Timing of stereotactic radiosurgery and surgery and wound healing in patients with spinal tumors: a systematic review and expert opinions

Abstract

Background and Purpose:

Stereotactic radiosurgery (SRS) and surgery may be used in combination to manage cord compression due to spinal tumors. Procedure sequence and interval affect wound healing. We aimed to review the evidence on effects of timing and sequence of surgery and SRS on wound healing and bone fusion in patients with spine tumors.

Materials and Methods:

We performed a comprehensive literature search (Medline, Embase, Google Scholar, Cochrane Database of Systematic Reviews) to identify relevant studies published in 2000–2011. Additional reports were identified in reference lists from relevant papers. Case reports and series discussing patients aged ≧18 with primary or metastatic tumors to the spine who underwent surgical excision with/without instrumentation and SRS before or after surgery were included. The apparent relationship of procedure sequence and interval on wound healing and bone fusion was assessed.

Results:

Evidence on outcomes following treatment with SRS and surgery was provided in 31 studies; neither wound healing nor bone fusion were endpoints in any study. Wound healing complications were discussed in six studies (20%) including 88 patients treated with both modalities. Animal studies and limited evidence in humans suggest that at least 1 week is indicated between SRS and surgery or surgery and SRS.

Conclusions:

Evidence to guide decisions regarding the sequence and timing of surgery and SRS with respect to wound healing is limited. Consistent reporting of wound healing complications will improve ability to develop guidelines for optimal treatment of spinal tumors.     

Hair cortisol,stress exposure,and mental health in humans: A systematic review

The deleterious effects of chronic stress on health and its contribution to the development of mental illness attract broad attention worldwide. An important development in the last few years has been the employment of hair cortisol analysis with its unique possibility to assess the long-term systematic levels of cortisol retrospectively. This review makes a first attempt to systematically synthesize the body of published research on hair cortisol, chronic stress, and mental health. The results of hair cortisol studies are contrasted and integrated with literature on acutely circulating cortisol as measured in bodily fluids, thereby combining cortisol baseline concentration and cortisol reactivity in an attempt to understand the cortisol dynamics in the development and/or maintenance of mental illnesses. The studies on hair cortisol and chronic stress show increased hair cortisol levels in a wide range of contexts/situations (e.g. endurance athletes, shift work, unemployment, chronic pain, stress in neonates, major life events). With respect to mental illnesses, the results differed between diagnoses. In major depression, the hair cortisol concentrations appear to be increased, whereas for bipolar disorder, cortisol concentrations were only increased in patients with a late age-of-onset. In patients with anxiety (generalized anxiety disorder, panic disorder), hair cortisol levels were reported to be decreased. The same holds true for patients with posttraumatic stress disorder, in whom – after an initial increase in cortisol release – the cortisol output decreases below baseline.     

表皮生长因子联合血糖控制对糖尿病创面愈合的影响：成纤维细胞生长因子蛋白及其mRNA表达的变化

背景：有研究表明急性创伤可导致内源性的重组人表皮生长因子(recombinant human epidermal growth factor,rhEGF)表达下调,导致不愈合的发生。 目的：观察局部应用rhEGF联合血糖控制下对糖尿病大鼠烫伤创面成纤维细胞生长因子表达的影响。 方法：将Wistar糖尿病大鼠制备背部深Ⅱ度烫伤模型。联合治疗组于烫伤前1周控制血糖至对照组水平,并在烫伤24 h内创面喷洒rhEGF;rhEGF组仅创面喷洒rhEGF;血糖控制组仅控制血糖;对照组不制备糖尿病模型,烫伤后处理同联合治疗组。烫伤后1,3,5,7,11,15,21 d取创面皮肤组织采用免疫组织化学染色及原位杂交法检测成纤维细胞生长因子蛋白及mRNA的表达,并观察各组大鼠创面愈合情况。 结果与结论：烫伤后各组大鼠创面成纤维细胞生长因子蛋白及mRNA表达均明显增多,分别在5~7 d及7~11 d达高峰,且联合治疗、对照组峰值较rhEGF、血糖控制组高(P < 0.05)。烫伤后7~21 d,联合治疗、对照组创面愈合率高于rhEGF、血糖控制组(P < 0.05)。说明局部应用rhEGF在联合血糖控制下可促进糖尿病大鼠烫伤创面的愈合,可能与促进创面成纤维细胞生长因子表达有关。     

