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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.

Yiting Huang,1,2 Siyi Yu,2 Georgia Wilson,2 Joel Park,2 Ming Cheng,2 Xuejun Kong,3 Tao Lu,1 Jian Kong2 1School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Martino Imaging Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Tao LuSchool of Life Sciences, Beijing University of Chinese Medicine, No. 11 East Road, North 3rd Ring Road, Beijing, 100029, People’s Republic of ChinaEmail taolu@bucm.edu.cnJian KongDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 120 2nd Ave, Room 101C, Charlestown, MA, 02129, USAEmail jkong2@mgh.harvard.eduIntroduction: Previous studies have suggested that cerebral projections of the norepinephrine (NE) and dopamine (DA) systems have important etiology and treatment implications for autism spectrum disorder (ASD).Methods: We used functional magnetic resonance imaging to evaluate spontaneous resting state functional connectivity in boys aged 7– 15 years with ASD (n=86) and age-, intelligence quotient-matched typically developing boys (TD, n=118). Specifically, we investigated functional connectivity of the locus coeruleus (LC) and ventral tegmental area (VTA), the main source projection of neurotransmitters NE and DA, respectively.Results: 1) Both the LC and VTA showed reduced connectivity with the postcentral gyrus (PoCG) in boys with ASD, reflecting the potential roles of NE and DA in modulating the function of the somatosensory cortex in boys with ASD. 2) The VTA had increased connectivity with bilateral thalamus in ASD; this alteration was correlated with repetitive and restrictive features. 3) Altered functional connectivity of both the LC and VTA with brain regions such as the angular gyrus (AG), middle temporal gyrus visual area (MT/V5), and occipital face area (OFA) in ASD group.Discussion: Our findings implicate the role of LC-NE and VTA-DA systems from the perspective of functional neuroimaging and may shed light on pharmacological studies targeting NE and DA for the treatment of autism in the future.Keywords: autism spectrum disorder, locus coeruleus, ventral tegmental area, norepinephrine, dopamine, functional connectivity

Metabolic acidosis is a severe complication of chronic kidney disease (CKD) which is associated with nefarious impairments such as bone demineralization, muscle wasting, and hormonal alterations, for example, insulin resistance. Whilst it is possible to control this condition with alkali treatment, consisting in the oral administration of sodium citrate or sodium bicarbonate, this type of intervention is not free from side effects. On the contrary, opting for the implementation of a targeted dietetic-nutritional treatment for the control of CKD metabolic acidosis also comes with a range of additional benefits such as lipid profile control, increased vitamins, and antioxidants intake. In our review, we evaluated the main dietary-nutritional regimens useful to counteract metabolic acidosis, such as the Mediterranean diet, the alkaline diet, the low-protein diet, and the vegan low-protein diet, analyzing the potentialities and limits of every dietary-nutritional treatment. Literature data suggest that the Mediterranean and alkaline diets represent a valid nutritional approach in the prevention and correction of metabolic acidosis in CKD early stages, while the low-protein diet and the vegan low-protein diet are more effective in CKD advanced stages. In conclusion, we propose that tailored nutritional approaches should represent a valid therapeutic alternative to counteract metabolic acidosis.

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.

Background Previous studies have found widespread pain processing alterations in the brain in chronic low back pain (cLBP) patients. We aimed to (1) identify brain regions showing altered amplitude of low-frequency fluctuations (ALFF) using MRI and use these regions to discriminate cLBP patients from healthy controls (HCs) and (2) identify brain regions that are sensitive to cLBP pain intensity changes. Methods We compared ALFF differences by MRI between cLBP subjects (90) and HCs (74), conducted a discriminative analysis to validate the results, and explored structural changes in key brain regions of cLBP. We also compared ALFF changes in cLBP patients after pain-exacerbating manoeuvres. Results ALFF was increased in the post-/precentral gyrus (PoG/PrG), paracentral lobule (PCL)/supplementary motor area (SMA), and anterior cingulate cortex (ACC), and grey matter volume was increased in the left ACC in cLBP patients. PCL/SMA ALFF reliably discriminated cLBP patients from HCs in an independent cohort. cLBP patients showed increased ALFF in the insula, amygdala, hippocampal/parahippocampal gyrus, and thalamus and decreased ALFF in the default mode network (DMN) when their spontaneous low back pain intensity increased after the pain-exacerbating manoeuvre. Conclusions Brain low-frequency oscillations in the PCL, SMA, PoG, PrG, and ACC may be associated with the neuropathology of cLBP. Low-frequency oscillations in the insula, amygdala, hippocampal/parahippocampal gyrus, thalamus, and DMN are sensitive to manoeuvre-induced spontaneous back pain intensity changes.

