Internal Capsule Hemorrhage Research Articles

Development of Novel Drugs to Promote Functional Recovery After Brain Injury

The central nervous system injury such as stroke can severely cause motor paralysis.Although the approach of rehabilitative training is developed, many patients still face restrictions in their daily living after rehabilitation. Thereby, a new compound with a strong potential to enhance motor function recovery with rehabilitation is an unmet medical need. We focus on the one of glutamate receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which plays an important role in learning and memory. Here, we found a novel small low molecular compound, edonerpic maleate, that facilitated experience-dependent synaptic AMPA receptor delivery in the barrel cortex and dramatically accelerated motor function recovery after brain damage in a rodent model. Furthermore, edonerpic maleate enhanced the upper limb function recovery of macaque monkeys with internal capsule hemorrhage. Currently, a phase 2 clinical trial is being conducted to verify the efficacy of edonerpic maleate in stroke patients and has attracted global attention.

Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats.

Reorganization of residual descending motor circuits underlies poststroke recovery. We previously clarified a causal relationship between the cortico-rubral tract and intensive limb use-induced functional recovery after internal capsule hemorrhage (ICH). However, other descending tracts, such as the cortico-reticular tract, might also be involved in rehabilitation-induced compensation. To investigate whether rehabilitation-induced recovery after ICH involves a shift in the compensatory circuit from the cortico-rubral tract to the cortico-reticular tract, we established loss of function of the cortico-rubral tract or/and cortico-reticular tract using two sets of viral vectors comprising the Tet-on system and designer receptors exclusively activated by the designer drug system. We used an ICH model that destroyed almost 60% of the corticofugal fibers. Anterograde tracing in rehabilitated rats revealed abundant sprouting of axons from the motor cortex in the red nucleus but not in the medullary reticular formation during the early phase of recovery. This primary contribution of the cortico-rubral tract was demonstrated by its selective blockade, whereas selective cortico-reticular tract silencing had little effect. Interestingly, cortico-rubral tract blockade from the start of rehabilitation induced an obvious increase of axon sprouting in the reticular formation with substantial functional recovery. Additional cortico-reticular tract silencing under the cortico-rubral tract blockade significantly worsened the recovered forelimb function. Furthermore, the alternative recruitment of the cortico-reticular tract was gradually induced by intensive limb use under cortico-rubral tract blockade, in which cortico-reticular tract silencing caused an apparent motor deficit. These findings indicate that individual cortico-brainstem pathways have dynamic compensatory potency to support rehabilitative functional recovery after ICH.SIGNIFICANCE STATEMENT This study aimed to clarify the interaction between the cortico-rubral and the cortico-reticular tract during intensive rehabilitation and functional recovery after capsular stroke. Pathway-selective disturbance by two sets of viral vectors revealed that the cortico-rubral tract was involved in rehabilitation-induced recovery of forelimb function from an early phase after internal capsule hemorrhage, but that the cortico-reticular tract was not. The sequential disturbance of both tracts revealed that the cortico-reticular tract was recruited and involved in rehabilitation-induced recovery when the cortico-rubral tract failed to function. Our data demonstrate a dynamic compensatory action of individual cortico-brainstem pathways for recovery through poststroke rehabilitation.

Both endoplasmic reticulum and mitochondrial pathways are involved in oligodendrocyte apoptosis induced by capsular hemorrhage.

The white matter injury caused by intracerebral hemorrhage (ICH) includes demyelination and axonal injury. Oligodendrocyte apoptosis is reported to be involved in triggering demyelination. Experimental observations indicate that both endoplasmic reticulum and mitochondrial pathways could mediate cell apoptosis. The purpose of this study was to investigate the demyelination and the possible mechanisms in an autologous blood-injected rat model of internal capsule hemorrhage. Transmission electron microscope was applied to examine the pathological changes of myelinated nerve fibers in internal capsule. Western blotting was used to detect the myelin basic protein (MBP) which was an important component of myelin sheath. Double immunofluorescence and Western blotting were used to determine the apoptosis and apoptotic pathways. The levels of caspase-12 (a representative protein of endoplasmic reticulum stress) and cytochrome c (an apoptosis factor released from mitochondria) were assessed in this study. Demyelination occurred on day 1, 3, and 7 after ICH onset. Myelin sheaths of internal capsule nerve fibers were swollen and broken down in ICH groups. MBP expression showed a downregulation after ICH with its minimum value occurred on day 7 post-ICH. Besides, neuron and oligodendrocyte apoptosis were observed at different time intervals post-ICH accompanied with an upregulated caspase-12 expression and enhanced cytochrome c release. These results suggested that oligodendrocyte and neuron apoptosis may contribute to the demyelination induced by internal capsule hemorrhage and oligodendrocyte apoptosis is positively mediated through both endoplasmic reticulum and mitochondrial pathways.