Psychological therapies for people with intellectual disabilities: A systematic review and meta-analysis

The aim of this study was to evaluate the efficacy of psychological therapies for people with intellectual disabilities (IDs) through a systematic review and meta-analysis of the current literature. A comprehensive literature search identified 143 intervention studies. Twenty-two trials were eligible for review, and 14 of these were subsequently included in the meta-analysis. Many studies did not include adequate information about their participants, especially the nature of their IDs; information about masked assessment, and therapy fidelity was also lacking. The meta-analysis yielded an overall moderate between-group effect size, g = .682, while group-based interventions had a moderate but smaller treatment effect than individual-based interventions. Cognitive-behaviour therapy (CBT) was efficacious for both anger and depression, while interventions aimed at improving interpersonal functioning were not effectual. When CBT was excluded, there was insufficient evidence regarding the efficacy of other psychological therapies, or psychological therapies intended to treat mental health problems in children and young people with IDs. Adults with IDs and concurrent mental health problems appear to benefit from psychological therapies. However, clinical trials need to make use of improved reporting standards and larger samples.     

The dopaminergic response to acute stress in health and psychopathology: A systematic review

Previous work in animals has shown that dopamine (DA) in cortex and striatum plays an essential role in stress processing. For the first time, we systematically reviewed the in vivo evidence for DAergic stress processing in health and psychopathology in humans. All studies included (n studies = 25, n observations = 324) utilized DA D2/3 positron emission tomography and measured DAergic activity during an acute stress challenge. The evidence in healthy volunteers (HV) suggests that physiological, but not psychological, stress consistently increases striatal DA release. Instead, increased medial prefrontal cortex (mPFC) DAergic activity in HV was observed during psychological stress. Across brain regions, stress-related DAergic activity was correlated with the physiological and psychological intensity of the stressor. The magnitude of stress-induced DA release was dependent on rearing conditions, personality traits and genetic variations in several SNPs. In psychopathology, preliminary evidence was found for stress-related dorsal striatal DAergic hyperactivity in psychosis spectrum and a blunted response in chronic cannabis use and pain-related disorders, but results were inconsistent. Physiological stress-induced DAergic activity in striatum in HV may reflect somatosensory properties of the stressor and readiness for active fight-or-flight behavior. DAergic activity in HV in the ventral striatum and mPFC may be more related to expectations about the stressor and threat evaluation, respectively. Future studies with increased sample size in HV and psychopathology assessing the functional relevance of stress-induced DAergic activity, the association between cortical and subcortical DAergic activity and the direct comparison of different stressors are necessary to conclusively elucidate the role of the DA system in the stress response.     

Sleep management in posttraumatic stress disorder: a systematic review and meta-analysis

ObjectivePost-traumatic stress disorder (PTSD) can lead to many negative secondary outcomes for patients, including sleep disturbances. The objective of this meta-analysis is (1) to evaluate the effect of interventions for adults with PTSD on sleep outcomes, PTSD outcomes, and adverse events, and (2) to evaluate the differential effectiveness of interventions aiming to improve sleep compared to those that do not.MethodsNine databases were searched for relevant randomized controlled trials (RCTs) in PTSD from January 1980 to October 2019. Two independent reviewers screened 7176 records, assessed 2139 full-text articles, and included 89 studies in 155 publications for this review. Sleep, PTSD, and adverse event outcomes were abstracted and meta-analyses were performed using the Hartung-Knapp-Sidik-Jonkman method for random effects.ResultsInterventions improved sleep outcomes (standardized mean difference [SMD] −0.56; confidence interval [CI] −0.75 to −0.37; 49 RCTs) and PTSD symptoms (SMD -0.48; CI -0.67 to −0.29; 44 RCTs) across studies. Adverse events were not related to interventions overall (RR 1.17; CI 0.91 to 1.49; 15 RCTs). Interventions targeting sleep improved sleep outcomes more than interventions that did not target sleep (p = 0.03). Improvement in PTSD symptoms did not differ between intervention types.ConclusionsInterventions for patients with PTSD significantly improve sleep outcomes, especially interventions that specifically target sleep. Treatments for adults with PTSD directed towards sleep improvement may benefit patients who suffer from both ailments.     

