Daily Caffeine Consumption Does Not Influence Acupuncture Analgesia in Healthy Individuals: A Preliminary Study.

Animal studies suggest that caffeine may interfere with acupuncture analgesia. This study investigated the modulation effect of daily caffeine intake on acupuncture analgesia in 27 healthy subjects using a crossover design. We found that real acupuncture increased pain thresholds compared to sham acupuncture. Further, there was no association between caffeine intake measurements of daily caffeine use, duration of caffeine consumption, or their interaction and preacupuncture and postacupuncture pain threshold changes. Our findings suggest that daily caffeine intake may not influence acupuncture analgesia in the cohort of healthy subjects who participated in study.

Acupuncture Treatment Modulates the Connectivity of Key Regions of the Descending Pain Modulation and Reward Systems in Patients with Chronic Low Back Pain.

Chronic low back pain (cLBP) is a common disorder with unsatisfactory treatment options. Acupuncture has emerged as a promising method for treating cLBP. However, the mechanism underlying acupuncture remains unclear. In this study, we investigated the modulation effects of acupuncture on resting state functional connectivity (rsFC) of the periaqueductal gray (PAG) and ventral tegmental area (VTA) in patients with cLBP. Seventy-nine cLBP patients were recruited and assigned to four weeks of real or sham acupuncture. Resting state functional magnetic resonance imaging data were collected before the first and after the last treatment. Fifty patients completed the study. We found remission of pain bothersomeness in all treatment groups after four weeks, with greater pain relief after real acupuncture compared to sham acupuncture. We also found that real acupuncture can increase VTA/PAG rsFC with the amygdala, and the increased rsFC was associated with decreased pain bothersomeness scores. Baseline PAG-amygdala rsFC could predict four-week treatment response. Our results suggest that acupuncture may simultaneously modulate the rsFC of key regions in the descending pain modulation (PAG) and reward systems (VTA), and the amygdala may be a key node linking the two systems to produce antinociceptive effects. Our findings highlight the potential of acupuncture for chronic low back pain management.

Dao Yin (a.k.a. Qigong): Origin, Development, Potential Mechanisms, and Clinical Applications.

Dao Yin is a form of exercise combining physical movements, mental focus, and breathing originated in ancient China. In this review, we introduce the history in the development and the scope of Dao Yin, the relationship between Dao Yin with Taoist culture and Qigong, and the potential mechanisms of how Dao Yin promotes health and alleviate illnesses. Empirical research studies using Dao Yin for treatment of lumbar spondylosis, peripheral musculoskeletal diseases, cervical spondylosis, heart diseases, central nervous system disorders, immunological dysfunction, and psychological disorders are detailed.

Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: An fMRI study.

BACKGROUND: Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine. METHODS: Twenty-nine patients with migraine were recruited from outpatient neurology clinics. Each patient attended two magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) scan sessions separated by one week. Each session included a pre-stimulation resting state fMRI scan, fMRI scans during real or sham 1 Hz taVNS (with block design), and a post-stimulation resting state fMRI scan. RESULTS: Twenty-six patients were included in the final analyses. Real taVNS evoked fMRI signal decreases in brain areas belonging to the default mode network (DMN) and brain stem areas including the locus coeruleus (LC), raphe nuclei, parabrachial nucleus, and solitary nucleus. Sham taVNS evoked fMRI signal decreases in brain areas belonging to the DMN. Compared to sham taVNS, real taVNS produced greater deactivation at the bilateral LC. Resting state functional connectivity (rsFC) analysis showed that after taVNS, LC rsFC with the right temporoparietal junction and left secondary somatosensory cortex (S2) significantly increased compared to sham taVNS. The increased rsFC of the left LC-left S2 was significantly negatively associated with the frequency of migraine attacks during the preceding month. CONCLUSION: Our results suggest that taVNS at 1 Hz can significantly modulate activity/connectivity of brain regions associated with the vagus nerve central pathway and pain modulation system, which may shed light on the neural mechanisms underlying taVNS treatment of migraine.

Different exercise modalities relieve pain syndrome in patients with knee osteoarthritis and modulate the dorsolateral prefrontal cortex: A multiple mode MRI study.

