An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice

Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12−/− and PANX1−/− mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

Vagus Nerve Stimulation Amplifies Task-Induced Cerebral Blood Flow Increase

BackgroundVagus nerve stimulation (VNS) is an established palliative surgical treatment for refractory epilepsy. Recently, pairing VNS with rehabilitation received growing attention for their joint effect on neural plasticity. However, objective biological measurements proving the interaction between VNS effects and cortical recruitment are lacking. Studies reported that VNS induced little blood flow increase in the cerebral cortex.ObjectiveThis study tested the hypothesis that pairing VNS with a cognitive task amplifies task-induced cerebral blood flow (CBF).MethodsThis study included 21 patients implanted with vagus nerve stimulator to treat refractory epilepsy. Near-infrared spectroscopy (NIRS) with sensors on the forehead measured CBF changes in the frontal cortices in response to VNS. Cerebral blood flow was measured when VNS was delivered during a resting state or a verbal fluency task. We analyzed the VNS effect on CBF in relation to stimulation intensity and clinical responsiveness.ResultsWe observed no CBF change when VNS was delivered during rest, irrespective of stimulation intensity or responsiveness. Cerebral blood flow changed significantly when a verbal fluency task was paired with VNS in a stimulation intensity-dependent manner. Cerebral blood flow changes in the non-responders showed no intensity-dependency.ConclusionOur results could be an important biological proof of the interaction between VNS effects and cortical recruitment, supporting the validity of pairing VNS with rehabilitation.

Cerebral hyperperfusion syndrome after intracranial stenting: Case report and systematic review

Background Cerebral Hyperperfusion Syndrome (CHS) is an uncommon complication observed after intracranial angioplasty or stenting procedures. Given to the increasing use of new devices for intracranial angioplasty and stenting (INCS), in selected patients with high ischemic stroke risk, an equally increasing knowledge of complications related to these procedures is mandatory. Case description: a 63-year-old man was diagnosed with an hyperperfusion syndrome after percutaneous angioplasty and stenting for severe symptomatic right internal carotid artery (ICA) siphon stenosis. After treatment he complained generalized seizures and respiratory failure. While conventional imaging did not demonstrate any acute brain lesions, Pseudo-Continuous Arterial Spin Labeling (PCASL) Perfusion MRI early documented right hemisphere blood flow increase suggestive for CHS. Conclusions Monitoring of perfusion changes after INCS could play an important a role in determining patients with high risk of CHS. ASL Perfusion MRI might be used for promptly, early diagnosis of CHS after treatment of severe intracranial artery stenosis.

Ablation of Vitamin D Signaling Compromises Cerebrovascular Adaptation to Carotid Artery Occlusion in Mice

Vitamin D insufficiency has been associated with increased incidence and severity of cerebrovascular disorders. We analyzed the impact of impaired vitamin D signaling on the anatomical and functional aspects of cerebrovascular adaptation to unilateral carotid artery occlusion (CAO), a common consequence of atherosclerosis and cause of ischemic stroke. Cerebrocortical blood flow (CoBF) showed a significantly increased drop and delayed recovery after CAO in mice carrying a functionally inactive vitamin D receptor (VDR) with the most sustained perfusion deficit in the temporal cortex. To identify the cause(s) for this altered adaptation, the extent of compensatory blood flow increase in the contralateral carotid artery and the morphology of pial collaterals between the anterior and middle cerebral arteries were determined. Whereas VDR deficiency had no significant influence on the contralateral carotid arterial blood flow increase, it was associated with decreased number and increased tortuosity of pial anastomoses resulting in unfavorable changes of the intracranial collateral circulation. These results indicate that VDR deficiency compromises the cerebrovascular adaptation to CAO with the most sustained consequences in the temporal cortex. The dysregulation can be attributed to the altered development and function of pial collateral circulation whereas extracranial vessels may not be impaired.

Abstract WP59: Cerebral Blood Flow Increase After Endovascular Thrombectomy on Perfusion Weighted Image is Associated With Hemorrhagic Transformation

Introduction: The role of increased CBF after endovascular thrombectomy in post-ischemic hyperperfusion has not been studied in detail. We aimed to investigate the timing of CBF increases on PWI after thrombectomy in association with hemorrhagic transformation. Methods: We analyzed prospectively collected data in consecutive patients treated with endovascular thrombectomy. Inclusion criteria were: (1) patients with ICA or M1 occlusion, and (2) PWI and GRE obtained within 12 hours and 12-48 hours after thrombectomy. We compared each rCBF with early hemorrhage (within 12 hours after thrombectomy), late hemorrhage (12-48 hour) and non-hemorrhage in basal ganglia (BG) and MCA cortical or subcortical (CS) region. In each PWI dataset, ROIs were placed in two slice levels of the BG and three slice levels of the CS region. Results: Fifty-three patients met inclusion criteria. Early BG hemorrhages were noted in 13 patients, with 4 late BG hemorrhage, 8 early CS hemorrhage and 3 late CS hemorrhage. There were no significant differences on rCBF in PWI within 12 hours after thrombectomy between early hemorrhage, late hemorrhage and non-hemorrhage groups. In contrast, rCBF on 12-48 hours PWI in the BG region was significantly higher in the early BG hemorrhage than non-BG hemorrhage (lower BG slice 1.36 vs 1.01, p<0.001, upper BG slice 1.33 vs 0.96, p<0.001) and rCBF in CS region were significantly higher in early CS hemorrhage than non-CS hemorrhage (lower CS slice 1.55 vs 0.98, p=0.001, middle CS slice 1.31 vs 0.92, p=0.018). There were no significant differences in rCBF on 12-48 hours PWI between the late hemorrhage and non-hemorrhage group. Conclusions: Most intracerebral hemorrhages after thrombectomy were seen within 12 hours after intervention. A rCBF increase in hemorrhage cases was not seen on PWI within 12 hours after thrombectomy. rCBF increases on PWI 12-48 hours after thrombectomy, however, was associated with post-thrombectomy hemorrhage within 12 hours.

Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors

The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).