Alterations in cortical thickness of frontoparietal regions in patients with social anxiety disorder.

Although functional changes of the frontal and (para)limbic area for emotional hyper-reactivity and emotional dysregulation are well documented in social anxiety disorder (SAD), prior studies on structural changes have shown mixed results. This study aimed to identify differences in cortical thickness between SAD and healthy controls (CON). Thirty-five patients with SAD and forty-two matched CON underwent structural magnetic resonance imaging. A vertex-based whole brain and regional analyses were conducted for between-group comparison. The whole-brain analysis revealed increased cortical thickness in the left insula, left superior parietal lobule, left superior temporal gyrus, and left frontopolar cortex in patients with SAD compared to CON, as well as decreased thickness in the left superior/middle frontal gyrus and left fusiform gyrus in patients (after multiple-correction). The results from the ROI analysis did not align with these findings at the statistically significant level after multiple corrections. Changes in cortical thickness were not correlated with social anxiety symptoms. While consistent results were not obtained from different analysis methods, the results from the whole-brain analysis suggest that patients with SAD exhibit distinct neural deficits in areas involved in salience, attention, and socioemotional processing.

Investigation of daily patterns for smartphone keystroke dynamics based on loneliness and social isolation.

This study examined the relationship between loneliness levels and daily patterns of mobile keystroke dynamics in healthy individuals. Sixty-six young healthy Koreans participated in the experiment. Over five weeks, the participants used a custom Android keyboard. We divided the participants into four groups based on their level of loneliness (no loneliness, moderate loneliness, severe loneliness, and very severe loneliness). The very severe loneliness group demonstrated significantly higher typing counts during sleep time than the other three groups (one-way ANOVA, F = 3.75, p < 0.05). In addition, the average cosine similarity value of weekday and weekend typing patterns in the very severe loneliness group was higher than that in the no loneliness group (Welch's t-test, t = 2.27, p < 0.05). This meant that the no loneliness group's weekday and weekend typing patterns varied, whereas the very severe loneliness group's weekday and weekend typing patterns did not. Our results indicated that individuals with very high levels of loneliness tended to use mobile keyboards during late-night hours and did not significantly change their smartphone usage behavior between weekdays and weekends. These findings suggest that mobile keystroke dynamics have the potential to be used for the early detection of loneliness and the development of targeted interventions.

Association of executive function with suicidality based on resting-state functional connectivity in young adults with subthreshold depression.

Subthreshold depression (StD) is associated an increased risk of developing major depressive disorder (MDD) and suicidality. Suicidality could be linked to distress intolerance and use of context-dependent strategies. We identified neural correlates of executive functioning among the hubs in the resting-state functional connectome (rs-FCN) and examined associations with recent suicidality in StD and MDD. In total, 79 young adults [27 StD, 30 MDD, and 23 healthy controls (HC)] were scanned using magnetic resonance imaging. Neurocognitive measures of the mean latency to correct five moves in the One Touch Stockings of Cambridge (OTSMLC5), spatial working memory between errors (SWMBE), rapid visual information processing A' (RVPA'), and the stop signal reaction time in the stop signal test (SSTSSRT) were obtained. Global graph metrics were calculated to measure the network integration, segregation, and their balance in the rs-FCN. Regional graph metrics reflecting the number of neighbors (degree centrality; DC), participation in the shortcuts (betweenness centrality; BC), and accessibility to intersections (eigenvector centrality; EC) in the rs-FCN defined group-level hubs for StD, HC, and MDD, separately. Global network metrics were comparable among the groups (all P > 0.05). Among the group-level hubs, regional graph metrics of left dorsal anterior insula (dAI), right dorsomedial prefrontal cortex (dmPFC), right rostral temporal thalamus, right precuneus, and left postcentral/middle temporal/anterior subgenual cingulate cortices were different among the groups. Further, significant associations with neurocognitive measures were found in the right dmPFC with SWMBE, and left dAI with SSTSSRT and RVPA'. Shorter OTSMLC5 was related to the lower centralities of right thalamus and suffer of recent 1-year suicidal ideation (all Ps < 0.05 in ≥ 2 centralities out of DC, BC, and EC). Collectively, salience and thalamic networks underlie spatial strategy and planning, response inhibition, and suicidality in StD and MDD. Anti-suicidal therapies targeting executive function and modulation of salience-thalamic network in StD and MDD are required.

