Objective: Clinical and radiological findings on neurosyphilis are fairly non-specific and there is a paucity of functional neuroimaging studies on neurosyphilis other than case reports and case series. The purpose of this study was to investigate brain perfusion abnormalities in patients with neurosyphilis. Methods: Four HIV-negative neurosyphilis patients and 4 healthy controls underwent clinical evaluation, brain technetium-99m ethyl cysteinate dimer (99mTc-ECD) single-photon emission computed tomography (SPECT) imaging, and neuropsychological assessments which included the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and Global Deterioration Scale (GDS). Voxel-wise differences in regional cerebral blood flow were compared between the two groups. Results: Neuropsychological test results indicated cognitive impairment in all patients. SPECT analysis revealed multifocal hypoperfusion predominantly in the frontal, insular, and posterior cingulate regions in neurosyphilis patients compared with healthy controls (family-wise error corrected p < 0.05). Conclusions: Together with previous findings, our results suggest that the hypoperfusion in the frontal, insular, and posterior cingulate regions may reflect cognitive impairments observed in neurosyphilis patients. Further studies with larger samples are needed to confirm our findings.

Object: Diabetes is associated with cerebral vascular dysfunction and increased vascular cognitive impairment. The objective of this study was to use arterial spin labeling (ASL) perfusion-weighted magnetic resonance imaging to investigate whether cerebral perfusion was changed in newly-diagnosed children with type 1 diabetes mellitus (T1DM) and the possible relationship between aberrant cerebral blood flow (CBF) with cognitive as well as clinical variables. Methods: Between January 2017 and February 2018, 34 children with newly-diagnosed T1DM and 34 age, gender, and education-matched healthy controls were included. Three dimensional pseudo-continuous ASL perfusion MRI was used to evaluate CBF. A conventional T2WI sequence was added to exclude intracranial disease. Regions with CBF differences between T1DM children and the controls were detected via voxel-wise comparisons in REST software. Associations among the result of neuropsychological test, clinical variables, and CBF values of different brains were investigated by using partial correlation analysis. Results: Compared with the controls, T1DM children show decreased CBF in the left calcarine and postcentral gyrus, and right precentral gyrus. The perfusion in the postcentral gyrus was positively correlated with IQ performance. No significant correlations were found between CBF and HbA1c, blood glucose level before imaging and IQ in other brain regions in T1DM children. Conclusion: There is an abnormal cerebral perfusion in children with newly diagnosed T1DM. The visual and sensorimotor areas are brain areas where perfusion is prone to change at the beginning of T1DM. Our study provided clues for cerebral pathophysiological changes in the initial stage of T1DM.

White matter hyperintensities (WMHs) are common neuroimaging findings in the aging population and are associated with various clinical symptoms, especially cognitive impairment. Abnormal global cerebral blood flow (CBF) and specific functional connections have been reported in subjects with higher WMH loads. Nevertheless, the comprehensive functional mechanisms underlying WMH are yet to be established. In this study, by combining resting-state functional magnetic resonance imaging and arterial spin labeling, we investigated the neurovascular dysfunction in subjects with WMH in CBF, functional connectivity strength (FCS), and CBF-FCS coupling. The whole-brain alterations of all these measures were explored among non-dementia subjects with different WMH loads using a fine-grained Human Brainnetome Atlas. In addition, exploratory mediation analyses were conducted to further determine the relationships between these neuroimaging indicators, WMH load, and cognition. The results showed that subjects with higher WMH loads displayed decreased CBF and FCS mainly in regions involving the cognitive- and emotional-related brain networks, including the default mode network, salience network, and central executive network. Notably, subjects with higher WMH loads also showed an abnormal regional CBF-FCS coupling in several regions of the thalamus, posterior cingulate cortex, and parahippocampal gyrus involving the default mode network. Furthermore, regional CBF in the right inferior temporal gyrus and right dorsal caudate may mediate the relationship between WMH load and cognition in WMH subjects. These findings indicated characteristic changes in cerebral blood supply, brain activity, and neurovascular coupling in regions involving specific brain networks with the development of WMH, providing further information on pathophysiology underpinnings of the WMH and related cognitive impairment.