ObjectiveTo investigate the dynamic functional connectivity of thalamocortical networks in interictal migraine patients and whether clinical features are associated with abnormal connectivity.MethodsWe 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.ResultsFive 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.ConclusionOur results demonstrated a transient pathologic state with atypical thalamocortical connectivity in migraineurs and extended current findings regarding abnormal thalamocortical networks and dysrhythmia in migraine.

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.

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.

Depression is a highly prevalent disorder with unsatisfactory treatment options. Recently, transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated great potential in the treatment of depression. In this chapter, we first summarize the results of clinical studies on the treatment effect of taVNS on depression. Then, we pose several hypotheses on the mechanism of taVNS treatment of depression, including modulating the activity and connectivity of key brain regions involved in depression and mood regulation, inflammation, hippocampal neurogenesis, and the microbiome-brain-gut axis. Finally, we outline current challenges and future directions of taVNS treatment of depression.

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.

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

There is an urgent need for safe and effective approaches to combat COVID-19. Here, we asked whether lessons learned from nanotoxicology and nanomedicine could shed light on the current pandemic. SARS-CoV-2, the causative agent, may trigger a mild, self-limiting disease with respiratory symptoms, but patients may also succumb to a life-threatening systemic disease. The host response to the virus is equally complex and studies are now beginning to unravel the immunological correlates of COVID-19. Nanotechnology can be applied for the delivery of antiviral drugs or other repurposed drugs. Moreover, recent work has shown that synthetic nanoparticles wrapped with host-derived cellular membranes may prevent virus infection. We posit that nanoparticles decorated with ACE2, the receptor for SARS-CoV-2, could be exploited as decoys to intercept the virus before it infects cells in the respiratory tract. However, close attention should be paid to biocompatibility before such nano-decoys are deployed in the clinic.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics., Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

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.

Background and Aims The diabetic foot (DF) was traditionally considered a local foot problem due to diabetes; however many observations support the concept that the DF is actually a part of a more complex diabetes related syndrome which includes several long-term complications and co-morbidities. In recent years, an increase in the incidence of ischemic diabetic foot ulcers (DFUs) amongst dialyzed subjects has been observed, going up from approximately 5-10% fifteen years ago to the current rate of approximately 30-35%. Today it is well recognized that end stage renal disease (ESRD) is an independent risk factor for non-healing ulcers and amputation in diabetic subjects. In clinical practice, the presence of foot problems in ESRD diabetic patients is identified as a specific entity termed “renal-diabetic foot”. The aim of this study is to describe the angiographic characteristics of peripheral arterial disease (PAD) in patients with DFUs receiving chronic dialysis treatment. Method The study group was composed of patients with DFUs and PAD who referred to our diabetic foot unit. All patients have been managed with a pre-set limb salvage protocol including revascularization of the affected limb. Arterial lesions (stenosis between 50-99% and occlusions) were retrospectively evaluated through angiogram analysis. According to the presence of dialytic treatment, patients were divided in two subgroups: renal-diabetic foot (RDF) and diabetic foot (DF). Patterns of PAD and immediate revascularization outcome (technical revascularization outcome) for RDF and DF were separately reported and compared Results The demographic and clinical characteristics were reported in Table 1.RDF reported greater number of affected vessels (n= 5±1.6 vs 3.9±1.5, p Conclusion It was interesting to highlight that the above mentioned findings could be specifically related to the effect of renal disease on the arteries of the lower extremity because the two groups, RDF and DF, did not report any difference in terms of other traditional cardiovascular risk factors (age, smoke, arterial hypertension, dyslipidemia, diabetes duration) which could influence the characteristics of PAD. RDF patients showed a widespread distribution of arterial lesions with a higher involvement of foot arteries in comparison to DF subjects. BTA arterial disease is an independent predictor of revascularization failure.

