Background: Patients with generalized anxiety disorder (GAD) usually present with various neurological symptoms, but the mechanisms remain unclear. We aimed to analyze the characteristics of dynamic cerebral autoregulation (dCA) in patients with GAD. Methods: Patients (aged ≥18 years) who were diagnosed with GAD were enrolled in this study. Medically and psychiatrically healthy volunteers were recruited as controls. Subjects received the Hamilton Rating Scale for Anxiety (HAMA) and 17-item Hamilton Depression Rating Scale (HAMD) evaluation. Noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity were recorded simultaneously from each subject. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference, gain, and coherence function. Results: A total of 57 patients with GAD and 40 healthy volunteers were enrolled. We found that the phase difference values were significantly compromised in patients with GAD. In the Spearman correlation analysis, the phase difference values were negatively correlated with the HAMA scores and the HAMD scores. In the multiple linear regression analysis, GAD is negatively correlated with the phase difference values, whereas age is positively correlated with the phase difference values. Conclusions: Our results suggested that the dCA was compromised in patients with GAD and negatively correlated with the score of anxiety. Improving the dCA may be a potential therapeutic method for treating the neurological symptoms of GAD patients. Keywords: Generalized anxiety disorder, Dynamic cerebral autoregulation, Transcranial Doppler Background the mechanisms of these symptoms, however, remain Generalized anxiety disorder (GAD) is one of the most unclear. It has been reported that in patients with GAD, common mental disorders in the world [1, 2] and can the cerebral hemodynamics show abnormal manifesta- negatively affect the life quality of patients and disrupt tions [3, 4], which may be a reason for the neurological important activities of daily living . Patients with symptoms of GAD. GAD usually present with various neurological symp- Cerebral autoregulation, which protects the brain toms, such as dizziness, headache, and sleep disorders; tissue from hyperperfusion or hypoperfusion, is critical in regulating cerebral hemodynamics and has been found to play an important role in many neurological * Correspondence: email@example.com; firstname.lastname@example.org Zhen-Ni Guo and Shan Lv contributed equally to this work. diseases [5–7]. Previous studies found that the factors Clinical Trail and Research Center for Stroke, Department of Neurology, The involved in cerebral autoregulation regulation, such as First Hospital of Jilin University, Chang Chun, China neuroregulation, myogenic response, and endothelial Department of Neurology, The First Hospital of Jilin University, Xinmin Street 71#, Chang Chun 130021, China regulation, etc., are dysfunctional in patients with GAD Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Guo et al. BMC Psychiatry (2018) 18:164 Page 2 of 7 Fig. 1 Hypothesis between generalized anxiety disorder (GAD) and cerebral autoregulation impairment. In patients with GAD, neuroregulation, myogenic response, and endothelial regulation may be dysfunctional, which could damage cerebral autoregulation (Fig. 1)[8–12]. Our previous study also showed that Patients whose chief complaint was poor sleep were patients with GAD cannot maintain normal cerebral selected for screening. Patients (aged ≥18 years) who met blood flow velocity from supine to standing . These the Diagnostic and Statistical Manual of Mental Disor- data imply that cerebral autoregulation may be impaired ders, Fourth Edition, Text Revision criteria for GAD  in GAD patients. were recruited from May 2016 to November 2016 in the Cerebral autoregulation is divided into static cerebral outpatient unit of the Neurological Department. Patients autoregulation and dynamic cerebral autoregulation who met Diagnostic and Statistical Manual of Mental (dCA), and the dCA is more sensitive to pathological Disorders criteria for Major Depressive Disorder were situations [14, 15]. When dCA is measured, continuous excluded. Patients were otherwise healthy, with no ascer- cerebral blood flow velocities (assessed using transcra- tained disorders in the nervous, cardiovascular, or respira- nial Doppler) and continuous finger blood pressure tory systems and without hypertension, diabetes, or (assessed using a servo-controlled plethysmograph) were hyperlipidemia. The clinical workup consisted of labora- recorded simultaneously. These data were then analyzed tory tests (liver and kidney function tests, hematology pro- using transfer function analysis, an approach used to file, blood glucose tests, and blood lipid tests), blood analyze dCA based on spontaneous fluctuations