Focal brain cooling suppresses spreading depolarization and reduces endothelial nitric oxide synthase expression in rats.

This study aimed to investigate the effects of focal brain cooling (FBC) on spreading depolarization (SD), which is associated with several neurological disorders. Although it has been studied from various aspects, no medication has been developed that can effectively control SD. As FBC can reduce neuronal damage and promote functional recovery in pathological conditions such as epilepsy, cerebral ischemia, and traumatic brain injury, it may also potentially suppress the onset and progression of SD. We created an experimental rat model of SD by administering 1 M potassium chloride (KCl) to the cortical surface. Changes in neuronal and vascular modalities were evaluated using multimodal recording, which simultaneously recorded brain temperature (BrT), wide range electrocorticogram, and two-dimensional cerebral blood flow. The rats were divided into two groups (cooling [CL] and non-cooling [NC]). Warm or cold saline was perfused on the surface of one hemisphere to maintain BrT at 37°C or 15°C in the NC and CL groups, respectively. Western blot analysis was performed to determine the effects of FBC on endothelial nitric oxide synthase (eNOS) expression. In the NC group, KCl administration triggered repetitive SDs (mean frequency = 11.57/h). In the CL group, FBC increased the duration of all KCl-induced events and gradually reduced their frequency. Additionally, eNOS expression decreased in the cooled brain regions compared to the non-cooled contralateral hemisphere. The results obtained by multimodal recording suggest that FBC suppresses SD and decreases eNOS expression. This study may contribute to developing new treatments for SD and related neurological disorders.

Safety of Tailored Transfemoral Carotid Artery Stenting for Symptomatic Elderly Patients: A Single Center Observational Study.

OBJECTIVE: Transfemoral carotid artery stenting (TFCAS) in symptomatic elderly patients (≥70 years old) may have a high periprocedural stroke rate. This study was performed to examine whether tailored TFCAS for symptomatic elderly patients is as safe as that for symptomatic nonelderly patients. METHODS: The subjects were 185 patients with symptomatic internal carotid artery stenosis. Tailored TFCAS including postoperative management was performed based on preoperative examinations of vascular anatomy, plaque imaging, platelet aggregation activity, and cerebral hemodynamic impairment. The major 30-day perioperative stroke rates were examined. RESULTS: The patients included 51 (27.6%) <70 (group Y) and 134 (72.4%) ≥70 (group E) years old. Group E included significantly more cases with an elongated aortic arch, tortuous target lesion, and longer plaques (all P < 0.05). Among all cases, 181 (97.8%) procedures were performed as per preoperative planning. Group E had more frequent use of a proximal embolic protection device and a closed-cell or dual-layer micromesh stent (all P < 0.05). Seven patients (3.8%) had major stroke. Rates of major ischemic stroke (2.0% vs. 3.0%, P = 1.00) and intracranial hemorrhage (2.0% vs. 0.8%, P = 0.48) were low and did not differ significantly between groups Y and E. CONCLUSIONS: Symptomatic elderly patients have several unfavorable factors. However, tailored TFCAS for each patient based on preoperative examinations in symptomatic elderly patients may be as safe as that in symptomatic nonelderly patients.

Progressive arteriopathy with vasospasm in focal cerebral arteriopathy in childhood: a case report.

BACKGROUND: Focal cerebral arteriopathy (FCA) is a clinically important disease that often causes progressive arteriopathy. We report a case of FCA with progressive arteriopathy due to arterial shrinkage of the outer diameter found on T2-weighted three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) imaging. CASE PRESENTATION: The patient was a 9-year-old girl who developed right hemiparesis. Acute infarction was detected in the basal ganglia. Vascular images revealed stenosis from the distal internal carotid artery (ICA) to the middle cerebral artery (MCA). Intravenous heparin was administered for 8 days, and the symptoms improved. However, 29 days after onset, right hemiparesis transiently developed again and magnetic resonance angiography (MRA) showed progressive stenosis from the ICA to MCA, while 3D-SPACE showed similar shrinkage of the outer diameter. Aspirin was started, and there was no subsequent recurrence. After 12 months, MRA and 3D-SPACE showed improvement of stenosis and arterial shrinkage. CONCLUSIONS: Given the time course, the change in the outer diameter was thought to be vasospasm. Thus, vasospasm may be one of the causes of progressive arteriopathy in FCA.