Central metabolites and peripheral parameters associated neuroinflammation in fibromyalgia patients: A preliminary study.

To identify central metabolites and peripheral measures associated with neuroinflammation in fibromyalgia (FM), we scanned [11C]-(R)-PK11195 positron emission tomography and magnetic resonance spectroscopy in FM patients. We measured associations between neurometabolite levels measured by magnetic resonance spectroscopy and the extent of neuroinflammation inferred by the distribution volume ratios of [11C]-(R)-PK11195 positron emission tomography in 12 FM patients and 13 healthy controls. We also examined the associations between peripheral parameters, such as creatinine and C-reactive protein, and neuroinflammation. In FM patients, we found negative correlations between neuroinflammation and the creatine (Cr)/total creatine (tCr; Cr + phosphocreatine) ratios in the right (r = -0.708, P = .015) and left thalamus (r = -0.718, P = .008). In FM patients, negative correlations were apparent between neuroinflammation and the glutamate/tCr ratio in the right insula (r = -0.746, P = .005). In FM patients, we found negative correlations between neuroinflammation in the left thalamus (r = -0.601, P = .039) and left insula (r = -0.598, P = .040) and the blood creatinine levels. Additionally, we found significant correlations of other peripheral measures with neuroinflammation in FM patients. Our results suggest that both central metabolites, such as Cr and glutamate, and peripheral creatinine and other parameters are associated with neuroinflammation in patients with FM.

Greater variability in daily sleep efficiency predicts depression and anxiety in young adults: Estimation of depression severity using the two-week sleep quality records of wearable devices.

Objectives: Sleep disturbances are associated with both the onset and progression of depressive disorders. It is important to capture day-to-day variability in sleep patterns; irregular sleep is associated with depressive symptoms. We used sleep efficiency, measured with wearable devices, as an objective indicator of daily sleep variability. Materials and methods: The total sample consists of 100 undergraduate and graduate students, 60% of whom were female. All were divided into three groups (with major depressive disorder, mild depressive symptoms, and controls). Self-report questionnaires were completed at the beginning of the experiment, and sleep efficiency data were collected daily for 2 weeks using wearable devices. We explored whether the mean value of sleep efficiency, and its variability, predicted the severity of depression using dynamic structural equation modeling. Results: More marked daily variability in sleep efficiency significantly predicted levels of depression and anxiety, as did the average person-level covariates (longer time in bed, poorer quality of life, lower extraversion, and higher neuroticism). Conclusion: Large swings in day-to-day sleep efficiency and certain clinical characteristics might be associated with depression severity in young adults.

Sex-specific bi­directional association between osteoporosis and depression from the national representative data of South Korea.

Both osteoporosis and depression are major health threats, but their interrelationship is not clear. This study elucidated the associations between osteoporosis and depression while considering the temporal sequence of the diagnoses. In this cross-sectional study, data were extracted from the Korean National Health and Nutrition Examination Surveys (2007-2009 and 2015-2019, n = 29,045). Osteoporosis and depression were defined by diagnoses thereof. The odds ratio (OR) of the incident osteoporosis among depression patients without a history of osteoporosis was calculated by multivariable logistic regression adjusted for potential confounders. A reverse association was also assessed. Participants were additionally stratified by their sex and age. As a result, male depression patients aged under 50 years showed higher ORs for osteoporosis than those without depression (OR 9.16, 95% CI 1.78-47.18). Female osteoporosis patients showed lower ORs for depression than those without osteoporosis (OR 0.71, 95% CI 0.58-0.88), especially in women aged 50 years and older. In the sensitivity analysis, the same results were obtained in women by their menopause status. Depression has a strong positive association with the occurrence of osteoporosis in young male adults, and osteoporosis has a negative association with the occurrence of depression in female adults.

Functional activation of insula and dorsal anterior cingulate for conflict control against larger monetary loss in young adults with subthreshold depression: a preliminary study.

