Anomalous neurovascular coupling in patients with generalized anxiety disorder evaluated by combining cerebral blood flow and functional connectivity strength
Introduction
Generalized anxiety disorder (GAD) is one of the most common anxiety disorders with persistent, excessive, and uncontrollable worry and accompanied by a number of somatic symptoms, such as feelings of threat, restlessness, muscle tension, sleep disturbance, and difficulty of concentration (DeMartini et al., 2019). GAD patients are characterized by negative self-perceptions such as low self-esteem (Henning et al., 2007), which is a possible etiological or contributory factor in anxiety (Robson, 1988). Reciprocal causality between low self-esteem and anxiety has been revealed by longitudinal studies (Sowislo and Orth, 2013), and self-esteem treatment was proved to be efficient for improving anxiety symptoms (Staring et al., 2016). Although the neural basis of GAD is still complex and vague till now, the neuroimaging findings of abnormal brain structure and function, especially those observed by using magnetic resonance imaging (MRI), have provided important information in understanding this disease.
Neuroanatomical alterations in the prefrontal–temporal network (Moon et al., 2015; Schienle et al., 2011; Strawn et al., 2015; Strawn et al., 2013), limbic system (Moon et al., 2015; Schienle et al., 2011), and portions of the parietal (Strawn et al., 2015; Strawn et al., 2013) and sensorimotor cortices (Strawn et al., 2013) are frequently reported in GAD during structural MRI analyses. Functional alterations of GAD are often reflected by task and resting-state functional MRI (rsfMRI). A previous review and a meta-analysis have identified network-based brain functioning and functional connectivity (FC) alterations across various anxiety disorders (Sylvester et al., 2012; Xu et al., 2019). Increased functioning in attention and salience networks and decreased functioning in executive control (ECN) and default mode (DMN) networks were observed in anxious individuals (Sylvester et al., 2012), accompanied by hypo-connectivity within and/or between these four networks (Xu et al., 2019). Among all changes, the attenuated prefrontal–subcortical FC coincides with the core findings of GAD (decreased prefrontal–amygdala FC) (Makovac et al., 2016a; Makovac et al., 2016b). The prefrontal–limbic hypo-connectivity is associated with cognitive and emotional dysregulation in GAD (Ball et al., 2013; Mochcoyitch et al., 2014) and plays an essential role in trait anxiety prediction (Wang et al., 2021b). Additionally, some specific network abnormalities were also found in GAD: increased FC within the limbic network; increased FC between the visual cortex (Cui et al., 2016), temporal lobe (Li et al., 2016; Liu et al., 2016), striatum (Liu et al., 2016), and limbic network; increased FC between the ECN and visual cortex (Wang et al., 2016); and decreased FC between the limbic and salience network (Chen and Etkin, 2013).
In recent years, cerebral blood flow (CBF) has received much attention in brain function-related studies due to its close relationships with normal brain function, brain metabolism, and brain connectivity (Liang et al., 2013; Zhu et al., 2017), which may provide considerable physiological information of the brain. CBF is defined as the amount of blood that passes through a fixed volume (100 g) per minute (Fantini et al., 2016) and quantified using noninvasive arterial spin labeling (ASL) MRI. Few studies have investigated CBF changes in GAD. A previous study reported that relative to the resting state, GAD patients exhibited increased CBF in the posterior associative temporo-occipital areas when they processed worry-inducing sentences, whereas no significant group differences were observed between patients and controls (Andreescu et al., 2011). Intriguingly, between-group differences in CBF at the inferior parietal lobule and the post- and precentral gyrus were found during worry induction in another study (Karim et al., 2017). Additionally, when patients were instructed to suppress their worry by reappraisal, aberrant CBF was identified in the striatum, prefrontal cortex (PFC), middle anterior cingulate cortex (ACC), and sensorimotor areas in GAD (Karim et al., 2017). Thus, better understanding of altered CBF in GAD may provide essential information about the complex blend of emotion and cognition in this disease.
Many studies on GAD mentioned above are based on unimodal MRI analysis. However, multimodal MRI is broadly used in numerous healthy and psychiatric samples due to its noninvasive nature and the possibility of providing much comprehensive information of the brain. Intriguingly, several studies have combined resting-state blood‑oxygen-level-dependent (BOLD) and ASL MRI to investigate neurovascular coupling in normal state and diseases. Neurovascular coupling is a useful marker reflecting the temporal and spatial relationships between blood supply and neural activity, which are important for brain health (Iadecola, 2017). Liang and colleagues have proved the tight coupling between CBF and FC strength (FCS) in the normal brain, where regions with high connectivity degree exhibited high CBF (Liang et al., 2013), supporting the neurovascular coupling hypothesis that dense FC tends to be accompanied by increasing blood perfusion (Zhu et al., 2017). Altered coupling between CBF and FC has been observed in healthy aging (Galiano et al., 2020) and several diseases such as schizophrenia (Zhu et al., 2017), primary open angle glaucoma (Wang et al., 2021a), and Wilson's disease (Hu et al., 2019). FC changes based on CBF fluctuations have been found in pontine infarction disease (Wei et al., 2020), attention-deficit/hyperactivity disorder (Tan et al., 2020), and Alzheimer's disease (Zhang et al., 2019). The abnormal neurovascular coupling was found to correlate with the clinical and cognitive impairments of aging and abovementioned illnesses, offering considerable pathophysiological information for the degeneration and dysfunction of the brain. Despite the reported alterations in CBF and FC in GAD patients, the potential CBF–FC coupling effects on GAD remain elusive.
