Capsular Infarct Research Articles

Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarct

Cortical neuromodulation (CNM) is widely used to promote recovery after stroke. Despite the beneficial results of CNM, the roles played by different neuron types in the effects of current CNM techniques are unable to be differentiated. Our aim was to use selective optogenetic cortical stimulation to explore how different subpopulations of neuronal cells contribute to poststroke recovery. We transduced the sensory-parietal cortex (SPC) of rats with CamKII-ChR2 (pyramidal neurons), PV-ChR2 (parvalbumin-expressing inhibitory neurons), or hSyn-ChR2 (pan-neuronal population) before inducing photothrombotic capsular infarct lesions. We found that selective stimulation of inhibitory neurons resulted in significantly greater motor recovery than stimulation of excitatory neurons or the pan-neuronal population. Furthermore, 2-deoxy-2-[18F] fluoro-D-glucose microPET (FDG-microPET) imaging revealed a significant reduction in cortical diaschisis and activation of the corticostriatal neural circuit, which were correlated with behavioral recovery in the PV-ChR2 group. The spatial pattern of brain-derived neurotrophic factor (BDNF) expression was evident in the stimulated cortex and underlying cortico-subcortical circuit. Our results indicate that the plasticity of inhibitory neurons is crucial for functional recovery after capsular infarct. Modifying CNM parameters to potentiate the stimulation of inhibitory neurons could improve poststroke outcomes.

Abulia without Motor Weakness - A Rare Presentation of a Lacunar Unilateral Internal Capsular Infarct

Introduction: Typical lacunar strokes arising from lesions of the internal capsule result in pure motor dense hemiplegia, ataxic hemiparesis, clumsy hand-dysarthria syndrome, and capsular warning syndrome. Abulia usually occurs secondary to lesions of the frontal lobe, basal ganglia, or anterior cingulate cortex (Brodmann area 24). Internal capsular infarcts have been only rarely been reported in a few case reports to result in abulia in the absence of any motor deficit. Methods: We report the case of a 40-year-old male presenting with an abrupt onset abulic state without any motor deficit resulting from a right internal capsular infarct. Results: A 40-year-old male patient presented with an abrupt onset abulic state on awakening from an overnight sleep. No motor deficit or corticospinal tract signs were observed. Magnetic resonance imaging brain revealed an acute right internal capsular infarct which was responsible for the acute-onset abulia. The patient had a significant improvement with resolution of the abulia within 2 weeks. Conclusion: Neurologists, psychiatrists, and internists should be aware of this clinical presentation of an abulic or akinetic mute state without any motor deficit which could be easily passed off as a metabolic or toxic encephalopathy or as a psychiatric illness, and a high index of clinical suspicion and appropriate imaging are required to define the appropriate etiology.

Spatial patterns of intrinsic brain activity in rats with capsular stroke.

To explore the neural changes of brain activity in rats with circumscribed capsular infarcts to find a new therapeutic target for promoting the functional recovery. A total of 18 capsular infarct rats and 18 normal rats were conducted in this study. All animal use procedures were strictly in accordance with the guide for the care and use of laboratory animals. After establishing the photothrombotic capsular infarct model, the functional magnetic resonance imaging (fMRI) data were collected and analyzed. The fMRI results indicated that the passive movement would induce strong activation in caudate, putamen, frontal association somatosensory cortex, thalamus dorsolateral, and thalamus midline dorsal in control group, and the passive movement would only induce limited activation mostly in somatosensory cortex, thalamus dorsolateral, and thalamus midline dorsal in capsular infarct models. Capsular infarct makes the cortical activity weaken in sensory-related cortex and subcortical nuclei, including capsular area and thalamus. Such findings imply that the posterior limb of internal capsule (PLIC) is connected to these structures in function, interacts together with them, and, accordingly, the lesion of PLIC manifests the related symptoms.

Clinical safety and possible efficacy of tirofiban in combination with intravenous thrombolysis by recombinant tissue plasminogen activator for early treatment of capsular warning syndrome (CWS).