Subthreshold depression (StD) is associated with higher risk of later developing major depressive disorder (MDD). Deficits of goal-directed behaviors regarding the motional, motivational, and conflict control are found in MDD. The current study examined neural underpinning of conflict control against monetary punishment in StD compared to MDD and healthy controls (HC). Seventy-one participants (HC, n = 27; StD, n = 21; MDD, n = 23) in their mid-20's completed self-reports. Preprocessing of functional magnetic resonance imaging acquired for the Simon task against larger or smaller monetary punishment was conducted using ENIGMA HALFpipe version 1.2.1. Neural correlates of conflict control against monetary punishment that could vary with either diagnosis or PHQ-9 total score were examined using a general linear model of FSL. Simon effect was effective for reaction time and accuracy in every subgroup of diagnosis and regardless of the size of monetary punishment. Conflict control against larger monetary loss was associated with higher functional activation of left insula in StD than HC and MDD. StD showed lower functional activation of left dorsal anterior cingulate (dACC) than MDD for conflict control against larger monetary loss. For conflict control against smaller monetary loss, StD demonstrated higher functional activation of left paracentral lobule and right putamen compared to HC. Directed acyclic graphs showed directional associations from suicidal ideation, sadness, and concentration difficulty to functional activation of paracentral lobule, ventromedial prefrontal cortex (vmPFC), and thalamus for conflict control against monetary loss. Differential functional activation of insula and dACC for conflict control against larger monetary loss could be a brain phenotype of StD. Item-level depressive symptoms of suicidal ideation, sadness, and concentration difficulty could be reflected in the conflict control-related functional activation of paracentral lobule (against smaller monetary loss), vmPFC and thalamus (against larger monetary loss), respectively.

The Effect of Postmigration Factors on Quality of Life among North Korean Refugees Living in South Korea.

North Korean refugees have not only endured traumatic experiences in North Korea and during defection but have also undergone an adaptation process after arrival in South Korea. Their quality of life (QoL) is likely to be affected by these traumatic life events, leading to subsequent posttraumatic stress disorder (PTSD), or postmigration adaptation-related stress, which involves a sense of dislocation with the culture, language, and people in South Korea. We investigated which aspects predicted the QoL of refugees from North Korea. Fifty-five participants currently living in South Korea completed a checklist about personal characteristics and traumatic experiences before, during and after migration. Diagnosis and symptom severity of PTSD, depressive mood, anxiety, and QoL were also assessed. A multiple regression analysis was performed to evaluate associations between QoL and other variables of interest. Overall, QoL was associated with previous economic status in North Korea, present occupation in South Korea, difficulty interacting with South Koreans, depressed mood, and state-trait anxiety. Finally, QoL was explained by having difficulty interacting with South Koreans, depressed mood, and state anxiety, with the model accounting for 51.3% of the variance. Our findings suggest that QoL among North Korean refugees in South Korea is influenced by the current level of their anxiety and depressed mood, and post-migration adaptation-related stress resulting from trying to integrate with South Koreans after settlement.

Neural Changes in Reward Processing Following Approach Avoidance Training for Depression.

Altered approach motivation is hypothesized to be critical for the maintenance of depression. Computer-administered approach-avoidance training programs to increase approach action tendencies toward positive stimuli produce beneficial outcomes. However, there have been few studies examining neural changes following approach-avoidance training. Participants with Major Depressive Disorder were randomized to an Approach Avoidance Training (AAT) manipulation intended to increase approach tendencies for positive social cues (n=13) or a control procedure (n=15). We examined changes in neural activation (primary outcome) and connectivity patterns using Group Iterative Multiple Model Estimation during a social reward anticipation task (exploratory). A laboratory-based social affiliation task was also administered following the manipulation to measure affect during anticipation of real-world social activity. Individuals in the AAT group demonstrated increased activation in reward processing regions during social reward anticipation relative to the control group from pre to post-training. Following training, connectivity patterns across reward regions were observed in the full sample and connectivity between the medial PFC and caudate was associated with anticipatory positive affect before the social interaction; preliminary evidence of differential connectivity patterns between the two groups also emerged. Results support models whereby modifying approach-oriented behavioral tendencies with computerized training leads to alterations in reward circuitry. (NCT02330744).

Dysfunctional energy metabolisms in fibromyalgia compared with healthy subjects.