Background: Changes in regional neural activity and functional connectivity in cervical spondylotic myelopathy (CSM) patients have been reported. However, resting-state cerebral blood flow (CBF) changes and coupling between CBF and functional connectivity in CSM patients are largely unknown. Methods: Twenty-seven CSM patients and 24 sex/age-matched healthy participants underwent resting-state functional MRI and arterial spin labeling imaging to compare functional connectivity strength (FCS) and CBF between the two groups. The CBF-FCS coupling of the whole gray matter and specific regions of interest was also compared between the groups. Results: Compared with healthy individuals, CBF-FCS coupling was significantly lower in CSM patients. The decrease in CBF-FCS coupling in CSM patients was observed in the superior frontal gyrus, bilateral thalamus, and right calcarine cortex, whereas the increase in CBF-FCS coupling was observed in the middle frontal gyrus. Moreover, low CBF and high FCS were observed in sensorimotor cortices and visual cortices, respectively. Conclusion: In general, neurovascular decoupling at cortical level may be a potential neuropathological mechanism of CSM.

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): -0.45, 95% confidence interval (CI): -0.64, -0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: -1.51, 95% CI: -1.94, -1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.

Posterior circulation involves the vertebrobasilar arteries, which supply oxygen and glucose to vital human brainstem structures and other areas. This complex circulatory- perfusion system is not homogenous throughout the day; rather, its hemodynamic changes rely on physiological demands, ensuring brainstem perfusion. This dynamic autoregulatory pattern maintains cerebral perfusion during blood pressure changes. Accumulative evidence suggests that activity within the autonomic nervous system is involved in the regulation of cerebral blood flow. Neither the sympathetic nor parasympathetic nervous systems work independently. Functional studies have shown a tight and complicated cross talk between these systems. In pathological processes where sympathetic stimulation is present, systemic vasoconstriction is followed, representing the most important CNS parasympathetic trigger that will promote local vasodilation. Stroke is a clear example of this process. The posterior circulation is affected in 30% of strokes, causing high morbidity and mortality outcomes. Currently, the management of ischemic stroke is focused on thrombolytic treatment and endovascular thrombectomy within an overall tight 4.5 to 6 h ischemic time window. Therefore, the autonomic nervous system could represent a potential therapeutic target to modulate reperfusion after cerebral ischemia through vasodilation, which could potentially decrease infarct size and increase the thrombolytic therapeutic ischemic window. In addition, shifting the autonomic nervous system balance toward its parasympathetic branch has shown to enhance neurogenesis and decrease local inflammation. Regretfully, the vast majority of animal models and human research on neuromodulation during brain ischemia have been focused on anterior circulation with disappointing results. In addition, the source of parasympathetic inputs in the vertebrobasilar system in humans is poorly understood, substantiating a gap and controversy in this area. Here, we reviewed current available literature regarding the parasympathetic vascular function and challenges of its stimulation in the vertebrobasilar system.

Background: Despite the increasing use of arterial spin labeling (ASL) in patients with epilepsy, little is known about its brain regional distribution pattern, including diaschisis, and its correspondence with FDG-PET. Here, we investigated the regional match and mismatch between FDG-PET and ASL in temporal lobe epilepsy (TLE). Methods: We recruited 27 patients with unilateral TLE, who underwent inter-ictal ASL and FDG-PET scans. These images were spatially normalized using Statistical Parametric Mapping 12, and the regional values in both ASL and FDG-PET were calculated using PMOD software within 20 volumes of interest (VOIs), including the temporal lobe, adjacent cortices, subcortical structures, and cerebellum. ASL images of 37 healthy controls were also analyzed and compared. Results: Whereas, ASL showed significant side differences, mainly in the temporal and frontal lobes, the significant abnormalities in FDG-PET were more widespread and included the insula and supramarginal gyrus. Ipsilateral thalamic reduction was found in FDG-PET only. The detectability of the focus side compared with the contralateral side was generally higher in FDG-PET. The discriminative values in ASL compared with healthy controls were higher in temporal neocortex and amygdala VOIs. Conclusions: There are similar and differing regional distributions between FDG-PET and ASL in TLE, possibly reflecting regional match and mismatch of cerebral blood flow and metabolism. At this stage, it seems that ASL couldn't present comparable clinical usefulness with FDG-PET. These findings deepen our knowledge of ASL imaging and are potentially useful for its further application.