of blood pressure, electrocardiography, transcranial Doppler (EMS- pressure and cerebral blood flow velocities at rest [16, 9 PB, Delica, China), carotid ultrasound (IU22, Phillips, 17]. In previous studies, dCA calculated by transfer Andover, MA, USA), cranial computed tomography/mag- function analysis has been applied in healthy subjects netic resonance imaging, and physical examination. , cerebrovascular disease [5, 19], cognitive impair- Patients were evaluated with the Hamilton Rating Scale ment , etc. However, dCA has not been studied in for Anxiety (HAMA)  and the 17-item Hamilton patients with GAD. Depression Rating Scale (HAMD) . Medically and In this study, we hypothesize that dCA is compro- psychiatrically healthy volunteers were recruited as mised in patients with GAD. If our hypothesis is valid, controls. Two blinded clinical psychiatrists evaluated the dCA may serve as a potential therapeutic target to im- patients’ mental health status. prove the neurological symptoms in patients with GAD. Dynamic cerebral autoregulation (dCA) protocol Methods The examination of dCA was performed as reported in Participants previous research [5, 7, 23]. Subjects were asked to avoid The prospective study design was approved by the ethics nicotine, caffeine, alcohol, and all kinds of sleep medi- committee of the First Hospital of Jilin University under cines for at least 24 h before the dCA examination. the guidelines of the Helsinki Declaration of 1975/1983. The examination was performed in a quiet, dedicated Written informed consent was obtained from all subjects. research room with minimal surrounding stimuli. First, Guo et al. BMC Psychiatry (2018) 18:164 Page 3 of 7 the baseline arterial blood pressure was measured at the Processing Toolbox in MATLAB with the Welch method brachial artery using an automatic blood pressure moni- for the estimation of power spectral density and hamming tor (Omron 711). Second, we simultaneously recorded window for the reduction of spectral leakage. The record- continuous spontaneous arterial blood pressure on the ings with averaged coherence < 0.4 at the low frequency middle finger using a servo-controlled plethysmograph band were considered with insufficient linearity and there- (Finometer Pro, Netherlands) and continuous bilateral fore excluded from the transfer function analysis. middle cerebral artery blood flow velocity at a depth of 45 mm to 60 mm with 2 MHz probes attached to a Statistical analysis customized head frame (MultiDop X2, DWL, Sipplingen, The Statistical Package for the Social Sciences Version 17.0 Germany). End-tidal carbon dioxide was recorded using (SPSS, IBM, West Grove, PA, USA) was used to analyze a capnograph with a facemask attached to the nasal the data. Continuous data are expressed as mean and cannula. Data were recorded for 10 min for further dCA standard deviation. Comparison between two groups were examination analysis. analyzed using Student’st-tests.The discrete variablesare expressed as the rate (percentage) and were analyzed using Data analysis chi-squared and Fisher’s exact tests. The Spearman correl- The dCA analysis was performed as previously reported ation analysis was used to analyze the relationship between [5, 7] and was analyzed blindly for each subject. Briefly, phase difference values and HAMA scores and the relation- dCA data were analyzed using MATLAB (MathWorks, ship between phase difference values and HAMD scores. Natick, MA, USA). Beat-to-beat alignment of the data Multiple linear regression analysis was used to explore the was achieved with a cross-correlation function to elimin- effects of covariates on phase or gain. Calculated two-tailed ate possible time lags. The relationship between dynamic P values < 0.05 were considered statistically significant. changes in spontaneous arterial blood pressure and bilateral middle cerebral artery blood flow velocity was assessed with a transfer function analysis. For each Results recording, arterial blood pressure and bilateral cerebral Demographic information artery blood flow velocity were divided into a number of In total, 57 patients with GAD (45.05 ± 14.83; 18 males) data segments by a 60-s window with a 30-s overlap. For and 40 healthy volunteers were enrolled in the study. one segment of arterial blood pressure and bilateral The baseline characteristics are presented in Table 1. cerebral artery blood flow velocity, the transfer function analysis was implemented as, S ðÞ f pv Table 1 Baseline characteristics, phase difference, and gain in HfðÞ ¼ ; ð1Þ S ðÞ f pp the patients and controls GAD Control t/χ p where H(f) denotes the frequency response. S (f) is the pp (n = 57) (n = 40) auto-spectrum of arterial blood pressure, and S (f)is pv Male, n (%) 18 (31.58%) 24 (60.00%) 6.773 0.009 the cross-spectrum between arterial