OBJECTIVES: Knee osteoarthritis (KOA) is a common degenerative joint disease with no satisfactory intervention. Recently, both physical and mindfulness exercises have received considerable attention for their implications in KOA pain management, and the dorsolateral prefrontal cortex (DLPFC) has displayed a critical role in pain modulation. This study aimed to comparatively investigate the modulation effects of different exercises using multidisciplinary measurements. METHODS: 140 KOA patients were randomized into Tai Chi, Baduanjin, stationary cycling, or health education control groups for 12 weeks. Knee Injury and Osteoarthritis Outcome Score (KOOS), resting state functional magnetic resonance imaging (fMRI), structural MRI, and serum biomarkers were measured at baseline and at the end of the study. RESULTS: We found: 1) increased KOOS pain subscores (pain reduction) and serum programmed cell death protein 1 (PD-1) levels in the three exercise groups compared to the control group; 2) decreased resting state functional connectivity (rsFC) of the DLPFC-supplementary motor area (SMA) and increased rsFC between the DLPFC and anterior cingulate cortex in all exercise groups compared to the control group; 3) significant associations between DLPFC-SMA rsFC with KOOS pain subscores and serum PD-1 levels at baseline; 4) significantly increased grey matter volume in the SMA in the Tai Chi and stationary cycling groups, and a trend toward significant increase in the Baduanjin group compared to the control group; 5) significant DLPFC rsFC differences among different exercise groups; and 6) that baseline DLPFC-SMA rsFC can predict the effect of mind-body exercise on pain improvement in KOA. CONCLUSION: Our results suggest that different exercises can modulate both common and unique DLPFC (cognitive control) pathways, and altered DLPFC-SMA rsFC is associated with serum biomarker levels. Our findings also highlight the potentials of neuroimaging biomarkers in predicting the therapeutic effect of mind-body exercises on KOA pain.

Modulatory effects of different exercise modalities on the functional connectivity of the periaqueductal grey and ventral tegmental area in patients with knee osteoarthritis: a randomised multimodal magnetic resonance imaging study.

BACKGROUND: Knee osteoarthritis is a prevalent disorder with unsatisfactory treatment options. Both physical and mindful exercises may be able to relieve its pain symptoms. We compared the modulatory effects of different exercise modalities on the periaqueductal grey (PAG) and ventral tegmental area (VTA), which play important roles in descending opioidergic pathways and reward/motivation systems in patients with knee osteoarthritis. METHODS: We recruited and randomised 140 patients into Tai Chi, Baduanjin, stationary cycling, and health education control groups for 12 weeks. Knee injury and Osteoarthritis Outcome Score (KOOS), functional and structural MRI, and blood biomarkers were measured at the beginning and end of the experiment. We used the PAG and VTA as seeds in resting-state functional connectivity (rsFC) analysis. RESULTS: Compared with the control group: (i) all exercises significantly increased KOOS pain sub-scores (pain reduction) and serum programmed death 1 (PD-1) concentrations; (ii) all exercises decreased right PAG rsFC with the medial orbital prefrontal cortex, and the decreased rsFC was associated with improvements in knee pain; and (iii) grey matter volume in the medial orbital prefrontal cortex was significantly increased in all exercise groups. There was also significantly decreased rsFC between the left VTA and the medial orbital prefrontal cortex in the Tai Chi and Baduanjin groups. CONCLUSIONS: Exercise can simultaneously modulate the rsFC of the descending opioidergic pathway and reward/motivation system and blood inflammation markers. Elucidating the shared and unique mechanisms of different exercise modalities may facilitate the development of exercise-based interventions for chronic pain. CLINICAL TRIAL REGISTRATION: ChiCTR-IOR-16009308.

Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain.

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ±â€¯12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ±â€¯13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources.

Mind-body exercise improves cognitive function and modulates the function and structure of the hippocampus and anterior cingulate cortex in patients with mild cognitive impairment.

Mild cognitive impairment (MCI) is a common neurological disorder. This study aims to investigate the modulation effect of Baduanjin (a popular mind-body exercise) on MCI. 69 patients were randomized to Baduanjin, brisk walking, or an education control group for 24 weeks. The Montreal Cognitive Assessment (MoCA) and Magnetic Resonance Imaging scans were applied at baseline and at the end of the experiment. Compared to the brisk walking and control groups, the Baduanjin group experienced significantly increased MoCA scores. Amplitude of low-frequency fluctuations (ALFF) analysis showed significantly decreased ALFF values in the right hippocampus (classic low-freqency band, 0.01-0.08 Hz) in the Baduanjin group compared to the brisk walking group and increased ALFF values in the bilateral anterior cingulate cortex (ACC, slow-5 band, 0.01-0.027 Hz) in the Baduanjin group compared to the control group. Further, ALFF value changes in the right hippocampus and bilateral ACC were significantly associated with corresponding MoCA score changes across all groups. We also found increased gray matter volume in the Baduanjin group in the right hippocampus compared to the brisk walking group and in the bilateral ACC compared to the control group. In addition, there was an increased resting state functional connectivity between the hippocampus and right angular gyrus in the Baduanjin group compared to the control group. Our results demonstrate the potential of Baduanjin for the treatment of MCI.

