Immediate and long-term brain activation of acupuncture on ischemic stroke patients: an ALE meta-analysis of fMRI studies

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Immediate and long-term brain activation of acupuncture on ischemic stroke patients: an ALE meta-analysis of fMRI studies

Yuan Zhang^1,2,3Hai Lu⁴Xuesong Ren^1,3Junfeng Zhang^1,2,3Yu Wang⁵Chunhong Zhang^6*†Xiaofeng Zhao^1,3*†

• ¹Department of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
• ²Graduate College, Tianjin University of Traditional Chinese Medicine, Tianjin, China
• ³National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
• ⁴Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
• ⁵Department of Rehabilitation, Second Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
• ⁶Department of Acupuncture and Moxibustion, Baoan Pure Traditional Chinese Medicine Treatment Hospital, Shenzhen, China

Background: Acupuncture, as an alternative and complementary therapy recommended by the World Health Organization for stroke treatment(Really? Why?), holds potential in ameliorating neurofunctional deficits induced by ischemic stroke (IS). Understanding the immediate and long-term effects of acupuncture and their interrelation would contribute to a better comprehension of the mechanisms underlying acupuncture efficacy.

Methods: Activation likelihood estimation (ALE) meta-analysis was used to analyze the brain activation patterns reported in 21 relevant functional neuroimaging studies. Among these studies, 12 focused on the immediate brain activation and 9 on the long-term activation. Single dataset analysis were employed to identify both immediate and long-term brain activation of acupuncture treatment in IS patients, while contrast and conjunction analysis were utilized to explore distinctions and connections between the two.

Results: According to the ALE analysis, immediately after acupuncture treatment, IS patients exhibited an enhanced cluster centered around the right precuneus (PCUN) and a reduced cluster centered on the left middle frontal gyrus (MFG). After long-term acupuncture treatment, IS patients showed an enhanced cluster in the left PCUN, along with two reduced clusters in the right insula (INS) and hippocampus (HIP), respectively. Additionally, in comparison to long-term acupuncture treatment, the right angular gyrus (ANG) demonstrated higher ALE scores immediately after acupuncture, whereas long-term acupuncture resulted in higher scores in the left superior parietal gyrus (SPG). The intersecting cluster activated by both of them was located in the left cuneus (CUN).

Conclusion: The findings provide initial insights into both the immediate and long-term brain activation patterns of acupuncture treatment for IS, as well as the intricate interplay between them. Both immediate and long-term acupuncture treatments showed distinct patterns of brain activation, with the left CUN emerging as a crucial regulatory region in their association.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42023480834.

1 Introduction

Ischemic stroke (IS), a critical subtype of stroke, stands out as a primary neurovascular factor contributing significantly to both mortality and disability (Feske, 2021). It is distinguished by specific disruptions in the blood circulation of the brain, leading to tissue damage and neurological impairment. Current statistics indicate that globally, over 77 million individuals have experienced IS, with an annual increase of approximately 7.6 million new cases (Feigin et al., 2022). Alarmingly, this number continues to rise, and considering the substantial long-term risk of recurrence, all these factors impose an immense burden on both global healthcare systems and societies at large (Ding et al., 2022; Fan et al., 2023). The current treatment approaches for IS encompass vascular reperfusion therapies, such as intravenous thrombolysis or mechanical thrombectomy, secondary prevention strategies involving antiplatelet drugs, anticoagulants, and statins, along with post-stroke care and rehabilitation interventions (Herpich and Rincon, 2020; Hasan et al., 2021). Despite notable progress in reducing the occurrence of stroke-related complications and mortality rates, certain limitations persist. For instance, the treatment window for thrombolytic drugs is relatively narrow and strictly regulated (Saini et al., 2021). Additionally, factors such as age and comorbidities significantly contribute to variations in rehabilitation outcomes (Stinear et al., 2020). Overcoming these limitations and exploring targeted prevention and intervention strategies is necessary for advancing IS research, as well as the pursuit of innovative therapies.