Posterior circulation cerebral infarction (PCCI) can lead to deceased infratentorial cerebral blood flow (CBF) and metabolism. Neural activity is closely related to regional cerebral blood flow both spatially and temporally. Transcranial Doppler (TCD) combined with quantitative electroencephalography (QEEG) is a technique that evaluates neurovascular coupling and involves synergy between the metabolic and vascular systems. This study aimed to monitor brain function using TCD-QEEG and estimate the efficacy of TCD-QEEG for predicting the prognosis of patients with PCCI. We used a TCD-QEEG recording system to perform quantitative brain function monitoring; we recorded the related clinical variables simultaneously. The data were analyzed using a Cox proportional hazards regression model. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the cut-off for the diastolic flow velocity (VD) and (delta + theta)/(alpha + beta) ratio (DTABR). The area under the ROC curve (AUROC) was calculated to assess the predictive validity of the study variables. Forty patients (aged 63.7 ± 9.9 years; 30 men) were assessed. Mortality at 90 days was 40%. The TCD indicators of VD [hazard ratio (HR) 0.168, confidence interval (CI) 0.047-0.597, p = 0.006] and QEEG indicators of DTABR (HR 12.527, CI 1.637-95.846, p = 0.015) were the independent predictors of the clinical outcomes. The AUROC after combination of VD and DTABR was 0.896 and showed better predictive accuracy than the Glasgow Coma Scale score (0.75), VD (0.76), and DTABR (0.781; all p < 0.05). TCD-QEEG provides a good understanding of the coupling mechanisms in the brain and can improve our ability to predict the prognosis of patients with PCCI.

Objective: Exercise rehabilitation is an effective therapy in reducing the disability rate after stroke and should be carried out as early as possible. However, very early rehabilitation exercise exacerbates brain injury and is difficult to conduct in stroke patients due to their weakened and potentially disabled state. It is valuable to explore additional early rehabilitation strategies. Remote Ischemic Conditioning (RIC) is a novel therapy designed to protect vital organs from severe lethal ischemic injury by transient sublethal blood flow to non-vital organs, including the distal limbs, in order to induce endogenous protection. RIC has previously been conducted post-stroke for neuroprotection. However, whether combined early RIC and exercise (RICE) therapy enhances stroke rehabilitation remains to be determined. Methods: This is a single-center, double-blinded, randomized controlled trial that will enroll acute ischemic stroke patients within 24 h of symptom onset or symptom exacerbation. All enrolled patients will be randomly assigned to either the RICE group (exercise with RIC) or the control group (exercise with sham RIC) at a ratio of 1:1, with 20 patients in each group. Both groups will receive RIC or sham RIC within 24 h after stroke onset or symptom exacerbation, once a day, for 14 days. All patients will begin exercise training on the fourth day, twice a day, for 11 days. Their neurological function [Modified Rankin Scale (mRS) score, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index, and walking ability], infarct volume (nuclear magnetic resonance, MRI), and adverse events will be evaluated at different time points in their post-stroke care. Results: The primary outcome is safety, measured by the incidence of any serious RICE-related adverse events and decreased adverse events during hospitalization. The secondary outcome is a favorable prognosis within 90 days (mRS score < 2), determined by improvements in the mRS score, NIHSS score, Barthel Index, walking ability after 90 days, and infarct volume after 12 ± 2 days. Conclusion: This study is a prospective randomized controlled trial to determine the rehabilitative effect of early RIC followed by exercise on patients with acute ischemic stroke. Trial Registration: www.chictr.org.cn, identifier: ChiCTR2000041042.