Abnormal thalamocortical network dynamics in migraine.

OBJECTIVE: To investigate the dynamic functional connectivity of thalamocortical networks in interictal migraine patients and whether clinical features are associated with abnormal connectivity. METHODS: We investigated dynamic functional network connectivity (dFNC) of the migraine brain in 89 interictal migraine patients and 70 healthy controls. We focused on the temporal properties of thalamocortical connectivity using sliding window cross-correlation, clustering state analysis, and graph-theory methods. Relationships between clinical symptoms and abnormal dFNC were evaluated using a multivariate linear regression model. RESULTS: Five dFNC brain states were identified to characterize and compare dynamic functional connectivity patterns. We demonstrated that migraineurs spent more time in a strongly interconnected between-network state, but they spent less time in a sparsely connected state. Interestingly, we found that abnormal posterior thalamus (pulvinar nucleus) dFNC with the visual cortex and the precuneus were significantly correlated with headache frequency of migraine. Further topologic measures revealed that migraineurs had significantly lower efficiency of information transfer in both global and local dFNC. CONCLUSION: Our results demonstrated a transient pathologic state with atypical thalamocortical connectivity in migraineurs and extended current findings regarding abnormal thalamocortical networks and dysrhythmia in migraine.

Treating Depression With Tai Chi: State of the Art and Future Perspectives.

Major depressive disorder (MDD) is one of the most prevalent mental illnesses in America. Current treatments for MDD are unsatisfactory given high non-response rates, high relapse rates, and undesirable side effects. Accumulating evidence suggests that Tai Chi, a popular mind-body intervention that originated as a martial art, can significantly regulate emotion and relieve the symptoms of mood disorders. In addition, the availability of instructional videos and the development of more simplified and less structured Tai Chi has made it a promising low-intensity mind-body exercise. In this article, we first examine a number of clinical trials that implemented Tai Chi as a treatment for depression. Then, we explore several mechanisms by which Tai Chi may alleviate depressive symptoms, hypothesizing that the intervention may modulate the activity and connectivity of key brain regions involved in mood regulation, reduce neuro-inflammatory sensitization, modulate the autonomic nervous system, and regulate hippocampal neurogenesis. Finally, we discuss common challenges of the intervention and possible ways to address them. Specifically, we pose developing a simplified and tailored Tai Chi protocol for patients with depression, comparatively investigating Tai Chi with other mind-body interventions such as yoga and Baduanjin, and developing new mind-body interventions that merge the advantages of multiple mind-body exercises.

Non-pharmacological and pharmacological interventions relieve insomnia symptoms by modulating a shared network: A controlled longitudinal study.

BACKGROUND: Primary insomnia (PI) is one of the most common complaints among the general population. Both non-pharmacological and pharmacological therapies have proven effective in treating primary insomnia. However, the underlying mechanism of treatment remains unclear, and no studies have compared the underlying mechanisms of different treatments. METHODS: In this study, we investigated gray matter volume (GMV) and resting-state functional connectivity (rsFC) changes following both pharmacological and non-pharmacological treatments in patients with PI. A total of 67 PI patients were randomized into benzodiazepine treatment, cupping treatment, or a wait-list control group for 4 weeks. The Pittsburgh Sleep Quality Index (PSQI), gray matter volume (GMV), and resting-state functional connectivity (rsFC) of the hippocampus were measured at the beginning and end of the experiment. RESULTS: We found 1) significantly decreased PSQI scores in the cupping and benzodiazepine treatment groups compared to the control group with no significant differences between the two treatment groups; 2) significant GMV increases in the cupping group compared to the control group at the right hippocampus after 4 weeks of treatment; 3) significantly increased rsFC between the right hippocampus and left rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) in the two treatment groups, which was significantly associated with PSQI score decreases. DISCUSSION: Our findings suggest that benzodiazepine and cupping may share a common mechanism to relieve the symptoms of patients with PI.

Different modulation effects of Tai Chi Chuan and Baduanjin on resting-state functional connectivity of the default mode network in older adults.