blood pressure and Age (years) 45.05 ± 14.83 43.10 ± 11.51 0.698 0.487 cerebral artery blood flow velocity. For each subject, HAMA 19.79 ± 5.93 3.60 ± 1.71 19.501 < 0.001 S (f) and S (f) were averaged over the segments to pp pv HAMD 13.96 ± 4.08 4.37 ± 1.33 16.534 < 0.001 improve statistical reliability. The gain |H(f)| and phase difference ϕ(f) can then be computed as, Mean ABP, mmHg 89.12 ± 7.48 86.60 ± 9.73 1.443 0.152 qﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ Heart rate 76.07 ± 8.99 74.10 ± 8.20 1.101 0.274 2 2 jj HfðÞ ¼ jj H ðÞ f þjj H ðÞ f ; ð2Þ R I End-title CO , mmHg 35.23 ± 3.12 35.16 ± 2.56 0.613 0.542 Phase difference, degree H ðÞ f −1 ∅ðÞ f ¼ tan ; ð3Þ Left hemisphere 43.43 ± 14.39 55.00 ± 8.86 −4.891 < 0.001 H ðÞ f Right hemisphere 43.30 ± 15.40 54.07 ± 9.36 − 4.273 < 0.001 where H (f) and H (f) are the real and imaginary parts R I Gain, %/% of H(f), respectively. Low phase difference and high gain Left hemisphere 0.89 ± 0.31 0.85 ± 0.24 0.820 0.414 values at a low frequency band (0.06-0.12 Hz) indicate Right hemisphere 0.86 ± 0.29 0.86 ± 0.22 −0.064 0.949 that cerebral artery blood flow velocity follows changes of arterial blood pressure passively, thus suggesting Smoking, n (%) 12 (21.1) 7 (17.5) 0.188 0.664 impairment of autoregulation [16, 17]. We also calcu- Drinking, n (%) 4 (7.0) 1 (2.5) 0.646 0.310 lated coherence function to quantify the linearity in the GAD generalized anxiety disorder, ABP arterial blood pressure, HAMA Hamilton frequency domain using a routine provided by Signal Rating Scale for Anxiety, HAMD Hamilton Depression Rating Scale Guo et al. BMC Psychiatry (2018) 18:164 Page 4 of 7 Dynamic cerebral autoregulation to be correlated with phase difference values. GAD is GAD patients negatively correlated to phase difference, whereas age is The patients with GAD showed no difference in phase positively correlated to phase difference after adjusting difference values between the left and right hemispheres. for covariates (Table 2). No factors were detected associ- However, when compared with the healthy controls, the ated with gain. phase difference values of both hemispheres of GAD pa- tients were significantly lower than the corresponding Discussion hemisphere of the healthy controls. In addition, there In the present study, we found that the dCA of both was no significant difference in the gain values between hemispheres in patients with GAD was significantly GAD patients and healthy controls in both the left and lower as compared with the healthy controls. In right hemispheres (Fig. 2, and Table 1). addition, the dCA function is negatively correlated with the anxiety score. Impaired dCA may be a mechanism Correlation analysis underlying the neurological symptoms of GAD and thus In the Spearman correlation analysis, both the left may serve as a potential therapeutic target to alleviate and right phase difference values were negatively the neurological symptoms in patients with GAD. correlated to HAMA scores (left: r = − 0.365, p < 0.001; Generally, phase difference between arterial blood right: r = − 0.348, p < 0.001). Similarly, both the left and pressure and cerebral artery blood flow velocity at a certain right phase difference values were negatively correlated to frequency can be considered as time delay between these HAMD scores (left: r = − 0.350, p <0.001; right: r = − 0.363, recordings. Therefore, lower phase difference (shorter time p < 0.001). delay) indicates that blood flow changes in pace (passively) with fluctuations of blood pressure, suggesting that the Multiple linear regression analysis distal arterioles and capillary do not respond to the changes The associations between clinical factors and phase of blood pressure. In contrast, notable phase difference difference are shown in Table 2. GAD and age are found (larger time delay) suggests that the phase of arterial blood Fig. 2 a The phase difference and gain derived from the transfer function within significant interval 0.06-0.12 Hz are plotted. (−: left middle cerebral artery [MCA] and —: right MCA). Phase difference values (parameter of dynamic cerebral autoregulation) were significant compromised in patients with generalized anxiety disorder (GAD) compared with the healthy group, indicating an impairment of dynamic cerebral autoregulation in patients with GAD. There was no difference of the gain values between GAD group and healthy group. b Statistical analysis of phase differences and gains are shown. Phase difference values in the GAD group were significantly lower than the corresponding MCA of the healthy group. There was no difference in gain values in the two groups Guo et al. BMC Psychiatry (2018) 18:164 Page 5 of 7 Table 2 Multiple regression Coefficients for mean phase difference values of left and right hemisphere Covariates