In the present study, we used a previously proposed approach (Liang et al., 2013) to investigate the neurovascular coupling in GAD patients. Blood perfusion was measured on the basis of CBF, and brain activity was assessed by FCS. The voxel-wise CBF and FCS correlation was performed to characterize the global neurovascular coupling, and the CBF/FCS ratio was employed to measure the local neurovascular coupling. In light of the widespread abnormalities in FC and CBF in GAD and the promising findings of neurovascular coupling in other psychiatric and neurological diseases, we expected that patients with GAD will also show abnormal neurovascular coupling, and such abnormalities can improve our understanding of the neuropathological mechanisms of GAD.
Section snippets
Participants
Fifty-seven patients with GAD were recruited from the Clinical Hospital of Chengdu Brain Science Institute, University of Electronic Science and Technology of China (UESTC). The patients were interviewed by two experienced psychiatrists on the basis of the Structured Clinical Interview for DSM-IV-TR-Patient Edition (SCID-P, 2/2001 revision). They were diagnosed according to the DSM-IV criteria for GAD. The exclusion criteria included schizophrenia, personality disorder, substance abuse, and
Spatial distribution of CBF, FCS, and CBF/FCS ratio
In this study, the spatial distribution maps of CBF, FCS, and CBF/FCS ratio in HC and GAD groups are presented in Fig. 1. The distributions in the HC group were similar to those observed in the GAD group. The regions with high CBF values were mainly found in the widespread area of the cortical and subcortical brain regions, including the medial PFC (MPFC) and lateral PFC, ACC, posterior cingulate cortex, lateral parietal cortex, lateral temporal cortex, sensorimotor cortex, visual cortex,
Discussion
This study investigated the alterations in neurovascular coupling in patients with GAD by combining resting-state BOLD and ASL MRI. Our primary results showed that the global neurovascular coupling was decreased in GAD, whereas the local neurovascular coupling was increased in the right SPG in GAD. The increased local neurovascular coupling was correlated with the decline of self-esteem in patients with GAD. Uncovering the anomalies in correlations between blood supply and functional brain
Conclusion
The combination of CBF and FCS was exploited for mapping abnormal neurovascular coupling in patients with GAD in the current study. Specifically, patients with GAD exhibited reduced global neurovascular coupling, which was reflected by decreased voxel-wise CBF–FCS correlation. Furthermore, patients with GAD showed regional neurovascular coupling changes in the right SPG, and the altered CBF/FCS ratio in this region was correlated with the abnormal self-esteem of patients. These findings may
Authors contributions
Yuyan Chen, Qian Cui, and Huafu Chen designed the study, and Yuyan Chen wrote the paper. Wei Sheng, Qin Tang, Xiaoyu Nan, Di Li, and Ting Lei collected the data of participants, in which Wei Sheng and Qin Tang also analysed the data. Yajing Pang, Zongling He, and Fengmei Lu revised the manuscript. The final manuscript was approved by all authors.
Ethical statement
The study was approved by the research ethical committee of the University of Electronic Science and Technology of China and also complied with the latest revision of the Declaration of Helsinki and registered at Clinical-Trials.gov (Registration Number: NCT02888509). Additionally, written informed consents were obtained from patients and HC before experimentation.
Declaration of Competing Interest
The authors declared no potential conflicts of interest.
Acknowledgments
This study was supported by the Key Project of Research and Development of Ministry of Science and Technology (2018AAA0100705), the Natural Science Foundation of China (U1808204, 62036003, 81771919, 62006038), and the Fundamental Research Funds for the Central Universities (ZYG2020K005-3).
References (68)
- et al.
Riluzole effect on occipital cortex: a structural and spectroscopy pilot study
Neurosci. Lett.
(2012) - et al.
A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD
Eur. Neuropsychopharmacol.
(2013) The role of physiological noise in resting-state functional connectivity
Neuroimage.
(2012)- et al.
Temporal profile of brain response to alprazolam in patients with generalized anxiety disorder
Psychiatry Res. Neuroimaging
(2015) - et al.
Abnormal dynamic functional connectivity density in patients with generalized anxiety disorder
J. Affect. Disord.
(2020) - et al.
Altered resting-state cerebral blood flow and functional connectivity of striatum in bipolar disorder and major depressive disorder
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2019) - et al.
Striatal cerebral blood flow, executive functioning, and fronto-striatal functional connectivity in clinical high risk for psychosis
Schizophr. Res.
(2018) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease
Neuron.
(2017)- et al.
Aberrant functional connectivity between the amygdala and the temporal pole in drug-free generalized anxiety disorder
Front. Hum. Neurosci.
(2016) - et al.
Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder
Biol. Psychiatry
(2016)