Acupuncture is a traditional Chinese medicine technique that regulates the flow of qi and restores the balance of yin and yang by inserting fine needles into specific acupoints on the human body, and is characterized by its simplicity, convenience, and cost-effectiveness (Kaptchuk, 2002). For 1,000 of years, acupuncture has been used to treat various diseases and disorders, including stroke (Huang et al., 2021). Both clinical and experimental evidence suggest that acupuncture holds significant potential in improving neurological deficits induced by IS, especially for the sequelae of stroke, making acupuncture an increasingly promising intervention for stroke patients (Zhang et al., 2014; Yang et al., 2016; Zhong et al., 2022). However, the mechanism of acupuncture in improving IS is not clear yet. The modulation of neuroplasticity by acupuncture may be the key factor for its effectiveness (Chavez et al., 2017). Current researches show that acupuncture can modulate neuroplasticity in the central nervous system (CNS) by altering neural structure and function (Zhang et al., 2021). This neuroplasticity manifests as immediate functional changes and prolonged structural and functional alterations. During acupuncture, the body undergoes acute physiological responses, which may, in turn, stimulate processes such as neural generation, synaptic sprouting, and regeneration. These processes, in combination, promote the growth of new neurons and facilitate the brain’s self-reorganization through the formation of new neural connections, then lead to lasting changes in the neural circuits related to sensation, movement, cognition, and more (Qin et al., 2022; Mu et al., 2023).

However, previous meta-analyses have primarily focused on the long-term effects of acupuncture on IS, investigating alterations in brain activity or connectivity following regular acupuncture sessions. Interestingly, in our clinical practice, we have observed immediate symptom improvement in patients following acupuncture, a viewpoint supported by some studies (Du et al., 2016; Wang H. Q. et al., 2018). The immediate effect of acupuncture may play an important role in its efficacy, with its correlation to long-term effectiveness extending beyond cumulative effects. Currently, there is limited research in these aspects. A comprehensive understanding of both immediate and long-term effects of acupuncture, and their interaction, is essential for a better comprehension of the mechanisms underlying acupuncture efficacy. This knowledge is instrumental in optimizing acupuncture interventions in clinical settings and tailoring treatment plans to address diverse aspects of post-stroke recovery.

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that measures changes in blood oxygen level-dependent (BOLD) signals within the brain (Logothetis, 2008). As a primary tool in human neuroimaging research, fMRI offers a unique opportunity to reveal the neural processes underlying acupuncture modulation of brain regions and networks, thereby expanding our comprehension of the neural mechanisms involved in brain reorganization post-acupuncture (He et al., 2015). However, the heterogeneity of fMRI research results is a common challenge due to factors such as a limited number of subjects and variations in experimental procedures. To precisely elucidate the cerebral responses of acupuncture treatment for IS, it is imperative to integrate existing studies and conduct a comprehensive analysis of their results. Among the various techniques available, activation likelihood estimation (ALE) stands out as the most commonly used coordinate-based meta-analysis approach in neuroimaging data synthesis (Wager et al., 2007). ALE treats reported activation foci from different studies as spatial probability distributions centered around specific coordinates (Eickhoff et al., 2012). By calculating the joint probability of activation at each voxel, ALE maps integrate information about the location of brain activation across diverse studies (Eickhoff et al., 2012). In this study, we employed the ALE method to perform an integrative analysis of fMRI studies on acupuncture treatment for IS, aiming to obtain more reliable results than those found in single-study reports.

We have gathered previous fMRI studies on acupuncture treatment for IS and extracted the reported coordinate information. Specifically, we have divided the coordinates into two datasets, one dataset containing activated coordinates of brain regions immediately after acupuncture in IS patients, and the other containing activated coordinates after acupuncture treatment for one or several courses. By performing a series of ALE meta-analyses on the two datasets, we aim to further explore the immediate and long-term brain activation patterns of acupuncture treatment for IS and investigate the relationship between them. This exploration aims to provide novel insights into the neural mechanisms of acupuncture for IS from a macro perspective, thereby offering valuable considerations for designing and optimizing acupuncture treatment plans for future patients.

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