeys with a stronger hand preference are likely to show poorer recovery of contralesional hand fine motor skill after isolated brain lesions affecting the lateral frontal motor areas. These data may be extended to suggest that humans who exhibit weak hand dominance, and perhaps individuals who use both hands for fine motor tasks, may have a more favorable potential for recovery after a unilateral stroke or brain injury affecting the lateral cortical motor areas than individuals with a high degree of hand dominance.

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.

Minimal forced use without constraint stimulates spontaneous use of the impaired upper extremity following motor cortex injury.

The purpose of this study was to determine if recovery of neurologically impaired hand function following isolated motor cortex injury would occur without constraint of the non-impaired limb, and without daily forced use of the impaired limb. Nine monkeys (Macaca mulatta) received neurosurgical lesions of various extents to arm representations of motor cortex in the hemisphere contralateral to the preferred hand. After the lesion, no physical constraints were placed on the ipsilesional arm/hand and motor testing was carried out weekly with a maximum of 40 attempts in two fine motor tasks that required use of the contralesional hand for successful food acquisition. These motor tests were the only "forced use" of the contralesional hand. We also tested regularly for spontaneous use of the contralesional hand in a fine motor task in which either hand could be used for successful performance. This minimal intervention was sufficient to induce recovery of the contralesional hand to such a functional level that eight of the monkeys chose to use that hand on some trials when either hand could be used. Percentage use of the contralesional hand (in the task when either hand could be used) varied considerably among monkeys and was not related to lesion volume or recovery of motor skill. These data demonstrate a remarkable capacity for recovery of spontaneous use of the impaired hand following localized frontal lobe lesions. Clinically, these observations underscore the importance of therapeutic intervention to inhibit the induction of the learned nonuse phenomenon after neurological injury.

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.