Neuropeptide Y in PTSD,MDD, and chronic stress: A systematic review and meta-analysis

Previous studies have suggested that neuropeptide Y (NPY) levels may be altered in patients with major depressive disorder (MDD), post-traumatic stress disorder (PTSD) and chronic stress. We investigated, through systematic review and meta-analysis, whether the mean levels of NPY are significantly different in patients with MDD, PTSD or chronic stress, compared to controls. The main outcome was the pooled standardized mean difference (SMD) with 95% confidence intervals between cases and controls, using the random-effects model. Heterogeneity and publication bias were evaluated. Thirty-five studies met eligibility criteria. Meta-regression determined that medication and sex could explain 27% of the between-study variance. Females and participants currently prescribed psychotropic medications had significantly higher levels of NPY. NPY levels were significantly lower in plasma and cerebrospinal fluid (CSF) in PTSD patients versus controls. Patients with MDD had significantly lower levels of NPY in plasma compared to controls, but not in the CSF. The magnitudes of the decrease in plasma NPY levels were not significantly different between PTSD and MDD. However, chronic stress patients had significantly higher plasma NPY levels compared to controls, PTSD or MDD. Our findings may imply a shared role of NPY in trauma and depression: nevertheless, it is not clear that the association is specific to these disorders. Psychotropic medications may help restore NPY levels. Further controlled studies are needed to better delineate the contribution of confounding variables such as type of depression, body mass index, appetite or sleep architecture.     

Mindfulness mediates the physiological markers of stress: Systematic review and meta-analysis

Meditation is a popular form of stress management, argued to mediate stress reactivity. However, many studies in this field commonly fail to include an active control group. Given the frequency with which people are selecting meditation as a form of self-management, it is important to validate if the practice is effective in mediating stress-reactivity using well-controlled studies. Thus, we aimed to conduct a meta-analysis investigating the neurobiological effects of meditation, including focused attention, open monitoring and automatic self-transcending subtypes, compared to an active control, on markers of stress. In the current meta-analysis and systematic review, we included randomised controlled trials comparing meditation interventions compared to an active control on physiological markers of stress. Studied outcomes include cortisol, blood pressure, heart-rate, lipids and peripheral cytokine expression. Forty-five studies were included. All meditation subtypes reduced systolic blood pressure. Focused attention meditations also reduced cortisol and open monitoring meditations also reduced heart rate. When all meditation forms were analysed together, meditation reduced cortisol, C - reactive protein, blood pressure, heart rate, triglycerides and tumour necrosis factor-alpha. Overall, meditation practice leads to decreased physiological markers of stress in a range of populations.     

Emotional stress,cortisol response,and cortisol rhythm in autism spectrum disorders: A systematic review

BackgroundThis systematic review evaluated whether there is evidence for (i) increased emotional stress levels, and (ii) a different biological stress response or rhythm [i.e., cortisol stress response, diurnal rhythm, or cortisol awakening response (CAR)] in individuals with autism spectrum disorder (ASD) relative to controls. Thirdly, the evidence for an association between emotional and biological stress in ASD was reviewed.MethodMEDLINE, Cochrane Library, and SAGE journals were searched until December 2020. In this review, there were no limitations regarding age, sex, or intelligence quotient. Studies were only reviewed if results were compared with controls without a developmental disorder. Only salivary cortisol was considered as biological stress measure.ResultsThirty-one studies were reviewed. Significantly higher self- and parent-reported emotional stress levels were found in individuals with ASD compared to controls. Regarding biological stress, the few studies in adults reported comparable cortisol stress responses and rhythms between both groups. In children/adolescents with ASD relative to controls, an increased, blunted, or similar cortisol stress response was reported, whereas the CAR did not differ in most studies, and diurnal rhythm was described as blunted or similar. Most studies found no significant association between parent-reported emotional stress and biological stress in ASD.ConclusionsCurrent findings suggest that heightened emotional stress is a clinically significant factor in ASD. To unravel the cortisol response and rhythm, research in specific subgroups within the ASD spectrum is warranted, aiming at a higher frequency of cortisol measurements, preferably combined with momentary emotional stress measurements.     

