Chronic pain after cardiac surgery, whether or not related to the operation, is common and has negative impact on health related quality of life (HRQL). Frailty is a risk factor for adverse surgical outcomes, but its relationship with chronic pain after cardiac surgery is unknown. This study aimed to address the association between frailty and chronic pain following cardiac surgery.This sub-study of the Anesthesia Geriatric Evaluation study included 518 patients ≥ 70 years undergoing elective cardiac surgery. Pain was evaluated with the Short-Form 36 questionnaire prior to and one year after surgery. Associations between chronic postoperative pain and frailty domains, including medication use, nutritional status, mobility, physical functioning, cognition, HRQL, living situation and educational level, were investigated with multivariable regression analysis.Chronic pain one year after cardiac surgery was reported in 182 patients (35%). Medication use, living situation, mobility, gait speed, Nagi’s physical functioning and preoperative HRQL were frailty domains associated with chronic pain after surgery. For patients with chronic pain physical HRQL after one year was worse compared to patients without chronic pain .Preoperative polypharmacy, living alone, physical frailty and lower mental HRQL are associated with chronic pain following cardiac surgery. Chronic postoperative pain is related to worse physical HRQL one year after cardiac surgery. These findings may guide future preoperative interventions to reduce chronic pain and poor HRQL after cardiac surgery in older patients.NCT02535728 at clinicaltrials.gov. This trial has been registered before initiation under number The online version contains supplementary material available at 10.1186/s12871-022-01746-x. Chronic pain is a well-known complication after cardiac surgery and is reported by 18 to 35% of cardiac surgery patients in the Netherlands . AlthougFrailty is characterized by a limited resilience to surgical stress, and has been associated with poor postoperative outcomes –14. In cThis study therefore aimed to address whether specific frailty domains are associated with chronic pain following cardiac surgery in an older population. Additionally, the relationship of chronic pain to HRQL was evaluated..www.mec-u.nl), number R15.039). The study was first registered at clinicaltrials.gov under NCT02535728 at 31/08/2015. This manuscript adheres to the applicable STROBE guidelines. All participants provided written informed consent. Details on design and analyses of the AGE study have been previously reported [This sub-study of the Anesthesia Geriatric Evaluation and quality of life after cardiac surgery (AGE) study analyzed patients included at St. Antonius Hospital, The Netherlands , 17. Thereported .After routine preoperative screening, an additional geriatric assessment was performed to assess physical, mental and social frailty in eleven domains. Physical frailty included the following domains: medication use, nutritional status using the Mini Nutritional Assessment  (MNA), mPerioperative care was routinely performed according to local standard operating procedures. For intraoperative analgesia a continuous infusion of remifentanil was initiated directly after induction of anesthesia and intermittent fentanyl doses were used at predetermined times . The dose of remifentanil and fentanyl was determined at the discretion of the attending anesthesiologist, depending on patient characteristics and intraoperative vital parameters. All patients received a loading dose of 10 mg intravenous morphine 30 min before the anticipated end of surgery. Postoperative pain management at the intensive care unit (ICU) consisted of intravenous paracetamol (1 g every six hours) and a continuous infusion of morphine (1–2 mg/h) according to protocol. After ICU discharge a standardized postoperative pain protocol was started including Oxycontin 10 mg twice daily, Oxynorm 5 mg as needed (maximum 6 times a day) and paracetamol 1 g four times a day during the first and second day at the ward. On the third day at the ward opioids were reduced and Oxynorm 5 mg as needed was prescribed, together with paracetamol 1 g four times a day. From the fourth day onwards patients received paracetamol 1 g four times a day. Insufficient pain control was managed by consultation of the hospital acute pain service that advised on an individualized pain treatment plan. Patients that suffered chronic pain preoperatively continued their pain therapy, with the exception of NSAID use. Preoperative opioid use was taken into account when defining postoperative opioid dose.One year after cardiac surgery, study patients were invited by letter to complete and return the SF-36 questionnaire. One phone-call was used to remind non-responders. The primary outcome was chronic pain following cardiac surgery after 12 months. Data from the SF-36 questionnaires prior to and one year after surgery were used to determine chronic pain by the following question: ‘How much bodily pain did you have during the past 4 weeks?’ Answers were graded 1 to 6 and represented; ‘None’ (1), ‘Very Mild’ (2), ‘Mild’ (3), ‘Moderate’ (4), ‘Severe’ (5) and ‘Very Severe’ (6) , 23. Forp-value of 0.01 and used a CI of 99%. Bonferroni adjustment was deemed inappropriate and too conservative as the different frailty domains are highly dependent on each other [p-values ≤ 0.01 were considered statistical significant. To investigate the association of chronic pain with HRQL after one year, multivariable linear regression models were conducted, where physical and mental HRQL measured at 12 months were used as the outcome. All associations were adjusted for EuroSCORE II, preexisting chronic pain, overall frailty and physical or mental HRQL measured prior to surgery. Estimates are expressed as linear regression coefficients (β) with accompanying 99% CI. To assess the robustness of our findings, sensitivity analysis were performed using the same analytical approaches. The first post-hoc analysis excluded all patients who died within 12 months of follow up. In the second post-hoc analysis, only patients with new or worse pain one year after surgery (i.e. reclassified into a higher grade of pain) were scored as chronic pain and patients with preexistent moderate to severe pain were excluded from this definition. As SF-36 data was missing for 11% of cases and could lead to potential bias, multiple imputation was conducted using the ‘mice’ library in R [Data are presented as frequencies and percentages (%) for categorical data and as median with interquartile range (IQR) or mean with standard deviation (SD) for continuous data, as appropriate. Normal distribution of the variables was assessed with visual inspection of the histograms and Q-Q plots. Differences between patients with and without chronic pain one year after surgery were compared using the Chi square test for dichotomous or categorical variables or the Mann–Whitney U test or Student’s T-test for continuous variables as appropriate. To investigate the association between each frailty domain and chronic pain one year after cardiac surgery, multivariable log-binomial regression analysis was performed to present effect estimates as risk ratios (RR) with accompanying 99% confidence interval (99% CI). To take multiple testing into account, we tested against a ch other . As chroch other . All assch other , 26–30. ary in R , 32. Tweary in R . Data ann = 9) or cancellation of surgery (n = 17). Fifty-seven patients (11%) had one or more missing values . Additional file Table AOverall, 518 patients were included in the analysis. Reasons for exclusion were withdrawal (One hundred forty patients 27%) reported improvement of pain, 243 (47%) had no or unchanged pain and 135 patients (26%) reported new or worse chronic pain one year after surgery  decreased compared to the number of patients with pain prior to surgery (n = 331), and 27% of patients (140/518) reported an improvement in pain. This might be explained by an improved functional capacity, decreased ischemic chest pain and lower levels of anxiety following cardiac surgery. Nevertheless, increased pain symptoms were common. Considering that chronic pain had a profound effect on HRQL, identification of risk factors for development of chronic pain, especially in the frail and vulnerable population, is important and might help to initiate preventive strategies. Several risk factors including younger age, psychological impairment, preexisting pain, internal mammary artery harvest, use of remifentanil and emergency surgery have been described to increase the risk of chronic pain following cardiac surgery [This study confirmed that chronic pain is common in elderly cardiac surgery patients with a similar incidence reported in prior studies –3. Howev surgery –30. In cFrail patients had a higher risk of developing postoperative chronic pain following cardiac surgery. This association might be explained by impaired physical exertion as higher levels of activity have been described to reduce pain sensitivity by decreased pain facilitation and increased pain inhibition . ConversBesides impaired physical functioning, medication use, living situation and preoperative mental HRQL were associated with chronic postoperative pain. Polypharmacy is common in older patients, and might impede pain management for several reasons. Apart from age- and disease-related changes in physiology, disease-drug and drug-drug interactions might lead to a heterogeneity in response to medications and increased adverse drug effects. Frailty further increases this heterogeneity and thus frail elderly with polypharmacy may be more susceptible to adverse events . Next toGender has been described to interact with multiple preoperative factors as well as cardiac surgery outcomes . Female p < 0.001). Understanding factors that are related to HRQL in older people can be used to preoperatively accommodate patients’ needs and preserve quality of life.Our study confirmed the existing relationship between chronic pain and HRQL. In general, polypharmacy, physical inactivity, reduced self-reliance and social isolation leads to an increase in health consumption, pain and poor HRQL , 37, 38.Risk stratification should lead to individualized evaluation and preparation for surgery. However, evidence for pre-habilitation is limited for cardiac surgery patients. However, preoperative exercise has been demonstrated to improve functional recovery . OptimizComprehensive evaluation of pharmacotherapy should be part of each preoperative assessment, but deserves additional attention of, for example, a pharmacist or geriatrician in patients with polypharmacy. Patients suffering from chronic pain preoperatively should receive an individualized perioperative pain