Unstandardized coefficients Standardized 95% CI for β P coefficients β Std. Error Lower Bound Upper Bound Constant 63.819 21.494 21.105 106.534 0.004 Age (years) 0.240 0.092 0.248 0.057 0.422 0.011 Mean ABP, mmHg −0.063 0.150 −0.041 −0.362 0.236 0.676 Heart rate −0.075 0.143 −0.050 −0.360 0.210 0.604 End-title CO , mmHg −0.229 0.389 −0.057 −1.003 0.544 0.557 Groups of mental disorder Control Reference Generalized anxiety disorder −11.052 2.629 −0.418 − 16.277 − 5.840 < 0.001 Gender Female Reference Male −0.143 3.024 0.005 −6.154 5.828 0.962 Smoking No Reference Yes −2.561 3.672 −0.078 −9.858 4.737 0.487 Drinking No Reference Yes −2.943 5.854 −0.050 −14.576 8.690 0.616 pressure is outpaced by the phase of cerebral artery blood increased perfusion in the left Broca’s area and left flow velocity, implying that the distal arterioles and capillary occipitotemporal region, and venlafaxine-treated GAD do not comply with the changes in blood pressure. The rea- patients showed increased cerebellar perfusion bilaterally son why patients with GAD present with impaired dCA re- . In the present study, the impairment of dCA can mains unclear and needs further investigation. As a chronic result in abnormal cerebral perfusion. Our previous stress disease, lower cardiac vagal control and hyperactivity study also yielded some meaningful results: we found of the sympathetic and hypothalamic-pituitary-adrenal axis that patients with anxiety showed more pronounced were reported in patients with GAD [24–29], leading to decreases in cerebral blood flow velocity with abrupt disorganized secretion of norepinephrine, serotonin, cortisol, standing, which indicates impaired dCA . etc. Some of these neuroendocrine substances are vasoactive It is worth mentioning that phase difference values substances that regulate cerebral autoregulation (Fig. 1). were negatively correlated with the HAMA scores, The integrity of structure and function of the endothe- which suggests that as the HAMA scores increase, the lium is essential to maintain a functional cerebral auto- phase difference values, i.e., dCA, tend to decrease. In regulation [30–33]. However, in patients with GAD, addition, the negative correlation between phase differ- both the structure and function of the endothelium may ence values and HAMD scale suggests a potential be damaged due to oxidative stress, which is another impact of depressive symptoms on phase difference characteristic of GAD [34–36]. In addition, CRP , values. This phenomenon deserves further study in TNF-α, and IL-17 [38, 39] are increased in patients with patients with major depressive disorder. The impairment GAD, indicating that the inflammatory process is acti- of dCA in patients with GAD indicates that cerebral vated and can induce endothelial cell dysfunction. vascular function is a therapeutic target of GAD. Thus, Furthermore, oxidative stress can alter the vascular methods to improve dCA may potentially relieve the smooth muscle tone, another indispensable mechanism in neurological symptoms in patients with GAD. regulating cerebral autoregulation, by changing reactive Both the studies from Ortega-Gutierrez and Yams sug- oxide species concentration (Fig. 1). gested that dCA remains intact in the elderly, though their As described above, the changes in neuroregulation, intracranial arteries may be affected by atherosclerosis [41, endothelial regulation, and myogenic response may 42]. In our study, we found age is a weak positive correl- collectively result in the impairment of dCA, leading to ation to phase difference; the causes are not clear. One unstable cerebral blood flow in patients with GAD. A possible reason is that the patients we included were rela- previous study by Kalk, et al. supports our findings . tively young, and the age span is relatively small. However, They found that patients with untreated GAD showed this explanation is inadequate. Guo et al. BMC Psychiatry (2018) 18:164 Page 6 of 7 This study has some limitations. The first is the gender Received: 18 September 2017 Accepted: 2 May 2018 mismatch of the GAD group and controls. Because gender affect cerebral blood flow via complex mechanisms , we References could not rule out the possible influence of sex on dCA. 1. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized However, it is worth mentioning that the regression anxiety disorder and panic disorder in adults. Am Fam Physician. analyses suggest no effect of gender in our study. Second, 2015;91:617–24. 2. Phillips MR, Zhang J, Shi Q, Song Z, Ding Z, Pang S, Li X, Zhang Y, Wang Z. we do not have the neuroendocrine results of our patients’ Prevalence, treatment, and associated disability of mental disorders in four blood to further support our results. 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Published: Jun 1, 2018