The purpose of this study was to assess the efficacy and safety of the combination of tirofiban with intravenous thrombolysis (IVT) in treating patients with capsular warning syndrome (CWS) who failed to respond to the treatment of intravenous thrombolysis alone. Tirofiban was approved for the treatment of CWS patients with fluctuating symptoms or no substantial improvement after intravenous thrombolysis within 24 h in our hospital from October 2019 to June 2021. Patients were evaluated with the National Institutes of Health Stroke Scale (NIHSS) at admission, at 72 h post-thrombolysis, at 1-week, and at 3-months with the modified Rankin Scales (MRS) score. A total of 12 patients received tirofiban and eight patients received control treatment with a history of CWS in our cohort. Among the patients, 13 patients smoked more than one pack of cigarettes a day, 17 had hypertension, 17 had hypercholesterolemia, 7 had diabetes, 1 had the history of cerebral infarction, 2 had atrial fibrillation, 7 had mild big vascular stenosis, 13 had lesions of the perforating branch by imaging, and 19 had acute capsular infarction. In both the tirofiban and control groups, NIHSS scores were significantly reduced after intravenous thrombolysis or 1-week after onset compared with before intravenous thrombolysis (P < 0.001). Before and after intravenous thrombolysis, there were no differences between the tirofiban group and control group (P = 0.970, P = 0.384, respectively). The tirofiban group, however, showed remarkably lower scores in both 1-week NIHSS and 3-month MRS than the control (P = 0.012, P = 0.003, respectively). Our study revealed that tirofiban did not increase the risk of hemorrhage and had favorable clinical efficacy as a remedial treatment for CWS patients with poor prognosis for intravenous thrombolysis, therefore indicating great potential for broader use.

Structural plasticity of motor cortices assessed by voxel-based morphometry and immunohistochemical analysis following internal capsular infarcts in macaque monkeys.

Compensatory plastic changes in the remaining intact brain regions are supposedly involved in functional recovery following stroke. Previously, a compensatory increase in cortical activation occurred in the ventral premotor cortex (PMv), which contributed to the recovery of dexterous hand movement in a macaque model of unilateral internal capsular infarcts. Herein, we investigated the structural plastic changes underlying functional changes together with voxel-based morphometry (VBM) analysis of magnetic resonance imaging data and immunohistochemical analysis using SMI-32 antibody in a macaque model. Unilateral internal capsular infarcts were pharmacologically induced in 5 macaques, and another 5 macaques were used as intact controls for immunohistochemical analysis. Three months post infarcts, we observed significant increases in the gray matter volume (GMV) and the dendritic arborization of layer V pyramidal neurons in the contralesional rostral PMv (F5) as well as the primary motor cortex (M1). The histological analysis revealed shrinkage of neuronal soma and dendrites in the ipsilesional M1 and several premotor cortices, despite not always detecting GMV reduction by VBM analysis. In conclusion, compensatory structural changes occur in the contralesional F5 and M1 during motor recovery following internal capsular infarcts, and the dendritic growth of pyramidal neurons is partially correlated with GMV increase.

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Long-term disabilities induced by stroke impose a heavy burden on patients, families, caregivers, and public health systems. Extensive studies have demonstrated the therapeutic value of neuromodulation in enhancing post-stroke recovery. Among them, chemogenetic neuromodulation activated by clozapine-N-oxide (CNO) has been proposed as the potential tool of neuromodulation. However, recent evidence showed that CNO does not cross the blood − brain barrier and may in fact have low binding affinity for chemogenetic tool. Thus, clozapine (CLZ) has been suggested for use in chemogenetic neuromodulation, in place of CNO, because it readily crosses the blood–brain barrier. Previously we reported that low doses of CLZ (0.1 mg/kg) successfully induced neural responses without off-target effects. Here, we show that low-dose clozapine (0.1 mg/kg) can induce prolonged chemogenetic activation while avoiding permeability issues and minimizing off-target effects. In addition, clozapine-induced excitatory chemogenetic neuromodulation (CLZ-ChemoNM) of sensory-parietal cortex with hsyn-hM3Dq-YFP-enhanced motor recovery in a chronic capsular infarct model of stroke in rats, improving post-stroke behavioral scores to 56% of pre-infarct levels. Longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET (FDG-microPET) scans showed that a reduction in diaschisis volume and activation of corticostriatal circuits were both correlated with post-stroke recovery. We also found c-Fos increases in bilateral cortices and BDNF increases in the cortices and striatum after CLZ-ChemoNM, indicating an increase in neural plasticity. These findings suggest the translational feasibility of CLZ-ChemoNM for augmenting recovery in chronic stroke.