Multi-systemic evaluation of biological and emotional responses to the Trier Social Stress Test: A meta-analysis and systematic review

Humans experience multiple biological and emotional changes under acute stress. Adopting a multi-systemic approach, we summarized 61 studies on healthy people’s endocrinological, physiological, immunological and emotional responses to the Trier Social Stress Test. We found salivary cortisol and negative mood states were the most sensitive markers to acute stress and recovery. Biomarkers such as heart rate and salivary alpha-amylase also showed sensitivity to acute stress, but the numbers of studies were small. Other endocrinological (e.g., dehydroepiandrosterone), inflammatory (C-Reactive Protein, Interleukin-6) and physiological (e.g., skin conductance level) measures received modest support as acute stress markers. Salivary cortisol showed some associations with mood measures (e.g., state anxiety) during acute stress and recovery, and heart rate showed preliminary positive relationship with calmness ratings during response to TSST, but the overall evidence was mixed. While further research is needed, these findings provide updated and comprehensive knowledge on the integrated psychobiological response profiles to TSST.     

A systematic review and meta-analysis of mindfulness-based stress reduction for the fibromyalgia syndrome

Objectives

This paper presents a systematic review and meta-analysis of the effectiveness of mindfulness-based stress reduction (MBSR) for FMS.

Methods

The PubMed/MEDLINE, Cochrane Library, EMBASE, PsychINFO and CAMBASE databases were screened in September 2013 to identify randomized and non-randomized controlled trials comparing MBSR to control interventions. Major outcome measures were quality of life and pain; secondary outcomes included sleep quality, fatigue, depression and safety. Standardized mean differences and 95% confidence intervals were calculated.

Results

Six trials were located with a total of 674 FMS patients. Analyses revealed low quality evidence for short-term improvement of quality of life (SMD = − 0.35; 95% CI − 0.57 to − 0.12; P = 0.002) and pain (SMD = − 0.23; 95% CI − 0.46 to − 0.01; P = 0.04) after MBSR, when compared to usual care; and for short-term improvement of quality of life (SMD = − 0.32; 95% CI − 0.59 to − 0.04; P = 0.02) and pain (SMD = − 0.44; 95% CI − 0.73 to − 0.16; P = 0.002) after MBSR, when compared to active control interventions. Effects were not robust against bias. No evidence was further found for secondary outcomes or long-term effects of MBSR. Safety data were not reported in any trial.

Conclusions

This systematic review found that MBSR might be a useful approach for FMS patients. According to the quality of evidence only a weak recommendation for MBSR can be made at this point. Further high quality RCTs are required for a conclusive judgment of its effects.     

Stress decreases, while central nucleus amygdala lesions increase, IL-8 and MIP-1alpha gene expression during tissue healing in non-human primates

Stress impairs healing and in part this effect is thought to be mediated by glucocorticoids. However, the brain systems that underlie the effects of stress on healing remain to be determined. Since the central nucleus of the amygdala (CeA) plays a role in mediating an individual's behavioral and physiological reactivity to stress, we investigated, in rhesus monkeys, whether selective lesions of the CeA altered the gene expression of chemokines (IL-8 and MIP-1alpha) that are associated with early dermal healing. We used rhesus monkeys because they provide an excellent animal model to investigate brain mechanisms relevant to human stress, anxiety, and psychopathology. Hypothalamic-pituitary-adrenal (HPA) activity was assessed in the monkeys prior to the wound healing experiment demonstrating that the CeA lesions reduce HPA activity. In the healing experiment, stress decreased IL-8 and MIP-1alpha gene expression in both CeA lesioned and non-lesioned animals. Conversely, the CeA lesions increased the tissue expression of IL-8 and MIP-1alpha mRNA prior to and after stress exposure. These results demonstrate that in primates the CeA is a key brain region involved in the regulation of processes associated with wound healing. Because of brain and behavioral similarities between rhesus monkeys and humans, these results are particularly relevant to understanding brain mechanisms that influence healing in humans.     

Stroke and dementia risk: A systematic review and meta-analysis

Introduction

Stroke is an established risk factor for all-cause dementia, though meta-analyses are needed to quantify this risk.

Suicidal behaviour and memory: A systematic review and meta-analysis

Objectives. Suicidal behaviour results from a complex interplay between stressful events and vulnerability factors, including cognitive deficits. It is not yet clear if memory impairment is part of this specific vulnerability. Therefore, the objective of this study was to examine the association between memory deficits and vulnerability to suicidal acts. Methods. A literature review was performed using Medline, Embase, and PsycInfo databases. Twenty-four studies (including 2,595 participants) met the selection criteria. Four different types of memory (i.e., working memory, short- and long-term memory, and autobiographical memory) were assessed in at least three different studies. Results. Autobiographical memory was significantly less specific and more general in patients with a history of suicide attempt relative to those without such a history (Hedges’ g = 0.8 and 0.9, respectively). Long-term memory and working memory were both more impaired in suicide attempters than in patient and healthy controls. Only short-term memory did not differentiate suicide attempters from patient controls. Conclusions. Memory may play a significant role in the risk of suicidal acts, perhaps by preventing these individuals from using past experiences to solve current problems and to envision the future, and by altering inhibitory processes. More studies are necessary to better clarify these relationships.     