Objective: Many noninvasive brain stimulation techniques have been applied to treat depressive disorders. However, the target brain region in most noninvasive brain stimulation studies is the dorsolateral prefrontal cortex. Exploring new stimulation locations may improve the efficacy of noninvasive brain stimulation for depressive disorders. We aimed to explore potential noninvasive brain stimulation locations for depressive disorders through a meta-analysis and a functional connectivity approach. Methods: We conducted a meta-analysis of 395 functional magnetic resonance imaging studies to identify depressive disorder–associated brain regions as regions of interest. Then, we ran resting-state functional connectivity analysis with three different pipelines in 40 depression patients to find brain surface regions correlated with these regions of interest. The 10–20 system coordinates corresponding to these brain surface regions were considered as potential locations for noninvasive brain stimulation. Results: The 10–20 system coordinates corresponding to the bilateral dorsolateral prefrontal cortex, bilateral inferior frontal gyrus, medial prefrontal cortex, supplementary motor area, bilateral supramarginal gyrus, bilateral primary motor cortex, bilateral operculum, left angular gyrus and right middle temporal gyrus were identified as potential locations for noninvasive brain stimulation in depressive disorders. The coordinates were: posterior to F3, posterior to F4, superior to F3, posterior to F7, anterior to C4, P3, midpoint of F7–T3, posterior to F8, anterior to C3, midpoint of Fz–Cz, midpoint of Fz–Fp1, anterior to T4, midpoint of C3–P3, and anterior to C4. Conclusion: Our study identified several potential noninvasive brain stimulation locations for depressive disorders, which may serve as a basis for future clinical investigations.

Objectives Noninvasive brain stimulation (NIBS) is an emerging tool for treating autism spectrum disorder (ASD). Exploring new stimulation targets may improve the efficacy of NIBS for ASD. Materials and Methods We first conducted a meta-analysis on 170 functional magnetic resonance imaging studies to identify ASD-associated brain regions. We then performed resting state functional connectivity analysis on 70 individuals with ASD to investigate brain surface regions correlated with these ASD-associated regions and identify potential NIBS targets for ASD. Results We found that the medial prefrontal cortex, angular gyrus, dorsal lateral prefrontal cortex, inferior frontal gyrus, superior parietal lobe, postcentral gyrus, precentral gyrus, middle temporal gyrus, superior temporal sulcus, lateral occipital cortex, and supplementary motor area/paracentral gyrus are potential locations for NIBS in ASD. Conclusion Our findings may shed light on the development of new NIBS targets for ASD.

Background: This study aims to investigate the resting state functional connectivity (rsFC) changes of the hypothalamus in Fibromyalgia patients and the modulation effect of effective treatments. Methods: Fibromyalgia patients and matched healthy controls (HC’s) were recruited. Resting state fMRI data were collected from fibromyalgia patients before and after a 12-week Tai Chi intervention and once from HC’s. Results: Data analysis showed that fibromyalgia patients displayed significantly decreased medial hypothalamus (MH) rsFC with the thalamus and amygdala when compared to HC’s at baseline. After the intervention, fibromyalgia patients showed increased (normalized) MH rsFC in the thalamus and amygdala. Effective connectivity analysis showed disrupted MH and thalamus interaction in fibromyalgia, which nonetheless could be partially restored by Tai Chi. Conclusions: Elucidating the role of the diencephalon and limbic system in the pathophysiology and development of fibromyalgia may facilitate the development of new treatment methods for this prevalent disorder. Trial registration: Trial registration ClinicalTrials.gov Identifier: NCT02407665. Registered 3 April 2015 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02407665

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.

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.

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 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 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. Keywords: Chronic low back pain, Acupuncture, Resting-state functional connectivity, Machine learning analysis, Treatment responses