Abnormal Anatomical and Functional Connectivity of the Thalamo-sensorimotor Circuit in Chronic Low Back Pain: Resting-state Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging Study.

Thalamocortical dysfunction is thought to underlie the pathophysiology of chronic pain revealed by electroencephalographic studies. The thalamus serves as a primary relay center to transmit sensory information and motor impulses via dense connections with the somatosensory and motor cortex. In this study, diffusion tensor imaging (DTI) (probabilistic tractography) and resting-state functional magnetic resonance imaging (functional connectivity) were used to characterize the anatomical and functional integrity of the thalamo-sensorimotor pathway in chronic low back pain (cLBP). Fifty-four patients with cLBP and 54 healthy controls were included. The results suggested significantly increased anatomical connectivity of the left thalamo-motor pathway characterized by probabilistic tractography in patients with cLBP. Moreover, there was significantly altered resting-state functional connectivity (rsFC) of bilateral thalamo-motor/somatosensory pathways in patients with cLBP as compared to healthy controls. We also detected a significant correlation between pain intensity during the MRI scan and rsFC of the right thalamo-somatosensory pathway in cLBP. Our findings highlight the involvement of the thalamo-sensorimotor circuit in the pathophysiology of cLBP.

Modulatory Effects of Actual and Imagined Acupuncture on the Functional Connectivity of the Periaqueductal Gray and Ventral Tegmental Area.

OBJECTIVE: Both acupuncture and guided imagery hold promise for treating pain. The mechanisms underlying these alternative interventions remain unclear. The reported study aimed to comparatively investigate the modulation effect of actual and imagined acupuncture on the functional connectivity of descending pain modulation system and reward network. METHODS: Twenty-four healthy participants (mean [standard error], 25.21 [0.77] years of age; 66.67% female) completed a crossover study that included five sessions, a training session and four intervention sessions administered in randomized order. We investigated the modulation effect of real acupuncture, sham acupuncture, video-guided acupuncture imagery treatment (VGAIT) and VGAIT control on the resting-state functional connectivity (rsFC) of periaqueductal gray (PAG) and ventral tegmental area (VTA). These are key regions of the descending pain modulatory system and dopaminergic reward system, respectively. RESULTS: Compared with sham acupuncture, real acupuncture produced decreased PAG-precuneus (Pcu) rsFC and increased VTA-amygdala/hippocampus rsFC. Heat pain threshold changes applied on the contralateral forearm were significantly associated with the decreased PAG-Pcu (r = 0.49, p = .016) and increased VTA-hippocampus rsFC (r = -0.77, p < .001). Compared with VGAIT control, VGAIT produced decreased PAG-paracentral lobule/posterior cingulate cortex/Pcu, middle cingulate cortex (MCC), and medial prefrontal cortex rsFC, and decreased VTA-caudate and MCC rsFC. Direct comparison between real acupuncture and VGAIT showed that VGAIT decreased rsFC in PAG-paracentral lobule/MCC, VTA-caudate/anterior cingulate cortex/nucleus accumbens, and VTA-MCC. CONCLUSIONS: Results suggest that both actual and imagined acupuncture can modulate key regions in the descending pain modulatory system and reward networks, but through different pathways. Identification of different pain relief mechanisms may facilitate the development of new pain management methods.

Altered functional connectivity between hypothalamus and limbic system in fibromyalgia.