The Interaction of Leukocytes and Adhesion Molecules in Mesenteric Microvessel Endothelial Cells after Internal Capsule Hemorrhage

To explore the correlation between hemorheological variations and the expression of cell adhesion molecules in mesenteric microvessel endothelial cells after internal capsule hemorrhage. We established an internal capsule hemorrhage model. Then leukocyte-endothelium interaction was observed and hemorheological variations in mesenteric microvessels were evaluated in the following aspects: blood flow volume, diameter of microvessels, blood flow rate, and shear rate. We also measured the expression of vascular cell adhesion molecule-l and intercellular adhesion molecule-1 (ICAM-1) in mesenteric microvessel endothelial cells with immunohistochemistry stain. Leukocyte-endothelium interaction intensified after internal capsule hemorrhage. Besides, blood flow volume and velocity decreased, diameter narrowed, and shear rate reduced. Immunohistochemical staining of vascular cell adhesion molecule-l and ICAM-1in mesenteric microvessel endothelial cells was stronger. VCAM-1 and ICAM-1 expression in mesenteric microvessels increased as a result of decreased wall shear stress in stress state following internal capsule hemorrhage, and then further shear stress change from interaction of enhanced production of CAMs and leukocytes created a vicious cycle of leukocytes margination, adhesion, and transmigration that could ultimately result in stress gastrointestinal ulcer.

Differential effects of early and late forced-use of impaired forelimb on functional recovery and expressions of growth-related factors after internal capsule hemorrhage in rats

To determine whether the combination of Constraint-Induced Movement Therapy (CIMT) and conventional rehabilitation techniques can produce meaningful motor improvement in chronic stroke patients with initially fisted hands.Case series.University hospital outpatient laboratory.Consecutive sample (N=6) >1 year poststroke with plegic hands.Treatment consisted of an initial period of 3 weeks (phase A) when adaptive equipment in the home, orthotics, and splints were employed to improve ability to engage in activities of daily living. This was continued in phase B, when CIMT and selected neurodevelopmental treatment techniques were added.Motor Activity Log (MAL), accelerometry, Fugl-Meyer Motor Assessment (F-M).Patients exhibited a large improvement in spontaneous real-world use of the more-affected arm (mean lower-functioning MAL change=1.3±0.4 points; P<.001; d′=3.0) and a similar pattern of increase in an objective measure of real-world more-affected arm movement (mean change in ratio of more- to less-affected arm accelerometer recordings=0.12±0.1 points; P=.016; d′=1.2). A large improvement in motor status was also recorded (mean F-M change=5.3±3.3 points; P=.005; d′=1.6).The findings of this pilot study suggest that stroke patients with plegic hands can benefit from CIMT combined with some conventional rehabilitation techniques, even long after brain injury. More research is warranted.

Early onset of forced impaired forelimb use causes recovery of forelimb skilled motor function but no effect on gross sensory-motor function after capsular hemorrhage in rats

Intensive use of the impaired forelimb promotes behavioral recovery and induces plastic changes of the central nervous system after stroke. However, the optimal onset of intensive use treatment after stroke is controversial. In this study, we investigated whether early forced impaired limb use (FLU) initiated 24 h after intracerebral hemorrhage (ICH) of the internal capsule affected behavioral recovery and histological damage. Rats were subjected to ICH via low-dose collagenase infusion or sham stroke. One day after surgery, the ipsilateral forelimbs of half of the ICH and sham rats were casted for a week to induce the use of their contralateral forelimbs. Behavioral assessments were performed on days 10–12 and 26–28 after the surgery and followed by histological assessments. Improvements in skilled reaching and coordinated stepping function were found in the FLU-treated group in comparison with the untreated group after ICH. Additionally, FLU-treated ICH animals showed more normal and precise reaching and stepping movements as compared with ICH control animals. In contrast, FLU did not have a significant impact on gross sensory-motor functions such as the motor deficit score, contact placing response and spontaneous usage of the impaired paw. The volume of tissue lost and the number of spared corticospinal neurons in lesioned motor cortex were not affected by early FLU after ICH. These findings demonstrate the efficacy of early focused use of an impaired limb after internal capsule hemorrhage.