The default mode network (DMN) plays an important role in age-related cognitive decline. This study aims to explore the modulation effect of two mind-body interventions (Tai Chi Chuan and Baduanjin) on DMN in elderly individuals. Participants between 50 and 70 years old were recruited and randomized into a Tai Chi Chuan, Baduanjin or control group. The Wechsler Memory Scale-Chinese Revision and resting-state fMRI scans were administered at baseline and following 12 weeks of exercise. Seed-based resting-state functional connectivity (rsFC) was calculated. We found that (i) compared to the Baduanjin group, Tai Chi Chuan was significantly associated with increased rsFC between the medial prefrontal cortex (mPFC) and right putamen/caudate and (ii) compared to the control group, Tai Chi Chuan increased posterior cingulate cortex rsFC with the right putamen/caudate, while Baduanjin decreased rsFC between the mPFC and orbital prefrontal gyrus/putamen. Baseline mPFC rsFC with orbital prefrontal gyrus was negatively correlated with visual reproduction subscore. These results suggest that both Tai Chi Chuan and Baduanjin can modulate the DMN, but through different pathways. Elucidating the mechanisms underlying different mind-body interventions may shed light on the development of new methods to prevent age-related diseases as well as other disorders associated with disrupted DMN.

Analgesic Effects Evoked by Real and Imagined Acupuncture: A Neuroimaging Study.

Acupuncture can provide therapeutic analgesic benefits but is limited by its cost and scheduling difficulties. Guided imagery is a commonly used method for treating many disorders, such as chronic pain. The present study examined a novel intervention for pain relief that integrates acupuncture with imagery called video-guided acupuncture imagery treatment (VGAIT). A total of 27 healthy subjects were recruited for a crossover-design study that included 5 sessions administered in a randomized order (i.e., baseline and 4 different interventions). We investigated changes in pain threshold and fMRI signals modulated by: 1) VGAIT, watching a video of acupuncture previously administered on the participant's own body at baseline while imagining it being concurrently applied; 2) a VGAIT control condition, watching a video of a cotton swab touching the skin; 3) real acupuncture; and 4) sham acupuncture. Results demonstrated that real acupuncture and VGAIT significantly increased pain threshold compared with respective control groups. Imaging showed that real acupuncture produced greater activation of the insula compared with VGAIT. VGAIT produced greater deactivation at the rostral anterior cingulate cortex. Our findings demonstrate that VGAIT holds potential clinical value for pain management.

A Double-Blind Study on Acupuncture Sensations with Japanese Style of Acupuncture: Comparison between Penetrating and Placebo Needles.

To investigate the acupuncture sensations elicited by the Japanese style of acupuncture, penetrating acupuncture and skin-touch placebo needles were randomly administered at various insertion depths (5 and 10 mm for the penetrating needles and 1 and 2 mm for the placebo needles) at LI4 to 50 healthy subjects. Among the 12 acupuncture sensations in the Massachusetts General Hospital Acupuncture Sensation Scale (MASS), "heaviness" was the strongest and most frequently reported sensation with the 10 mm needles, but not with the 5 mm needles. There were no significant differences in number of sensations elicited, MASS index, range of spreading, and intensity of needle pain for 5 mm penetration versus 1 mm skin press and 10 mm penetration versus 2 mm skin press. The MASS index with 2 mm skin-touch needles was significantly larger than that with 1 mm skin-touch and 5 mm penetrating needles. The factor structures in the 12 acupuncture sensations between penetrating and skin-touch needles were different. The acupuncture sensations obtained in this study under satisfactorily performed double-blind (practitioner-patient) conditions suggest that a slight difference in insertion depth and skin press causes significant differences in quantity and quality of acupuncture sensations.

Frequency-dependent functional connectivity of the nucleus accumbens during continuous transcutaneous vagus nerve stimulation in major depressive disorder.

Transcutaneous vagus nerve stimulation (tVNS) may be a promising treatment for major depressive disorder (MDD). In this exploratory study, fMRI scans were acquired during continuous real or sham tVNS from 41 MDD patients. Then, all patients received real or sham tVNS treatment for four weeks. We investigated the functional connectivity (FC) of the nucleus accumbens (NAc) at different frequency bands during real and sham tVNS and explored their associations with depressive symptom changes after one month of treatment. The results revealed: 1) significant positive FCs between the NAc and surrounding areas including the putamen, caudate, and distinct areas of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) during continuous real and sham tVNS; 2) compared with sham tVNS, real tVNS increased the FC between the left NAc and bilateral MPFC/rACC in the slow-5 band (0.008-0.027) and between the right NAc and left insula, occipital gyrus, and right lingual/fusiform gyrum in the typical low band (0.008-0.09); and 3) the FC of the NAc-MPFC/rACC during real tVNS showed a negative association with Hamilton Depression Rating Scale (HAMD) score changes in the real tVNS group after one month of treatment, but not in the sham group. Our findings demonstrate that tVNS can modulate low frequency intrinsic FC among key brain regions involved in reward and motivation processing and provide insights into the brain mechanism underlying tVNS treatment of MDD.