The hypothalamus links the nervous system to the endocrine system and plays a crucial role in maintaining the human body's homeostasis. This study aims to investigate the resting state functional connectivity (rsFC) changes of the hypothalamus in fibromyalgia patients. 24 Fibromyalgia patients and 24 matched healthy controls (HCs) were recruited. Resting state fMRI data were collected from the fibromyalgia patients and HC's. Fibromyalgia patients went through a second scan after 12 weeks of Tai Chi mind-body intervention. Data analysis showed that fibromyalgia patients displayed less medial hypothalamus (MH) rsFC with the thalamus and amygdala when compared to the functional connectivity in the HCs. After the Tai Chi mind-body intervention, fibromyalgia patients showed increased MH rsFC with the thalamus and amygdala accompanied by clinical improvement. Effective connectivity analysis showed disrupted MH and thalamus interaction in the fibromyalgia patients, which was altered by mind-body exercise. Our findings suggest that fibromyalgia is associated with altered functional connectivity within the diencephalon and limbic system. Elucidating the roles of the diencephalon and limbic system in the pathophysiology and development of fibromyalgia may facilitate the development of a new biomarker and effective treatment methods for this prevalent disorder.Trial Registration ClinicalTrials.gov, NCT02407665. Registered: 3 April 2015, https://clinicaltrials.gov/ct2/show/NCT02407665?term=NCT02407665&draw=2&rank=1.

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.

Imagined and Actual Acupuncture Effects on Chronic Low Back Pain: A Preliminary Study.

Background: Research suggests that imagined experiences can produce brain responses similar to those produced by actual experiences. Shared brain responses that support both imagination and perception may underlie the functional nature of mental imagery. In a previous study, we combined acupuncture and imagery to develop a new treatment method, video-guided acupuncture imagery treatment (VGAIT). We found that VGAIT significantly increased pain thresholds in healthy subjects. The aim of this study is to extend our previous finding by investigating whether VGAIT can relieve symptoms in patients with chronic low back pain. Methods: We first performed a single-arm study in which we administered video-guided acupuncture imagery treatment (VGAIT) on patients with chronic low back pain (cLBP) (Study 1, n = 18, 12 females). We then compared our findings to those from a recently published study in which real or sham acupuncture treatment was applied on patients with cLBP (Study 2, n = 50, 31 females) using a similar protocol. All patients in Studies 1 and 2 received 6 treatments over 4 weeks. Results: All three treatments (VGAIT, real, and sham acupuncture) significantly reduced pain severity as measured by a low back pain bothersomeness score. VGAIT produced similar effects to real acupuncture (p = 0.97) and nonsignificantly greater pain bothersomeness relief compared to sham acupuncture (p = 0.14). Additional analysis showed that there was no significant difference on the sensations evoked by different treatment modalities. Conclusion: These findings support VGAIT as a promising method for pain management.

Characterizing the analgesic effects of real and imagined acupuncture using functional and structure MRI.

Acupuncture and imagery interventions for pain management have a long history. The present study comparatively investigated whether acupuncture and video-guided acupuncture imagery treatment (VGAIT, watching a video of acupuncture on the participant's own body while imagining it being applied) could modulate brain regional connectivity to produce analgesic effects. The study also examined whether pre-intervention brain functional and structural features could be used to predict the magnitude of analgesic effects. Twenty-four healthy participants were recruited and received four different interventions (real acupuncture, sham acupuncture, VGAIT, and VGAIT control) in random order using a cross-over design. Pain thresholds and magnetic resonance imaging (MRI) data were collected before and after each intervention. We first compared the modulatory effects of real acupuncture and VGAIT on intra- and inter-regional intrinsic brain connectivity and found that real acupuncture decreased regional homogeneity (ReHo) and functional connectivity (FC) in sensorimotor areas, whereas VGAIT increased ReHo in basal ganglia (BG) (i.e., putamen) and FC between the BG subcortical network and default mode network. The altered ReHo and FC were associated with changes in pain threshold after real acupuncture and VGAIT, respectively. A multimodality fusion approach with pre-intervention ReHo and gray matter volume (GMV) as features was used to explore the brain profiles underlying individual variability of pain threshold changes by real acupuncture and VGAIT. Variability in acupuncture responses was associated with ReHo and GMV in BG, whereas VGAIT responses were associated with ReHo and GMV in the anterior insula. These results suggest that, through different pathways, both real acupuncture and VGAIT can modulate brain systems to produce analgesic effects.

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.

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.

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.

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.

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.