Background: Persistent post-traumatic symptoms (PPS) after traumatic brain injury (TBI) can lead to significant chronic functional impairment. Pseudocontinuous arterial spin labeling (pCASL) has been used in multiple studies to explore changes in cerebral blood flow (CBF) that may result in acute and chronic TBI, and is a promising neuroimaging modality for assessing response to therapies. Methods: Twenty-four subjects with chronic mild-moderate TBI (mmTBI) were enrolled in a pilot study of 10 days of computerized executive function training combined with active or sham anodal transcranial direct current stimulation (tDCS) for treatment of cognitive PPS. Behavioral surveys, neuropsychological testing, and magnetic resonance imaging (MRI) with pCASL sequences to assess global and regional CBF were obtained before and after the training protocol. Results: Robust improvements in depression, anxiety, complex attention, and executive function were seen in both active and sham groups between the baseline and post-treatment visits. Global CBF decreased over time, with differences in regional CBF noted in the right inferior frontal gyrus (IFG). Active stimulation was associated with static or increased CBF in the right IFG, whereas sham was associated with reduced CBF. Neuropsychological performance and behavioral symptoms were not associated with changes in CBF. Discussion: The current study suggests a complex picture between mmTBI, cerebral perfusion, and recovery. Changes in CBF may result from physiologic effect of the intervention, compensatory neural mechanisms, or confounding factors. Limitations include a small sample size and heterogenous injury sample, but these findings suggest promising directions for future studies of cognitive training paradigms in mmTBI.

Background: Previous neuroimaging studies have demonstrated brain abnormalities in patients with hepatic diseases. However, the identified liver-brain associations are largely limited to disease-affected populations, and the nature and extent of such relations in healthy subjects remain unclear. We hypothesized that serum liver function markers within a normal level would affect brain properties. Method: One hundred fifty-seven healthy young adults underwent structural, resting-state functional, and arterial spin labeling MRI scans. Gray matter volume (GMV), regional homogeneity (ReHo), and cerebral blood flow (CBF) analyses were performed to assess brain structure, function, and perfusion, respectively. Peripheral venous blood samples were collected to measure serum liver function markers. Correlation analyses were conducted to test potential associations between liver function markers and brain imaging parameters. Results: First, serum proteins showed relations to brain structure characterized by higher albumin associated with increased GMV in the parahippocampal gyrus and amygdala and lower globulin and a higher albumin/globulin ratio with increased GMV in the olfactory cortex and parahippocampal gyrus. Second, serum bilirubin was linked to brain function characterized by higher bilirubin associated with increased ReHo in the precuneus, middle cingulate gyrus, inferior parietal lobule, and supramarginal gyrus and decreased ReHo in the caudate nucleus. Third, serum alanine transaminase (ALT) was related to brain perfusion characterized by higher ALT associated with increased CBF in the superior frontal gyrus and decreased CBF in the middle occipital gyrus, angular gyrus, precuneus, and middle temporal gyrus. More importantly, we found that CBF in the superior frontal gyrus was a significant mediator of the association between serum ALT level and working memory performance. Conclusion: These findings may not only expand existing knowledge about the relationship between the liver and the brain but also have clinical implications for studying brain impairments secondary to liver diseases as well as providing potential neural targets for their diagnosis and treatment.

Many modern people suffer from sleep debt that has accumulated in everyday life but is not subjectively noticed [potential sleep debt (PSD)]. Our hypothesis for this study was that resolution of PSD through sleep extension optimizes mood regulation by altering the functional connectivity between the amygdala and prefrontal cortex. Fifteen healthy male participants underwent an experiment consisting of a baseline (BL) evaluation followed by two successive interventions, namely, a 9-day sleep extension followed by one night of total sleep deprivation (TSD). Tests performed before and after the interventions included a questionnaire on negative mood and neuroimaging with arterial spin labeling MRI for evaluating regional cerebral blood flow (rCBF) and functional connectivity. Negative mood and amygdala rCBF were significantly reduced after sleep extension compared with BL. The amygdala had a significant negative functional connectivity with the medial prefrontal cortex (FCamg-MPFC), and this negative connectivity was greater after sleep extension than at BL. After TSD, these indices reverted to the same level as at BL. An additional path analysis with structural equation modeling showed that the FCamg-MPFC significantly explained the amygdala rCBF and that the amygdala rCBF significantly explained the negative mood. These findings suggest that the use of our sleep extension protocol normalized amygdala activity via negative amygdala-MPFC functional connectivity. The resolution of unnoticed PSD may improve mood by enhancing frontal suppression of hyperactivity in the amygdala caused by PSD accumulating in everyday life.