Forced-use of impaired forelimb increases expression of neurotrophic factors in rats motor cortex and induces recovery of skilled reaching and stepping following internal capsule hemorrhage

Forced-use of impaired forelimb increases expression of neurotrophic factors in rats motor cortex and induces recovery of skilled reaching and stepping following internal capsule hemorrhage

Effects of constraint-induced movement therapy on affected forelimb movement in internal capsule hemorrhage rats

Effects of constraint-induced movement therapy on affected forelimb movement in internal capsule hemorrhage rats

Effect of intracranial hypertension on cerebral hemorrhage induced autonomic nerve imbalance*** ○

Background Cerebral hemorrhage can cause the imbalance of nerve function, whereas its mechanism and main impact factors are still not quite clear. Objective To explore the rules about the changes of intracranial pressure in brainstem hemorrhage and internal capsule hemorrhage, and analyze the role of intracranial hypertension in the changes of nerve function caused by cerebral hemorrhage. Design A self-controlled trial. Setting Department of Physiology, Tianjin Medical University. Materials Sixty-five healthy male Japanese white rabbits with long ears (1.5–1.8 kg) were supplied and fed by the Department of Animal Experiment of Tianjin Medical University. The RM6240B biological signal collecting and processing system was used. Methods The experiments were conducted in the Department of Physiology, Tianjin Medical University from August 2001 to May 2006. ▪ The rabbits were anesthetized, then fixed onto the brain stereotaxic apparatus, and afterwards fenestration on skull and intubation to lateral ventricle were performed. The dynamic changes of intracranial pressure were monitored continuously. Rabbits were infused with autologous arterial blood (0.3 mL) into midbrain corpora quadrigemina inferior colliculus to induce model of acute brainstem hemorrhage; models of internal capsule hemorrhage were established by infusing autologous arterial blood into internal capsule. ▪ The dynamic intracranial pressures under the above conditions were recorded continuously with the RM6240B biological signal collecting and processing system. ▪ An animal model of persistent intracranial hypertension was established by infusion of physiologic saline into lateral ventricle. ▪ The changes of the intensity of autonomic nerve discharge were analyzed, using the biological signal collecting and processing system before and after hemorrhage and under persistent intracranial hypertension. ▪ Ten animal models of internal capsule hemorrhage and 10 of brainstem hemorrhage were selected respectively, then gross pathological samples were cut open, and the accuracy of hemorrhage models was affirmed. Histological sections in hemorrhage point and around this point were prepared for with hematoxylin and eosin staining, and the pathological changes were observed under light microscope. Main outcome measures ▪ Changes of intracranial pressures before and after internal capsule hemorrhage and brainstem hemorrhage; ▪ Changes of the discharge intensity of cervical vagus nerve trunk in animal models of internal capsule hemorrhage, brainstem hemorrhage and persistent intracranial hypertension without hemorrhage; ▪ Accuracy of location of internal capsule hemorrhage and brainstem hemorrhage confirmed by gross pathological samples and sections. Results Totally 65 rabbits were involved in the analysis of results. ▪ Dynamic state of intracranial pressure: Intracranial pressure increased obviously at 45 minutes after internal capsule hemorrhage and brainstem hemorrhage, the intracranial pressures were (1.31±0.30), (1.82±0.45) kPa, which were obviously higher than those before hemorrhage [(1.04±0.18), (1.05±0.19) kPa, P < 0.01]. ▪ Discharge of vagus nerve: Under intracranial hypertension, the discharge of cervical vagus nerve trunk was enhanced, and the discharge intensity of vagus nerve trunk was significantly different before and after persistent intracranial hypertension [(364.28±78.55), (1252.19±151.75) μV·s, P < 0.01]. The discharges of cervical vagus nerve trunk were significantly enhanced after internal capsule hemorrhage and brainstem hemorrhage ( P < 0.01). ▪ Validation of hemorrhage sites: The hemorrhage sites were internal capsule and brainstem on histopathological sections. Conclusion Intracranial pressure may play an important role in the pathophysiological process of vagus nerve imbalance caused by cerebral hemorrhage.

Semantic Jargonaphasia: A Taiwanese-Japanese bilingual case

In this paper, we intend to explore the nature of semantic Jargonaphasia in a Taiwanese-Japanese bilingual who was fluent in both languages prior to illness. Even now, aside from his jargon phrases, he is still fluent in both languages. We, therefore, conducted a series of neurolinguistic tests to see if a pattern can be found regarding his use of the two languages and so as to determine the degree of damage with respect to his language functions. Although jargon would come out on occasions when the tests were conducted in Taiwanese, we discovered that his jargon involved code-switching in that the jargon came out in Japanese even though the tests in progress were in Taiwanese. This was particularly true when testing his abilities for naming. He had very little trouble in pointing, however, which means that his comprehension was probably intact in both languages. Paraphasias of this nature were not infrequent when the target language was Taiwanese, which is his native tongue, but became very frequent when the target language was Japanese, which he used to handle very well and can still do so other than his semantic jargon. We are, thus, inclined to believe that the amount of jargon in a bilingual depends very much on which language is the patient's first (or possibly native) language: the second or nonnative language will most likely show up more often as jargon than the first or native language notwithstanding that further evidence is needed for this claim. The patient was admitted to the VA Hospital in Taichung due to internal capsule hemorrhage involving the left putamen. It will be of significance to theorize how this subcortical lesion caused semantic jargon.