Suppressive effects of a transient receptor potential melastatin 8 (TRPM8) agonist on hyperthermia-induced febrile seizures in infant mice.

Background: Febrile seizures (FSs) are the most frequent type of seizures in infancy and childhood. Epileptiform discharges (EDs) on electroencephalogram at the time of first FS recurrence can increase the risk of epilepsy development. Therefore, inhibition of EDs is important. Recently, WS-3, a transient receptor potential melastatin 8 (TRPM8) agonist, reportedly suppressed penicillin G-induced cortical-focal EDs. However, the effects of TRPM8 agonists on FSs remain unknown. In this study, we aimed to clarify the effects of the TRPM8 agonist, and the absence of TRPM8 channels, on hyperthermia-induced FS by analyzing the fast ripple band. Methods: Hyperthermia (43°C for 30 min) induced by a heating pad caused FSs in postnatal day 7 wild-type (WT) and TRPM8 knockout (TRPM8KO) mice. FSs were defined as EDs occurring during behavioral seizures involving hindlimb clonus and loss of the righting reflex. Mice were injected with 1% dimethyl sulfoxide or 1 mM WS-3 20 min before the onset of hyperthermia, and electroencephalograms; movies; and rectal, brain and heating pad temperatures were recorded. Results: In wild-type mice, WS-3 reduced the fast ripple amplitude in the first FS without changing rectal and brain temperature thresholds. In contrast, the anti-FS effect induced by the TRPM8 agonist was not observed in TRPM8KO mice and, compared with wild-type mice, TRPM8 deficiency lowered the rectal and brain temperature thresholds for FSs, exacerbated the fast ripple amplitude, and prolonged the duration of the initial FS induced by hyperthermia. Conclusion: Our findings suggest that TRPM8 agonists can be used to treat hyperthermia-induced FSs.

Outcome prediction of pediatric moyamoya disease using midterm cerebral blood flow measured between staged anastomoses.

PURPOSE: Cognitive outcomes of pediatric moyamoya disease are variable and difficult to predict on the basis of initial neurological signs and examinations. To determine the best early time point for outcome prediction, we retrospectively analyzed the correlation between cognitive outcomes and the cerebrovascular reserve capacity (CRC) measured before, between, and after staged bilateral anastomoses. METHODS: Twenty-two patients aged 4-15 years were included in this study. CRC was measured before the first hemispheric surgery (preoperative CRC), 1 year after the first surgery (midterm CRC), and 1 year after the surgery on the other side (final CRC). The cognitive outcome was the Pediatric Cerebral Performance Category Scale (PCPCS) grade more than 2 years after the final surgery. RESULTS: The 17 patients with favorable outcomes (PCPCS grades 1 or 2) showed a preoperative CRC of 4.9% ± 11.2%, which was not better than that of the five patients with unfavorable outcomes (grade 3; 0.3% ± 8.5%, p = 0.5). The 17 patients with favorable outcomes showed a midterm CRC of 23.8% ± 15.3%, which was significantly better than that of the five patients with unfavorable outcomes (-2.5% ± 12.1%, p = 0.004). The difference was much more significant for the final CRC, which was 24.8% ± 13.1% in the patients with favorable outcomes and -11.3% ± 6.7% in those with unfavorable outcomes (p = 0.00004). CONCLUSION: Cognitive outcomes were first clearly discriminated by the CRC after the first-side unilateral anastomosis, which is the optimal early timing for the prediction of individual prognosis.

Endoscopically observed outer membrane of chronic subdural hematoma after endovascular embolization of middle meningeal artery.