Background: The current lack of effective tools for prehospital identification of Large Vessel Occlusion (LVO) represents a significant barrier to efficient triage of stroke patients and detriment to treatment efficacy. The validation of objective Transcranial Doppler (TCD) metrics for LVO detection could provide first responders with requisite tools for informing stroke transfer decisions, dramatically improving patient care. Objective: To compare the diagnostic efficacy of two such candidate metrics: Velocity Asymmetry Index (VAI), which quantifies disparity of blood flow velocity across the cerebral hemispheres, and Velocity Curvature Index (VCI), a recently proposed TCD morphological biomarker. Additionally, we investigate a simple decision tree combining both metrics. Methods: We retrospectively compare accuracy/sensitivity/specificity (ACC/SEN/SPE) of each method (relative to standard CT-Angiography) in detecting LVO in a population of 66 subjects presenting with stroke symptoms (33 with CTA-confirmed LVO), enrolled consecutively at Erlanger Southeast Regional Stroke Center in Chattanooga, TN. Results: Individual VCI and VAI metrics demonstrated robust performance, with area under receiver operating characteristic curve (ROC-AUC) of 94% and 88%, respectively. Additionally, leave-one-out cross-validation at optimal identified thresholds resulted in 88% ACC (88% SEN) for VCI, vs. 79% ACC (76% SEN) for VAI. When combined, the resultant decision tree achieved 91% ACC (94% SEN). Discussion: We conclude VCI to be superior to VAI for LVO detection, and provide evidence that simple decision criteria incorporating both metrics may further optimize. Performance: Our results suggest that machine-learning approaches to TCD morphological analysis may soon enable robust prehospital LVO identification. Registration: Was not required for this feasibility study.

Vascular dementia (VaD), the second most common cause of cognitive impairment in the population, is a disease that results from reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Co-ultramicronized PEALut (co-ultra PEALut) is a new compound with beneficial effects, which include anti-inflammatory and antioxidant properties. Recently, co-ultraPEALut has been shown to exhibit neuroprotective effects in models of Parkinson's disease, cerebral ischemia and Alzheimer's disease. However, its effects on VaD remain unknown. Therefore, the purpose of the present study was to highlight the potential neuroprotective actions of co-ultraPEALut containing N-palmitoylethanolamine (PEA) and the antioxidant flavonoid luteolin (Lut) (10:1 by mass) in a mouse model of VaD induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, mice were orally treated with 1 mg/kg co-ultraPEALut daily for 15 days. On the 15th day, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Our results clearly demonstrate that co-ultraPEALut improved learning, memory ability, locomotor activity, and the reciprocal social interaction. In addition, the mice subjected to VaD and treated with the co-ultraPEALut showed a reorganization of CA1 and CA3 regions of the hippocampus and restored the number of hippocampal neurons as evidenced by NeuN expression, a specific marker of neurons. Furthermore following carotid arteries ligation, mice treated with co-ultraPEALut showed a modification of proinflammatory, proapoptotic proteins and of oxidative stress as evidenced by the expression of IκB-α, NF-κB p65, Bax, Bcl-2, inducible nitric oxide synthase, and cyclooxygenase-2. In order, co-ultraPEALut treatment restored VaD-induced loss of brain-derived neurotrophic factor and neurotrophins 3 (NT-3) expression in mice. These results confirmed that the neuroprotective effects of co-ultraPEALut were associated with its anti-inflammatory and antioxidant properties.