A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder.

BACKGROUND: Major depression is the fourth leading cause of disability worldwide and poses a socioeconomic burden worldwide. Transcutaneous vagus nerve stimulation (tVNS) is a promising noninvasive clinical device that may reduce the severity of major depression. However, the neural mechanism underlying continuous tVNS has not yet been elucidated. OBJECTIVE: We aimed to explore the effect of hypothalamic subregion functional connectivity (FC) changes during continuous tVNS treatment on major depressive disorder (MDD) patients and to identify the potential biomarkers for treatment outcomes. METHODS: Forty-one mild to moderate MDD patients were recruited and received either real or sham tVNS treatment for 4 weeks. We used a seed-to-whole brain approach to estimate the FC changes of hypothalamic subregions and their surrounding control areas during continuous tVNS treatment and explored their association with clinical outcome changes after 4 weeks of treatment. RESULTS: Of the thirty-six patients that completed the study, those in the tVNS group had significantly lower scores on the 24-item Hamilton Depression (HAM-D) Rating Scale compared to the sham tVNS group after 4 weeks of treatment. The FC between the bilateral medial hypothalamus (MH) and rostral anterior cingulate cortex (rACC) was significantly decreased during tVNS but not during sham tVNS. The strength of this FC was significantly correlated with HAM-D improvements after 4 weeks of tVNS. CONCLUSION: The FC between the bilateral MH and rACC may serve as a potential biomarker for the tVNS state and predict treatment responses. Our results provide insights into the neural modulation mechanisms of continuous tVNS and reveal a potential therapeutic target for MDD patients.

Repeated acupuncture treatments modulate amygdala resting state functional connectivity of depressive patients.

As a widely-applied alternative therapy, acupuncture is gaining popularity in Western society. One challenge that remains, however, is incorporating it into mainstream medicine. One solution is to combine acupuncture with other conventional, mainstream treatments. In this study, we investigated the combination effect of acupuncture and the antidepressant fluoxetine, as well as its underlying mechanism using resting state functional connectivity (rsFC) in patients with major depressive disorders. Forty-six female depressed patients were randomized into a verum acupuncture plus fluoxetine or a sham acupuncture plus fluoxetine group for eight weeks. Resting-state fMRI data was collected before the first and last treatments. Results showed that compared with those in the sham acupuncture treatment, verum acupuncture treatment patients showed 1) greater clinical improvement as indicated by Montgomery-Åsberg Depression Rating Scale (MADRS) and Self-Rating Depression Scale (SDS) scores; 2) increased rsFC between the left amygdala and subgenual anterior cingulate cortex (sgACC)/preguenual anterior cingulate cortex (pgACC); 3) increased rsFC between the right amygdala and left parahippocampus (Para)/putamen (Pu). The strength of the amygdala-sgACC/pgACC rsFC was positively associated with corresponding clinical improvement (as indicated by a negative correlation with MADRS and SDS scores). Our findings demonstrate the additive effect of acupuncture to antidepressant treatment and suggest that this effect may be achieved through the limbic system, especially the amygdala and the ACC.

Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression.

BACKGROUND: The amygdala is a key region in emotion processing, and studies have suggested that amygdala-frontal functional connectivity deficits could be modulated by antidepressants in major depressive disorder (MDD). Transcutaneous vagus nerve stimulation (tVNS), a non-invasive, peripheral neuromodulation method at the ear, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism underlying tVNS treatment of depression has not been fully investigated. In this study, we investigated how tVNS can modulate the amygdala-lateral prefrontal network resting state functional connectivity (rsFC) in mild or moderate major depressive disorder (MDD) patients. METHODS: Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments for four weeks. Resting state fMRI scans were applied before and after treatments. RESULTS: After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale (HAMD) scores were reduced significantly in the tVNS group as compared with the sham tVNS group. The rsFC in the tVNS group between the right amygdala and left dorsolateral prefrontal cortex was increased compared with sham tVNS. All the rsFC increases were also associated with HAMD reduction as well as reductions in the anxiety and retardation HAMD subscales. CONCLUSIONS: tVNS can significantly modulate the amygdala-lateral prefrontal rsFC of MDD patients; our results provide insights into the brain mechanism of tVNS treatment for MDD patients.