Background: Embolization of the middle meningeal artery (MMA) has been established for chronic subdural hematoma (CSDH). Neuroendoscopic observation of the outer membrane of the hematoma was carried out after embolization. The treatment mechanism of embolization is discussed, focusing on the vasculature and inflammation of the membrane. Methods: Four patients with recurrent CSDH were included in this study. The MMA was embolized using Embosphere® particles in three patients. The outer membrane was observed with normal and narrow band images (NBIs). Results: The net-like vessels were not obstructed in the whole area of the outer membrane, but in a patchy fashion of embolized areas surrounded by nonembolized areas. In two patients, the nonembolized areas showed a hemorrhagic inflammatory red color. Histopathological examination confirmed hypertrophic dura with leukocyte infiltration. Dilated dural arteries and proliferated sinusoid arteries were located in the deep and superficial border cell layers. These arteries were visualized as green and brown on NBI, respectively. In the embolized area, the red membrane turned pink, indicating ischemia and subsiding inflammatory hyperemia. In the third patient, the outer membrane was white in both the nonembolized and embolized areas in endoscopic view, and the net-like vessels were sparse in both endoscopy and histology, indicating a scar inflammatory phase. The membrane transition was not observed in the patient that did not undergo embolization. Conclusion: Endoscopic observation revealed that embolization of the MMA blocked both the dural and sinusoidal arteries. Ischemic transformation causing the suppression of inflammation of the outer membrane is a suggested mechanism of MMA embolization.

Timing of Direct Oral Anticoagulants for Hemorrhagic Transformation After Endovascular Treatment in Acute Ischemic Stroke.

OBJECTIVES: The purpose of this study is to investigate the relationship between the timing of starting direct oral anticoagulants (DOACs) and subsequent clinical outcomes in patients with hemorrhagic transformation (HT) after endovascular treatment (EVT). MATERIALS AND METHODS: The subjects were patients with acute cardioembolic stroke who underwent EVT and received DOACs in our department from February 2017 to August 2021. Based on CT at 24 h after EVT, the patients were classified using European Collaborative Acute Stroke Study criteria into three groups: no HT, hemorrhagic infarction (HI), and parenchymal hematoma (PH). Outcomes were assessed for incidence of recurrent ischemic stroke (RIS), new intracranial hemorrhage (ICH), and worsened HT associated with DOACs. RESULTS: Of 111 patients, 29 (26.1%) had HT, including 16 (14.4%) with HI and 13 (11.7%) with PH. The start of DOACs was significantly delayed in the PH group (no HT: 1.0 (1.0-3.0) days vs. HI: 3.0 (2.0-5.0) days vs. PH: 7.0 (7.0-10.0) days, P < 0.01). The incidence of RIS did not differ significantly among the three groups, but tended to be higher in the PH group (no HT: 3.7% vs. HI: 6.3% vs. PH: 15.4%, p = 0.12). There were no cases of new symptomatic ICH. New asymptomatic ICH occurred in 2 cases in the no HT group. Worsened HT after initiation of DOACs did not occur in the HI or PH group. CONCLUSIONS: The timing of starting DOACs in patients with HT after EVT may be divided by subtypes of HI and PH. In patients with HI, early initiation of DOACs can prevent RIS and is unlikely to cause new ICH or worsened HI. In PH, initiation of DOACs within 14 days appears to be safe and does not exacerbate PH. The later the start of DOACs, the higher the frequency of RIS, so early initiation of DOACs is desirable.

CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis.

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.

Intracranial pressure spikes trigger spreading depolarizations.

Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply-demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain. Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply-demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence. Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.

Relationship between cerebral hyperperfusion syndrome and the immediate change of cerebral blood flow after carotid artery stenting evaluated by single-photon emission computed tomography.