Dysphagia treatments in Parkinson's disease: A systematic review and meta-analysis

Background

The majority of patients with Parkinson's disease (PD) develop oropharyngeal dysphagia during the course of their disease. However, the efficacy of dysphagia treatments for these patients remains controversial. Therefore, we conducted this systematic review and meta-analysis to evaluate treatment efficacy based on the evidence from randomized controlled trials (RCTs).

Methods

Five electronic databases were systematically searched from inception date to April 2022. Two reviewers independently extracted and analyzed the data. The outcome measures were changes in swallowing-related characteristics based on instrumental swallowing assessments.

Key Results

An initial search identified 187 RCT studies of relevance. After screening, nine studies with a total sample size of 286 were included in the meta-analysis. The pooled effect size for all dysphagia treatments compared with control comparators was significant and medium (SMD [95% CI] = 0.58 [0.22, 0.94], p = 0.001; I² = 50%). Subgroup analysis revealed a significant and medium pooled effect size for stimulation treatments (brain stimulation, peripheral neurostimulation and acupuncture) (SMD [95% CI] = 0.54 [0.15, 0.92]; p = 0.006; I² = 22%). Specifically, the effect sizes for the single RCTs on neuromuscular stimulation (SMD [95% CI] = 1.58 [0.49, 2.86]; p = 0.005) and acupuncture (SMD [95% CI] = 0.82 [0.27, 1.37]; p = 0.003) were significant and large.

Conclusions and Inferences

Our results showed that overall, dysphagia treatments, particularly stimulation treatments, can potentially benefit PD patients. However, given the limited number of small RCTs for each type of treatment, the evidence remains weak and uncertain. Further large-scale, multicenter RCTs are warranted to fully explore their clinical efficacy in the PD population.     

Chemokine alterations in bipolar disorder: A systematic review and meta-analysis

We aimed to perform a systematic review and meta-analysis of studies examining the levels of chemokines in peripheral blood of patients with bipolar disorder (BD) and healthy controls. Meta-analysis was based on random-effects models with Hedges’ g as the effect size estimate. We included 13 eligible studies (1221 BD patients and 663 controls). The following chemokines were analysed: interleukin-8 (IL-8), monocyte-chemoattractant protein-1 (MCP-1), eotaxin-1, eotaxin-2 and interferon-γ-induced protein 10 (IP-10). The levels of IL-8 (N = 8, g = 0.26, 95%CI: 0.11–0.41, p < 0.001), MCP-1 (N = 8, g = 0.40, 95%CI: 0.18–0.63), eotaxin-1 (N = 3, g = 0.55, 95%CI: 0.21–0.89, p = 0.001) and IP-10 (N = 4, g = 0.95, 95%CI: 0.67–1.22, p < 0.001) were significantly higher in BD patients as compared with controls. Subgroup analyses revealed that elevated levels of IL-8 (N = 5, g = 0.75, 95%CI: 0.42–1.07, p < 0.001) and MCP-1 (N = 4, g = 0.57, 95%CI: 0.28–0.86, p < 0.001) appeared only in BD patients during their depressive phase. Illness duration was associated with significantly lower levels of IL-8 in meta-regression analysis. In turn, elevated levels of IP-10 were present during euthymia (N = 2, g = 0.76, 95%CI: 0.43–1.10, p < 0.001) but not depression (N = 2, g = 1.81, 95%CI: −0.16 to 3.77, p = 0.072). The analysis of eotaxin-1 levels was mainly based on studies of euthymic BD patients (N = 3). Our results suggest that chemokine alterations in BD might be related to mood state. Elevated levels of IL-8 and MCP-1 might be specific to depression. Available evidence indicates that increased levels of eotaxin-1 and IP-10 appear in euthymia; however, more studies are needed to address these alterations in other mood states.     