Post-operative Corona Radiata Infarct in a High-flow EC-IC Bypass: Report of Unusual Complication

AbstractLong insular artery (LIA) infarct can occur after insular glioma surgery. LIA infarct after extracranial-intracranial (EC-IC) bypass is very rare, and so far, it is not reported in EC-IC bypass. Here, we report a case of high-flow EC-IC bypass, where postoperatively, the patient developed isolated LIA infarct. A 65-year-old female presented with recurrent severe headache along with altered sensorium. Computed tomography (CT) scan and CT angiography (CTA) of the brain showed ruptured large left internal carotid artery (ICA) fusiform aneurysm. She underwent left-sided, high-flow EC-IC bypass involving upper trunk of left middle cerebral artery (MCA) and ICA ligation at neck at its origin. Postoperatively, the patient developed right sided hemiplegia. Postoperative MRI of the brain showed left-sided external capsular infarct, extending up to the corona radiata resulted from LIA infarct. By the end of 6 months after operation, she could walk with support but her left upper limb remained more severely affected and magnetic resonance angiogram (MRA) showed almost disappearance of aneurysm with functioning bypass.

Precision Capsular Infarct Modeling to Produce Hand Motor Deficits in Cynomolgus Macaques.

Stroke research in non-human primates (NHPs) with gyrencephalic brains is a critical step in overcoming the translational barrier that limits the development of new pharmaceutical and rehabilitative strategies for stroke. White-matter stroke (WMS) has a unique pathophysiology from gray-matter stroke and is not well understood because of a lack of pertinent animal models. To create a precise capsular infarct model in the cynomolgus macaque, we first used electrical stimulation to map hand movements, followed by viral tracing of the hand motor fibers (hMFs). This enabled us to identify stereotactic targets in the posterior limb of the internal capsule (PLIC). Neural tracing showed that hMFs occupy the full width of the PLIC, owing to overlap with the motor fibers for the leg. Furthermore, the hMFs were distributed in an oblique shape, requiring coronal tilting of the target probe. We used the photothrombotic infarct lesioning technique to precisely destroy the hMFs within the internal capsule. Double-point infarct lesioning that fully compromised the hMFs resulted in persistent hand motor and walking deficits whereas single-point lesioning did not. Minor deviations in targeting failed to produce persistent motor deficits. Accurate stereotactic targeting with thorough involvement of motor fibers is critical for the production of a capsular infarct model with persistent motor deficits. In conclusion, the precision capsular infarct model can be translated to the NHP system to show persistent motor deficits and may be useful to investigate the mechanism of post-stroke recovery as well as to develop new therapeutic strategies for the WMS.

Early Detection of the Internal Capsule Infarction by Intraoperative Neuromonitoring in Mesial Temporal Epilepsy Surgery

Intraoperative neurophysiological monitoring (INM) is underutilized during the anteromesial temporal resection (AMTR) in epilepsy surgery. Herein we report a case with intraoperative capsular infarction which was early detected by INM. Among the modalities of INM, left motor evoked potentials (MEP) showed suddenly decreased amplitude of compound muscle action potentials, after the electrocoagulation in left mesial temporal areas. Postoperative neurologic and MRI findings were well correlated to the intraoperative MEP features. We also discuss the usefulness of INM during the AMTR.

Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.

Ultrastructural Dendritic Changes Underlying Diaschisis After Capsular Infarct

Diaschisis has been described as functional depression distant to the lesion. A variety of neuroscientific approaches have been used to investigate the mechanisms underlying diaschisis. However, few studies have examined the pathological changes in diaschisis at ultrastructural level. Here, we used a rat model of capsular infarct that consistently produces diaschisis in ipsilesional and contralesional motor and sensory cortices. To verify the occurrence of diaschisis and monitor time-dependent changes in diaschisis, we performed longitudinal 2-deoxy-2-[18F]-fluoro-d-glucose microPET (FDG-microPET) study. We also used light and electron microscopy to identify the microscopic and ultrastructural changes at the diaschisis site at 7, 14, and 21 days after capsular infarct modeling (CIM). FDG-microPET showed the occurrence of diaschisis after CIM. Light microscopic examinations revealed no significant histopathological changes at the diaschisis site except a mild degree of reactive astrogliosis. However, electron microscopy revealed swollen, hydropic degeneration of axial dendrites and axodendritic synapses, although the neuronal soma (including nuclear chromatin and cytoplasmic organelles) and myelinated axons were relatively well preserved up to 21 days after injury. Furthermore, number of axodendritic synapses was significantly decreased after CIM. These data indicate that a circumscribed subcortical white-matter lesion produces ultrastructural pathological changes related to the pathogenesis of diaschisis.