PURPOSE: Cerebral hyperperfusion syndrome (CHS) is a critical complication after carotid artery stenting (CAS). However, few CAS studies have evaluated immediate and temporary changes in ipsilateral cerebral blood flow (CBF) quantitatively. The study was performed to evaluate immediate changes in CBF after CAS and subsequent CBF changes in patients with cerebral hyperperfusion (HP) using 123I-IMP SPECT. METHODS: The subjects were 223 patients with chronic extracranial carotid artery stenosis who underwent CAS in our department between March 2010 and March 2020. Quantitative CBF and cerebrovascular reactivity to acetazolamide in the middle cerebral artery were assessed before CAS by 123I-IMP SPECT. CBF was also measured immediately after CAS by 123I-IMP SPECT. When HP was detected, CBF was measured again 3 and 7 days after CAS. RESULTS: The median (interquartile range) ipsilateral quantitative CBF change after CAS was - 0.1% (- 9.5-8.2%), and the upper value of the 95% CI of the quantitative CBF change was 48.2%. Thus, we defined HP after CAS as an increase in quantitative CBF of > 48.2% compared with the preoperative value. Of 223 patients, 5 (2.2%) had HP, and 4 of these patients (80%) developed CHS. In the CHS patients, HP was maintained for about 3 days and improved after about 7 days. CONCLUSION: An immediate CBF increase of > 48.2% after CAS may lead to development of CHS. In CHS after CAS, HP persisted for about 1 week and postoperative management may be required for at least 1 week.

Association Between Spreading Depolarization and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Post Hoc Analysis of a Randomized Trial of the Effect of Cilostazol on Delayed Cerebral Ischemia.

BACKGROUND: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) remains an important problem with a complex pathophysiology. We used data from a single-center randomized trial to assess the effect of a phosphodiesterase inhibitor, cilostazol, in patients with aneurysmal SAH to explore the relationships of DCI with vasospasm, spreading depolarization (SD) and microcirculatory disturbance. METHODS: A post hoc analysis of a single-center, prospective, randomized trial of the effect of cilostazol on DCI and SD after aneurysmal SAH was performed. From all randomized cohorts, patients who underwent both SD monitoring and digital subtraction angiography (DSA) on day 9 ± 2 from onset were included. Cerebral circulation time (CCT), which was divided into proximal CCT and peripheral CCT (as a measure of microcirculatory disturbance), was obtained from DSA. Logistic regression was conducted to determine factors associated with DCI. RESULTS: Complete data were available for 28 of 50 patients. Of the 28 patients, 8 (28.5%) had DCI during the study period. Multivariate analysis indicated a strong association between the number of SDs on the day DSA was performed (i.e., a delayed time point after SAH onset) and DCI (odds ratio 2.064, 95% confidence interval 1.045-4.075, P = 0.037, area under the curve 0.836), whereas the degree of angiographic vasospasm and peripheral CCT were not significant factors for DCI. CONCLUSIONS: There is a strong association between SD and DCI. Our results suggest that SD is an important therapeutic target and a potentially useful biomarker for DCI.

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations.

BACKGROUND AND PURPOSE: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. METHODS: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. RESULTS: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P=0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. CONCLUSIONS: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.

Cerebral hemodynamics associated with fluid-attenuated inversion recovery hyperintense vessels in patients with extracranial carotid artery stenosis.

PURPOSE: Fluid-attenuated inversion recovery hyperintense vessels (FHVs) are linked to sluggish or disordered blood flow. The purpose of this study is to compare FHVs with digital subtraction angiography (DSA) findings and cerebral hemodynamic changes on acetazolamide challenge SPECT and to determine the clinical and imaging metrics associated with FHVs in patients with extracranial carotid artery stenosis (ECAS). METHODS: The subjects were patients with chronic ECAS who underwent carotid artery stenting in our department between March 2011 and October 2018. Relationships of FHVs with age, sex, medical history, cerebral angiographic findings using DSA, and quantitative values of cerebral blood flow (CBF) were examined. The resting CBF (rCBF) and cerebrovascular reactivity (CVR) in the middle cerebral artery territory were measured quantitatively using SPECT with acetazolamide challenge. We used multivariate logistic regression analysis to identify independent predictors of FHVs. RESULTS: Of 173 patients included, 92 (53.2%) had FHVs. Patients with FHVs had more severe stenosis (P < 0.01) and more leptomeningeal collateral vessels (P < 0.01). FHV-positive cases had significantly reduced CVR compared with FHV-negative cases (P < 0.01), although there was no significant difference in rCBF between FHV-positive and FHV-negative cases. Logistic regression analysis showed that ipsilateral rCBF and ipsilateral CVR were significant predictors for FHVs (P < 0.01). CONCLUSION: In patients with ECAS, cerebral hemodynamic metrics, especially ipsilateral rCBF and ipsilateral CVR, are associated with the presence of FHVs.

Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need.

BACKGROUND: Delayed cerebral ischemia (DCI) is among the most dreaded complications following aneurysmal subarachnoid hemorrhage (SAH). Despite advances in neurocritical care, DCI remains a significant cause of morbidity and mortality, prolonged intensive care unit and hospital stay, and high healthcare costs. Large artery vasospasm has classically been thought to lead to DCI. However, recent failure of clinical trials targeting vasospasm to improve outcomes has underscored the disconnect between large artery vasospasm and DCI. Therefore, interest has shifted onto other potential mechanisms such as microvascular dysfunction and spreading depolarizations. Animal models can be instrumental in dissecting pathophysiology, but clinical relevance can be difficult to establish. METHODS: Here, we performed a systematic review of the literature on animal models of SAH, focusing specifically on DCI and neurological deficits. RESULTS: We find that dog, rabbit and rodent models do not consistently lead to DCI, although some degree of delayed vascular dysfunction is common. Primate models reliably recapitulate delayed neurological deficits and ischemic brain injury; however, ethical issues and cost limit their translational utility. CONCLUSIONS: To facilitate translation, clinically relevant animal models that reproduce the pathophysiology and cardinal features of DCI after SAH are urgently needed.

Hounsfield Unit Value of Interpeduncular Cistern Hematomas Can Predict Symptomatic Vasospasm.

Background and Purpose- Symptomatic vasospasm is an important factor that affects the outcomes of aneurysmal subarachnoid hemorrhage. Subarachnoid blood volume can predict symptomatic vasospasm, and we postulated that the blood clot density would also be an important factor involved in such events. The present study aimed to determine the relationship between the incidence of symptomatic vasospasm and the Hounsfield unit (HU) value of the interpeduncular cistern that reflects the density of hematomas. Methods- Data from 323 patients admitted and treated at a single center between 2008 and 2017 within 24 hours of subarachnoid hemorrhage onset were retrospectively analyzed. Initial HU values of the interpeduncular cistern were measured using CT, then correlations with the incidence of symptomatic vasospasm and HU values as well as other variables were assessed. Results- Symptomatic vasospasm developed in 54 (16.7%) of the 323 patients. The incidence of symptomatic vasospasm was low (1.8%, 2/166) for HU <50, but this incidence increased greatly when the HU value exceeded 50 (23.7%, 22/93 for HU >50 to ≤60, and 45.3%, 29/64 for HU >60). The odds ratio for symptomatic vasospasm was 2.0 (95% CI, 1.6-2.4) per 5 HU increase. Symptomatic vasospasm correlated significantly with intraventricular hemorrhage (P=0.05) and with intracerebral hematoma (P=0.046) but even more significantly with the HU value of the interpeduncular cistern (P<0.0001). Conclusions- The HU value of the interpeduncular cistern on initial CT is an accurate and reliable predictor of symptomatic vasospasm.

Revascularization of Remaining Branch of Aorta in Advanced Takayasu Arteritis Protects Against Wide Range of Perfusion.