Prognostic scores in status epilepticus: A systematic review and meta-analysis

The performance of prognostic scores of status epilepticus (SE) has been reported in very heterogeneous cohorts. We aimed to provide a summary of the available evidence on their respective performance. PubMed and EMBASE were searched for relevant articles. Studies were reviewed for eligibility for meta-analysis of the area under the receiver-operating characteristic curve (AUC) and for meta-analysis of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in predicting in-hospital mortality with scores in which at least two external evaluations had been published. This study was registered with PROSPERO (international prospective register of systematic reviews) (CRD42022325766). Study quality was assessed using Prediction model Risk Of Bias ASsessment Tool (PROBAST). In the meta-analysis of AUC, 21 studies were pooled for STESS (Status Epilepticus Severity Score), five for EMSE-EAC (Epidemiology-based Mortality Score in Status Epilepticus - Etiology, Age, level of Consciousness), five for EMSE-EACE (EMSE - Etiology, Age, level of Consciousness, EEG), and two for ENDIT (Encephalitis, nonconvulsive status epilepticus, Diazepam resistance, Imaging abnormalities, Tracheal intubation). The pooled AUC of STESS, EMSE-EAC, EMSE-EACE, and ENDIT was 0.74 (95% CI: 0.71–0.78), 0.68 (95% CI 0.63–0.72), 0.77 (95% CI: 0.72–0.81), and 0.78 (95% CI: 0.70–0.87), respectively. The pooled sensitivity of STESS-3, STESS-4, EMSE-EACE-64, and ENDIT-4 was 0.83 (95% CI: 0.80–0.86), 0.60 (95% CI: 0.55–0.65), 0.76 (95% CI: 0.67–0.83), and 0.70 (95% CI: 0.55–0.82), respectively. Their pooled specificity was 0.50 (95% CI: 0.48–0.52), 0.74 (95% CI: 0.72–0.76), 0.63 (95% CI: 0.59–0.67), and 0.65 (95% CI: 0.61–0.70), respectively. Their pooled PPV was 0.27 (95% CI: 0.24–0.30), 0.35 (95% CI: 0.29–0.41), 0.33 (95% CI: 0.24–0.43), and 0.20 (95% CI: 0.13–0.27). Their pooled NPV was 0.94 (95% CI: 0.93–0.96), 0.90 (95% CI: 0.89–0.92), 0.89 (95% CI: 0.80–0.98), and 0.95 (95% CI: 0.92–0.98). Variations in performance were observed in patients' subgroups, such as critically ill patients and refractory cases. Investigated scores only have acceptable AUC, sensitivity, and specificity for predicting in-hospital mortality, with the EMSE-EAC having a lower discriminative power. STESS-3 has the highest sensitivity, and STESS-4 the highest specificity, but neither combines acceptable sensitivity and specificity. All these scores had high NPV but very low PPV. Caution should be exercised in their clinical use. Further studies are required to develop more accurate scores.     

Profiling cerebrovascular function in migraine: A systematic review and meta-analysis

Previous studies have investigated whether migraine is a circulatory disorder, as migraineurs are at heightened risk of cerebrovascular disease. However, in most cases, systemic vascular function was evaluated, which may not reflect abnormalities in the cerebral circulation. Therefore, we aimed to determine whether cerebrovascular function differs between migraineurs and controls. A systematic literature search was conducted across three electronic databases to search for studies that compared cerebrovascular function in migraineurs to controls. Where applicable, meta-analyses were used to determine standardised mean differences (SMD) between migraineurs and controls. Seventy articles were identified, 40 of which contained quantitative data. Meta-analyses showed pulsatility index (PI) was higher (SMD = 0.23; 95%CI = 0.05 to 0.42, P = 0.01) and cerebrovascular responsiveness (CVR) to hypercapnia was lower (SMD=−0.34; 95%CI=−0.67 to −0.01, P = 0.04) in the posterior circulation of migraineurs, particularly those without aura. The meta-analyses also indicated that migraineurs have higher resting mean blood flow velocity in both anterior (SMD = 0.14; 95%CI = 0.05 to 0.23, P = 0.003) and posterior circulations (SMD = 0.20; 95%CI = 0.05 to 0.34, P = 0.007). Compared to healthy controls, migraineurs have altered cerebrovascular function, evidenced by elevated PI (representing arterial stiffness) and impaired CVR to hypercapnia (representing cerebral vasodilator function). Future studies should investigate whether improvement of cerebrovascular function is able to alleviate migraine.