This study aimed to investigate the levels of creatine (Cr) metabolites in the anterior cingulate cortex (ACC), thalamus, and insula of patients with fibromyalgia (FM) using proton magnetic resonance spectroscopy (MRS). The levels of Cr and phosphocreatine (PCr) relative to total Cr (tCr), which includes Cr and PCr, in the ACC, thalamus, and insula were determined using MRS in 12 patients with FM and in 13 healthy controls. The FM group had lower levels of PCr/tCr in the ACC and right insula compared to healthy controls. There was a negative correlation between Cr/tCr in the ACC and total pain levels (McGill Pain Questionnaire-Total; r = -0.579, p = 0.049) and between Cr/tCr in the left insula and affective pain levels (McGill Pain Questionnaire-Affective; r = -0.638, p = 0.047) in patients with FM. In addition, there were negative correlations between stress levels (Stress Response Inventory) and Cr/tCr in the right (r = -0.780, p = 0.005) and left thalamus (r = -0.740, p = 0.006), as well as in the right insula (r = -0.631, p = 0.028) in patients with FM. There were negative correlations between symptom levels of post-traumatic stress disorder (PTSD; PTSD checklist) and Cr/tCr in the right (r = -0.783, p = 0.004) and left thalamus (r = -0.642, p = 0.024) of patients with FM. These findings are paramount to understanding the decisive pathologies related to brain energy metabolism in patients with FM.

Impaired Performance in Mental Rotation of Hands and Feet and Its Association with Social Cognition in Patients with Complex Regional Pain Syndrome.

OBJECTIVES: So far, dysfunction in mental rotation has been assessed in relation to the left- or right-sided CRPS. Here we examined mental rotation in patients with upper or lower limb CRPS. Considering the potential role of socio-emotional functioning on the perception of body image, we further investigated the association between performance on mental rotation and socio-emotional characteristics. METHODS: We examined the performance of 36 patients with upper or lower limb CRPS on the limb laterality recognition. Accuracy and response times for pictures of hands and feet at 4 rotation angles were evaluated. Socio-emotional functioning was measured by the Interpersonal Reactivity Scale and the Toronto Alexithymia Scale. RESULTS: Patients with upper limb pain showed longer RTs to recognize the laterality of hands than feet (P = 0.002), whereas patients with lower limb pain showed longer RTs for feet than hands (P = 0.039). Exploratory correlation analyses revealed that RTs for feet were negatively correlated with the levels of empathic ability to take another's perspective (P = 0.006) and positively correlated with the level of emotional difficulty in identifying feelings (P = 0.006). CONCLUSIONS: This study is the first to report selectively impaired mental rotation of hands vs feet in patients with upper or lower limb CRPS. The findings suggest that impaired mental rotation derives from relative deficits in the representation of the affected limb. Correlations between impaired mental rotation and socio-emotional inability indicate that an altered body schema may be closely associated with impaired social cognitive aspects in CRPS patients.

Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET.

PURPOSE: Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain and neuroinflammation, which may contribute to the multifactorial pathological mechanisms in both FM and CRPS. The aim of this study was to assess neuroinflammation in FM patients compared with that in patients with CRPS and healthy controls. METHODS: Neuroinflammation was measured as the distribution volume ratio (DVR) of [11C]-(R)-PK11195 positron emission tomography (PET) in 12 FM patients, 11 patients with CRPS and 15 healthy controls. RESULTS: Neuroinflammation in FM patients was significantly higher in the left pre (primary motor cortex) and post (primary somatosensory cortex) central gyri (p < 0.001), right postcentral gyrus (p < 0.005), left superior parietal and superior frontal gyri (p < 0.005), left precuneus (p < 0.01), and left medial frontal gyrus (p = 0.036) compared with healthy controls. Furthermore, the DVR of [11C]-(R)-PK11195 in FM patients demonstrated decreased neuroinflammation in the medulla (p < 0.005), left superior temporal gyrus (p < 0.005), and left amygdala (p = 0.020) compared with healthy controls. CONCLUSIONS: To the authors' knowledge, this report is the first to describe abnormal neuroinflammation levels in the brains of FM patients compared with that in patients with CRPS using [11C]-(R)-PK11195 PET. The results suggested that abnormal neuroinflammation can be an important pathological factor in FM. In addition, the identification of common and different critical regions related to abnormal neuroinflammation in FM, compared with patients with CRPS and healthy controls, may contribute to improved diagnosis and the development of effective medical treatment for patients with FM.

Abnormal neurometabolites in fibromyalgia patients: Magnetic resonance spectroscopy study.

