Anomalous neurovascular coupling in patients with generalized anxiety disorder evaluated by combining cerebral blood flow and functional connectivity strength

https://doi.org/10.1016/j.pnpbp.2021.110379Get rights and content

Highlights

  • This study investigated neurovascular coupling in patients with GAD using multimodal MRI information.

  • Patients with GAD showed global neurovascular decoupling.

  • The increased local neurovascular coupling in the SPG was inversely correlated with decreased self-esteem in GAD.

  • The aberrant neurovascular coupling provide new insights into the brain dysfunction and abnormal cognition of GAD.

Abstract

Coupling between neuronal activity and blood perfusion is termed neurovascular coupling, and it provides a new mechanistic perspective into understanding numerous brain diseases. Although abnormal brain activity and blood supply have been separately reported in generalized anxiety disorder (GAD), whether anomalous neurovascular coupling would still be presented in such disease is hitherto unknown. In this study, the neuronal activity and blood supply were measured using the functional connectivity strength (FCS) and cerebral blood flow (CBF). The voxel-wise CBF–FCS correlations and CBF/FCS ratio were separately used to assess global and local neurovascular coupling in participants. Patients with GAD showed decreased voxel-wise CBF–FCS correlation, implicating global neurovascular decoupling. They also exhibited increased CBF/FCS ratio in the right superior parietal gyrus (SPG), and the enhanced CBF/FCS ratio in this region was negatively correlated with the self-esteem scores of GAD. The abnormal neurovascular coupling of GAD may indicate the disrupted balance between the intrinsic functional organization of the brain and corresponding blood perfusion of patients, and the abnormally increased local neurovascular coupling of the right SPG may be correlated with the abnormal self in GAD. These findings provide new information in understanding the brain dysfunction and abnormal cognition of GAD from the perspective of neurovascular coupling.

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)

  • C.-M. Moon et al.

    Explicit verbal memory impairments associated with brain functional deficits and morphological alterations in patients with generalized anxiety disorder

    J. Affect. Disord.

    (2015)
  • K. Murphy et al.

    The impact of global signal regression on resting state correlations: are anti-correlated networks introduced?

    Neuroimage.

    (2009)
  • A. Nalci et al.

    Global signal regression acts as a temporal downweighting process in resting-state fMRI

    Neuroimage.

    (2017)
  • G. Northoff et al.

    Self-referential processing in our brain - a meta-analysis of imaging studies on the self

    Neuroimage.

    (2006)
  • J.D. Power et al.

    Methods to detect, characterize, and remove motion artifact in resting state fMRI

    Neuroimage.

    (2014)
  • M. Rosenberg

    The association between self-esteem and anxiety

    J. Psychiatr. Res.

    (1962)
  • M. Sild et al.

    Major depressive disorder and anxiety disorders from the glial perspective: etiological mechanisms, intervention and monitoring

    Neurosci. Biobehav. Rev.

    (2017)
  • A.B.P. Staring et al.

    Self-esteem treatment in anxiety: a randomized controlled crossover trial of Eye Movement Desensitization and Reprocessing (EMDR) versus Competitive Memory Training (COMET) in patients with anxiety disorders

    Behav. Res. Ther.

    (2016)
  • J.R. Strawn et al.

    Neurostructural abnormalities in pediatric anxiety disorders

    J. Anxiety Disord.

    (2015)
  • C.M. Sylvester et al.

    Functional network dysfunction in anxiety and anxiety disorders

    Trends Neurosci.

    (2012)
  • X. Wang et al.

    Disrupted resting-state functional connectivity in minimally treated chronic schizophrenia

    Schizophr. Res.

    (2014)
  • W. Wang et al.

    Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging

    Neurosci. Lett.

    (2016)
  • J. Xu et al.

    Anxious brain networks: a coordinate-based activation likelihood estimation meta-analysis of resting-state functional connectivity studies in anxiety

    Neurosci. Biobehav. Rev.

    (2019)
  • B. Zhang et al.

    Abnormal brain functional connectivity coupled with hypoperfusion measured by resting-state fMRI: an additional contributing factor for cognitive impairment in patients with Alzheimer’s disease

    Psychiatry Res. Neuroimaging

    (2019)
  • C. Andreescu et al.

    Altered cerebral blood flow patterns associated with pathologic worry in the elderly

    Depress. Anxiety

    (2011)
  • K.M. Aquino et al.

    Identifying and removing widespread signal deflections from fMRI data: rethinking the global signal regression problem

    Neuroimage.

    (2020)
  • T.M. Ball et al.

    Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders

    Psychol. Med.

    (2013)
  • G. Caliskan et al.

    Hippocampal network oscillations at the interplay between innate anxiety and learned fear

    Psychopharmacology.

    (2019)
  • A.C. Chen et al.

    Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder

    Neuropsychopharmacology.

    (2013)
  • Y. Chen et al.

    Progressive brain structural alterations assessed via causal analysis in patients with generalized anxiety disorder

    Neuropsychopharmacology

    (2020)
  • H. Cui et al.

    Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder

    Hum. Brain Mapp.

    (2016)
  • Q. Cui et al.

    Disrupted dynamic local brain functional connectivity patterns in generalized anxiety disorder

    Progress Neuro-Psychopharmacol. Biol. Psychiatry

    (2020)
  • Q. Cui et al.

    Dynamic changes of amplitude of low-frequency fluctuations in patients with generalized anxiety disorder

    Hum. Brain Mapp.

    (2020)
  • J. DeMartini et al.

    Generalized anxiety disorder

    Ann. Intern. Med.

    (2019)
  • Cited by (0)

    View full text