BACKGROUND: Stroke is a major factor of morbidity in the patients with Takayasu arteritis (TA). Restenosis is more common with endovascular intervention than after bypass surgery, but vascular anastomosis is difficult due to calcification involving the whole thickness of the arterial wall in the burned-out stage of TA. We report a case of advanced TA in which endovascular treatment of the left subclavian artery improved cerebral blood flow (CBF) over a wide range of perfusion in the posterior and anterior circulation. CASE DESCRIPTION: During medical treatment for TA, a 57-year-old male patient gradually developed ischemic symptoms of both upper limbs and dizziness. Angiography showed occlusion of the brachiocephalic artery and severe stenosis of the left common carotid artery and left subclavian artery. Preoperative single-photon emission computed tomography revealed reductions in the resting CBF and vascular reactivity in the area of the carotid artery and vertebral basilar artery. Chest computed tomography showed calcification of the aortic arch and its branches, and this advanced diffuse calcification indicated probable difficulties in bypass surgery. Therefore we performed percutaneous transluminal angioplasty and stenting for the left subclavian artery. Postoperative single-photon emission computed tomography showed increases in resting CBF in the area of the bilateral internal carotid artery, as well as the vertebrobasilar artery. The patient's various ischemic symptoms improved significantly. CONCLUSIONS: As collateral circulation is common in advanced TA, the ischemic area is large when the remaining proximal large vessels are occluded. Therefore revascularization of the remaining branch of the aorta in advanced TA may protect against a wide range of perfusion.

Implantable Multi-Modality Probe for Subdural Simultaneous Measurement of Electrophysiology, Hemodynamics, and Temperature Distribution.

OBJECTIVE: The purpose of this paper is to demonstrate how the integration of the multi-channel measurement capabilities of near-infrared spectroscopy (NIRS), electrocorticography (ECoG), and negative temperature coefficient thermistor sensors into a single device compact enough for subdural implantation can provide beneficial information on various aspects of brain cortical activity and prove a powerful medical modality for pre-, intra-, and post-operative diagnoses in neurosurgery. METHODS: The development of a flexible multi-modal multi-channel probe for the simultaneous measurement of the NIRS, ECoG, and surficial temperature obtained from the cerebral cortex was carried out. Photoelectric bare chips for NIRS channels, miniature temperature-coefficient thermistors for measuring localized temperature variation, and 3-mm-diameter platinum plates for ECoG recording were assembled on a polyimide-based flexible printed circuit to create six channels for each modality. A conformal coating of Parylene-C was applied on all the channels except the ECoG to make the probe surface biocompatible. RESULTS: As a first-in-human study, the simultaneous measurement capability of the multi-modality probe, with sufficient signal-to-noise ratio and accuracy, to observe pathological neural activities in subjects during surgery and post-operative monitoring, with no complications two weeks since the implantation, was confirmed. CONCLUSION: The feasibility of using a single device to assess the dynamic pathological activity from three different aspects was determined for human patients. SIGNIFICANCE: The simultaneous and accurate multi-channel recording of electrical, hemodynamic, and thermographic cortical activities in a single device small enough for subdural implantation is likely to have major implications in neurosurgery and neuroscience.

Impact of Frailty on Medium-Term Outcome in Asymptomatic Patients After Carotid Artery Stenting.

OBJECTIVE: There are few reports on the relationship between carotid artery stenting (CAS) and frailty. In this study, medium-term outcome after CAS in patients with asymptomatic carotid artery stenosis was examined to see the effect of frailty itself. METHODS: A retrospective study was performed in 71 consecutive patients who were treated with CAS for asymptomatic lesions from January 2007 to June 2014. In this study, only patients without neurologic symptoms before treatment were included. Frailty was defined on the basis of the presence of ≥2 of the 5 items on the Cardiovascular Health Study (CHS) Index. The relationship of frailty with a composite endpoint of the incidence of stroke, disease requiring hospital admission, and death for 3 years after CAS was examined. RESULTS: There were 23 cases (average age 73.9 years, median CHS index 3) with frailty and 48 (average age 70.9 years, median CHS index 0) without frailty. There were no differences in comorbidities or CAS perioperative complications between these groups. However, there was a significantly higher incidence of the composite endpoint in patients with frailty (13/23 vs. 4/48, P < 0.001), and in multivariate analysis, frailty was strongly associated with this endpoint (odds ratio 28.24, 95% confidence interval 4.62-172.71). CONCLUSIONS: In CAS conducted for asymptomatic lesions, perioperative complications had no relationship with frailty. However, frailty is likely to be associated with lower activity of daily life in the medium term after CAS, and consideration of underlying diseases is required in patients with frailty.

Determinants of Optogenetic Cortical Spreading Depolarizations.

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.