This study aimed to investigate distinct neurometabolites in the anterior cingulate cortex (ACC), right and left thalamus, and insula of patients with fibromyalgia (FM) compared with healthy controls using proton magnetic resonance spectroscopy (MRS). Levels of N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), total NAA (tNAA = NAA + NAAG), myo-inositol (ml), glutamine (Gln), glutamate (Glu), Glx (Glu + Gln), glycerophosphocholine (GPC), total choline (tCho = GPC + phosphocholine) and glutathione (GSH) levels relative to total creatine (tCr) levels including creatine (Cr) and phosphocreatine (PCr) and relative to Cr levels were determined in the ACC, right and left thalamus, and insula in 12 patients with FM and 13 healthy controls using MRS. In the ACC, NAA/tCr (P = 0.028) and tCho/tCr (P = 0.047) were higher in patients with FM. In the right and left insula, tNAA/tCr (P = 0.019, P = 0.007, respectively) was lower in patients with FM. Patients with FM showed lower levels of ml/Cr (P = 0.037) in the right insula than healthy controls. These findings are paramount to understand decisive pathophysiological mechanisms related to abnormal features in the brain and parasympathetic nervous systems in FM. We suggest that the results presented herein may be essential to understand hidden pathological mechanisms and also life system potential as protective and recovering metabolic strategies in patients with FM.

Long-term beneficial effects of an online mind-body training program on stress and psychological outcomes in female healthcare providers: A non-randomized controlled study.

Mind-body training (MBT) programs are effective interventions for relieving stress and improving psychological capabilities. To expand our previous study which demonstrated the short-term effects of an 8-week online MBT program, the present study investigated whether those short-term effects persist up to a month after the end of the intervention.Among previous participants, 56 (64%) participated in this follow-up study, 25 in the MBT group and 31 in the control group. Outcome measures included the stress response, emotional intelligence, resilience, coping strategies, positive and negative affect, and anger expression of both groups at baseline, at 8 weeks (right after the training or waiting period), and at 12 weeks (a month after the training or waiting period).The MBT group showed a greater decrease in stress response at 8 weeks, and this reduction remained a month after the end of the intervention. The effect of MBT on resilience and effective coping strategies was also significant at 8 weeks and remained constant a month later. However, the improvement to emotional intelligence and negative affect did not persist a month after training.These findings suggest that the beneficial short-term effects of MBT may last beyond the training period even without continuous practice, but the retention of these benefits seems to depend on the outcome variables. Through a convenient, affordable, and easily accessible online format, MBT may provide cost-effective solutions for employees at worksites.

Effects of Paliperidone Palmitate on Healthcare Utilization and Costs for Patients with Schizophrenia: A Claim-based Mirror-image Study in South Korea.

OBJECTIVE: Long-acting injectable (LAI) antipsychotics, such as paliperidone palmitate (PP), are known to improve treatment adherence in patients with schizophrenia, which can lead to reductions in relapse and hospitalization rates. However, relatively few studies have demonstrated the economic impact of LAIs, especially in Asian populations. METHODS: We conducted a claim-based mirror-image study to explore changes in healthcare utilization and associated costs, among 1,272 South Korean patients with schizophrenia (ICD-10-CM code F20), between the 1-year periods before and after the initiation of PP treatment. RESULTS: Patients accessed outpatient services more frequently after versus before starting PP treatment, with the number of prescription days increasing by 133.45 (p ＜ 0.0001) and the associated costs increasing by USD 1,497.15 (p ＜ 0.0001). The number of admission days was reduced by 11.33 after starting PP treatment (p ＜ 0.0001) and the associated costs were reduced by USD 1,220.75 (p ＜ 0.0001). However, admission cost savings were different according to patients' oral drug compliance. The daily dosages for benztropine, procyclidine, and propranolol decreased, showing that there were fewer side-effects after PP-treatment (p ＜ 0.0001). CONCLUSION: Although the high acquisition cost of PP has been regarded as an obstacle to its clinical use, our results imply that the high prescription costs for PP may be counterbalanced by the reduced admission costs associated with its use. Economic outcomes for patients treated with LAIs should be investigated further to help healthcare decision-makers and providers to determine the value of LAIs relative to other treatment medications.

Sex-Specific Differences in Severity of Depressive Symptoms, Heart Rate Variability, and Neurocognitive Profiles of Depressed Young Adults: Exploring Characteristics for Mild Depression.