Lenticulostriate Artery Aneurysm: 2-Dimensional Operative Video.

Saccular aneurysms that arise from the origin of or along a lenticulostriate artery are rarely observed. In general, occlusion of the lenticulostriate artery is discouraged because of the risk of a capsular infarction. This patient was a woman with moyamoya disease who demonstrated a fusiform aneurysm of a lenticulostriate artery. Image guidance was critical to correctly identify the location of the aneurysm. The lenticulostriate artery was occluded by a surgical clip to obliterate the aneurysm and consequently the flow through the artery. However, the patient tolerated the procedure well and did not experience an ischemic stroke from the vessel occlusion. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

Clozapine-induced chemogenetic activation augment the post-stroke recovery in capsular infarct model

Clozapine-induced chemogenetic activation augment the post-stroke recovery in capsular infarct model

Comparative study of ipsilesional and contralesional repetitive transcranial magnetic stimulations for acute infarction

Background and purposeRepetitive transcranial magnetic stimulation (rTMS) is reported to improve chronic post-stoke hemiparesis. However, application of rTMS during the acute phase of post-stroke has not fully been investigated. We investigated the safety and the efficacy of intermittent theta-burst stimulation (iTBS) of the affected motor cortex and 1-Hz stimulation of the unaffected hemisphere during the acute phase in patients with hemiparesis due to capsular infarction. MethodsTwenty one patients who met the study criteria were randomly assigned to receive, starting within 7days after stroke onset and for a period of 10days, iTBS of the affected motor cortex hand area (n=8), 1-Hz stimulation of the unaffected motor cortex hand area (n=7), or sham stimulation (n=6). Upper limb motor function was evaluated before rTMS and 12weeks after onset of the stroke. Evaluation was based on the Fugl-Meyer Assessment (FMA), Stroke Impairment Assessment Set (SIAS), Modified Ashworth Scale (MAS), grip strength, and motor evoked potential (MEP) amplitude in the first dorsal interosseous (FDI) muscle. ResultsBoth iTBS applied to the affected motor cortex hand area and 1-Hz stimulation applied to the unaffected motor cortex hand area enhanced motor recovery. In comparison to sham stimulation, iTBS increased the SIAS finger-function test score, and 1-Hz stimulation decreased the MAS wrist and finger score. ConclusionsIpsilesional iTBS and contralesional 1-Hz stimulation applied during the acute phase of stroke have different effects: ipsilesional iTBS improves movement of the affected limb, whereas contralesional 1-Hz stimulation reduces spasticity of the affected limb.

Sensory-parietal cortical stimulation improves motor recovery in severe capsular infarct

The prevalence of subcortical white matter strokes in elderly patients is on the rise, but these patients show mixed responses to conventional rehabilitative interventions. To examine whether cortical electrical stimulation can promote motor recovery after white matter stroke, we delivered stimulation to a small or wide region of sensory-parietal cortex for two weeks in a rodent model of circumscribed subcortical capsular infarct. The sham-operated group (SOG) showed persistent and severe motor impairments together with decreased activation in bilateral sensorimotor cortices and striatum. In contrast, sensory-parietal cortex stimulation significantly improved motor recovery: final recovery levels were 72.9% of prelesion levels in the wide stimulation group (WSG) and 37% of prelesion levels in the small stimulation group (SSG). The microPET imaging showed reversal of cortical diaschisis in both groups: in both hemispheres for the WSG, and in the hemisphere ipsilateral to stimulation in the SSG. In addition, we observed activation of the corpus callosum and subcortical corticostriatal structures after stimulation. The results from the c-Fos mapping study were grossly consistent with the microPET imaging. Sensory-parietal cortex stimulation may therefore be a useful strategy for overcoming the limits of rehabilitative training in patients with severe forms of subcortical capsular infarct.

Circumscribed Capsular Infarct Modeling Using a Photothrombotic Technique

Recent increase in the prevalence rate of white matter stroke demands specific research in the field. However, the lack of a pertinent animal model for white matter stroke has hampered research investigations. Here, we describe a novel method for creating a circumscribed capsular infarct that minimizes damage to neighboring gray matter structures. We used pre-surgery neural tracing with adeno-associated virus-green fluorescent protein (AAV-GFP) to identify somatotopic organization of the forelimb area within the internal capsule. The adjustment of light intensity based on different optical properties of gray and white matter contributes to selective destruction of white matter with relative preservation of gray matter. Accurate positioning of optical-neural interface enables destruction of entire forelimb area in the internal capsule, which leads to a marked and persistent motor deficit. Thus, this technique produces highly replicable capsular infarct lesions with a persistent motor deficit. The model will be helpful not only to study white matter stroke (WMS) at the behavioral, circuit, and cellular levels, but also to assess its usefulness for development of new therapeutic and rehabilitative interventions.