Mild depressive symptoms (MDS) reflect vulnerability to major depression that does not meet the criteria for a major depressive disorder (MDD). Previous research indicates that it is difficult to identify MDS in young adults, and they exhibit diverse aspects of depressive symptoms caused by clinical depression, which can lead to poor academic performance, relationship difficulties, and even suicide. Additionally, many young adults remain unaware of their depressive symptoms during the early stages of MDD. Thus, the present study investigated clinical, neurocognitive, and physiological characteristics of young adults with various symptoms of depression and explored sex-specific differences. A total of 113 students aged 18-35 (MDD: n = 32; MDS: n =37; control [CON]: n = 44) participated in the study. Self-report clinical measures, short-term cardiac activity measured by finger sensors, and neurocognitive data were collected. Pearson's correlations, two-way analysis of variance (ANOVA), principal component analysis, and exploratory structural equation modeling were conducted for the statistical analyses. Furthermore, the measurement invariance of the latent factor model was tested, and fit indices were compared according to sex. The results revealed that male students showed greater sympatho-vagal activity than female students. Additionally, male MDS students tended to exhibit decreased performance levels in neurocognitive function tasks compared with MDD and CON males, whereas female MDS students showed distinct characteristics compared to MDD and CON females on self-report measures of anxiety. Correlation analyses identified a positive association between the level of anger perception and latency in the executive function test among both males and females. Additionally, the use of a structured model revealed significant sex-specific differences in factor estimates. The present results suggest that recognizing the early signs of MDS that account for sex-specific differences in both subjective and objective measures may improve the diagnosis and monitoring of young adults with MDS.

Publisher Correction: Frequency and Clinical Associating Factors of Valvular Heart Disease in Asymptomatic Korean Adults.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Commonalities and differences in abnormal peripheral metabolites between patients with fibromyalgia and complex regional pain syndrome.

Background: Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain that could contribute to multifactorial pathological mechanisms.Methods: We investigated peripheral metabolites in FM and CRPS patients compared to healthy controls based on cross-sectional study.Results: Mean corpuscular hemoglobin (p < 0.001), mean corpuscular volume (p = 0.014), and total bilirubin levels (p = 0.017) were lower in FM patients than in healthy controls. On the other hand, CRPS patients showed lower levels of total bilirubin than healthy controls (p = 0.037). Creatinine level was lower in FM patients (p = 0.057) compared to healthy controls, particularly when comparing the low-hemoglobin subgroup among FM patients (p = 0.035) with the low-hemoglobin subgroup among healthy controls. Red blood cell count (r = -0.620, p = 0.031), hematocrit (r = -0.593, p = 0.042), and creatinine level (r = -0.598, p = 0.040) showed negative correlations with McGill Pain Questionnaire-Affective (MPQ-A) scores in FM patients. A negative correlation was observed between MCV and McGill Pain Questionnaire-Sensory scores (r = -0.680, p = 0.015) in CRPS patients.Conclusion: We found specific peripheral metabolites that may exhibit different tendency between FM and CRPS patients as well as some common metabolites, which may be associated with peripheral pathology in the patients. Considering this study had a few limitations such as a small sample sizes and using a liberal threshold of significance in the correlation analysis, future studies with larger sample sizes may be needed to generalize these findings.

Disruption of Homeostasis Based on the Right and Left Hemisphere in Patients with Complex Regional Pain Syndrome.

OBJECTIVE: Although the clinical features and pathophysiology of complex regional pain syndrome (CRPS) have been studied in the peripheral and central nervous systems, few plausible pathological interactions are known among the metabolites in these systems. Thus, the purpose of this study was to investigate abnormal relationships and interactions between peripheral metabolites and central neurometabolites in patients with CRPS. METHODS: Various metabolites and molecules were measured in the peripheral blood, and central neurometabolites in the right and left thalamus using proton magnetic resonance spectroscopy in 12 patients with CRPS and 11 healthy controls. Interactions between peripheral metabolites in blood and central neurometabolites in the right and left thalamus were also investigated. RESULTS: The interactions between peripheral and central metabolites were different in the right and left hemispheres of healthy subjects, suggesting the presence of right hemisphere-dependent energy homeostasis and left hemisphere-dependent acid-base homeostasis that enables effective functioning. The interactions between central and peripheral metabolites in CRPS patients were distinct from those in healthy individuals, supporting the possibility of abnormal interactions and disrupted homeostasis between peripheral and central metabolites, which may result from neuroinflammation and immune system dysfunction. CONCLUSION: To the authors' knowledge, this is the first report describing abnormal metabolic dysfunction and disrupted homeostasis in interactions between metabolites of the peripheral and central nervous systems in CRPS. The approach used to uncover hidden pathophysiologies will improve understanding of how chronic pain can disrupt homeostasis in interactions between two systems and how alternative metabolites can be activated to recover and compensate for pathological dysfunctions in patients with CRPS.