Circumscribed Capsular Infarct Modeling Using a Photothrombotic Technique.

Recent increase in the prevalence rate of white matter stroke demands specific research in the field. However, the lack of a pertinent animal model for white matter stroke has hampered research investigations. Here, we describe a novel method for creating a circumscribed capsular infarct that minimizes damage to neighboring gray matter structures. We used pre-surgery neural tracing with adeno-associated virus-green fluorescent protein (AAV-GFP) to identify somatotopic organization of the forelimb area within the internal capsule. The adjustment of light intensity based on different optical properties of gray and white matter contributes to selective destruction of white matter with relative preservation of gray matter. Accurate positioning of optical-neural interface enables destruction of entire forelimb area in the internal capsule, which leads to a marked and persistent motor deficit. Thus, this technique produces highly replicable capsular infarct lesions with a persistent motor deficit. The model will be helpful not only to study white matter stroke (WMS) at the behavioral, circuit, and cellular levels, but also to assess its usefulness for development of new therapeutic and rehabilitative interventions.

Development and Characterization of a Macaque Model of Focal Internal Capsular Infarcts

Several studies have used macaque monkeys with lesions induced in the primary motor cortex (M1) to investigate the recovery of motor function after brain damage. However, in human stroke patients, the severity and outcome of motor impairments depend on the degree of damage to the white matter, especially that in the posterior internal capsule, which carries corticospinal tracts. To bridge the gap between results obtained in M1-lesioned macaques and the development of clinical intervention strategies, we established a method of inducing focal infarcts at the posterior internal capsule of macaque monkeys by injecting endothelin-1 (ET-1), a vasoconstrictor peptide. The infarcts expanded between 3 days and 1 week after ET-1 injection. The infarct volume in each macaque was negatively correlated with precision grip performance 3 days and 1 week after injection, suggesting that the degree of infarct expansion may have been a cause of the impairment in hand movements during the early stage. Although the infarct volume decreased and gross movement improved, impairment of dexterous hand movements remained until the end of the behavioral and imaging experiments at 3 months after ET-1 injection. A decrease in the abundance of large neurons in M1, from which the descending motor tracts originate, was associated with this later-stage impairment. The present model is useful not only for studying neurological changes underlying deficits and recovery but also for testing therapeutic interventions after white matter infarcts in primates.

Abstract 100: Right Insular Infarction is an Independent Predictor of Mortality in Ischemic Stroke

Introduction: The association between insular infarction and mortality has often been described. However, whether this is simply due to higher lesion volumes is still controversial. Hypothesis: We hypothesized that there is an association between insular infarction and mortality independent of lesion volume. Methods: We included consecutive stroke patients between 01.09.2008 and 11.11.2012 from the 1000Plus data base with an acute ischemic lesion on diffusion-weighted imaging on day one and a completed 90 days follow-up. Insular location of the infarction was determined using the Stroke Lesion Atlas (SLA). The SLA is an in-house developed spatial database for analyses of imaging studies (Figure). In multivariate regression analyses of mortality and insular infarcts we adjusted for age, lesion volume, atrial fibrillation, NIHSS, capsular infarcts, and left hemispheric infarcts. Results: We included 718 patients. Out of 165 patients with insular infarcts 20 patients died; among the 553 patients with lesions outside the Insula 16 patients died (mortality 12% vs. 3%; p&lt;.001). In analyses adjusting for all mentioned confounders insular infarction was not an independent predictor of mortality. After exclusion of NIHSS insular infarcts were independently associated with mortality (OR=3.003, CI 1.41 - 6.38, p=.004). Right insular infarction was an independent mortality predictor adjusted for all confounders including the NIHSS (OR=2.793, CI 1.27 - 6.15, p=.011). Conclusion: Right insular involvement is an independent predictor of mortality in ischemic stroke and may be used to improve identification of patients at risk. Figure. Lesion overlap of patients who survived (A) or died (B). Red indicates voxels involved in at least 15% of patients. Deceased patients show a maximum lesion overlap in the right Insula.

Internal Capsular Infarction Presented as Monoataxia

Internal Capsular Infarction Presented as Monoataxia