management plan, depending on their preoperative situation. Within this plan, additional pharmacotherapy, locoregional anesthesia and/or non-pharmacological interventions including may be considered to treat acute postoperative pain and prevent the increase of chronic pain symptoms following cardiac surgery.The following limitations should be considered. First, pain was determined by a health survey that was not specifically designed to assess pain or pain interference. This study population reported pain within the last 4 weeks at 12 months follow up after surgery, and defined it as chronic pain . UnfortuPostsurgical chronic pain is common in elderly cardiac surgery patients. Preoperative polypharmacy, living alone, physical frailty, living alone and lower mental HRQL were positively associated to chronic pain following cardiac surgery. Secondly, chronic pain was associated with worse physical HRQL following cardiac surgery. The results of our study advocate that early identification of these factors may be used to identify older patients at risk for chronic pain after cardiac surgery.Additional file 1:Figure A1. Adjusted relative risks for the development of new or worse chronic pain, sensitivity analysis (n=135). aRR Adjusted relative risk, CI Confidence interval, MMSE Minimal mental state examination, MNA Mini-nutritional assessment, HRQL Health related quality of life. Polypharmacy was added as factor with polypharmacy defined as ≥5 and <10 prescriptions and excessive polypharmacy defined as ≥10 prescriptions used. No polypharmacy was used as reference category. Log-binomial regression was used for statistical testing with correction for EuroSCORE II, intraoperative use of remifentanil, preexisting chronic pain and use of internal mammary artery. P-value ≤0.01 was considered statistically significant. #; per point decrease on physical and mental HRQL.Additional file 2:Figure A2. Adjusted relative risks for the development of chronic pain, sensitivity analysis without deceased patients (n=488). aRR Adjusted relative risk, CI Confidence interval, MMSE Minimal mental state examination, MNA Mini-nutritional assessment, HRQL Health related quality of life. Polypharmacy was added as factor with polypharmacy defined as ≥5 and <10 prescriptions and excessive polypharmacy defined as ≥10 prescriptions used. No polypharmacy was used as reference category. Log-binomial regression was used for statistical testing with correction for EuroSCORE II, intraoperative use of remifentanil, preexisting chronic pain and use of internal mammary artery. P-value ≤0.01 was considered statistically significant. #; per point decrease on physical and mental HRQL.Additional file 3:Table A1. Description of frailty domains.Additional file 4:Table A2. Baseline for patients with and without missing data.Additional file 5:Table A3. Baseline for patients with and without chronic pain prior to surgery (n = 518).


We also acquired resting-state functional MRI to determine functional connectivity of two key nodes in the somatosensory system, the thalamus and primary somatosensory cortex. Seed-to-whole brain resting-state static functional connectivity analyses revealed abnormally low functional connectivity for the hand area of the primary somatosensory cortex with the contralateral somatosensory association cortex  before surgery (P < 0.01). After clinically effective surgery: (i) Primary somatosensory functional connectivity was normalized with the contralateral somatosensory association cortex and reduced with the dorsolateral prefrontal cortex  and primary visual areas (P < 0.001) from pre-op levels; and (ii) Functional connectivity of the thalamus with the primary somatosensory and motor cortices was attenuated from pre-op levels (P < 0.001) but did not correlate with temporal summation of pain  or clinical measures. This study is the first to reveal treatment-related neuroplasticity in resting-state functional connectivity of the somatosensory system in carpal tunnel syndrome. The findings of dysfunctional resting-state functional connectivity point to aberrant neural synchrony between the brain’s representation of the hand with regions involved in processing and integrating tactile and nociceptive stimuli and proprioception in carpal tunnel syndrome. Aberrant neural communication between the primary somatosensory hand area and the dorsolateral prefrontal cortex could reflect increased attention to pain, paraesthesia, and altered sensation in the hand. Finally, reduced thalamocortical functional connectivity after surgery may reflect central plasticity in response to the resolution of abnormal sensory signals from the periphery. Our findings support the concept of underlying brain contributions to this peripheral neuropathy, specifically aberrant thalamocortical and corticocortical communication, and point to potential central therapeutic targets to complement peripheral treatments.Carpal tunnel syndrome is the most common entrapment neuropathy and is associated with altered brain function and structure. However, little is understood of the central mechanisms associated with its pain, symptom presentation, and treatment-related resolution. This longitudinal study evaluated carpal tunnel syndrome-related alterations in brain network communication and relationships to behavioural signs of central sensitization before and after carpal tunnel release surgery. We tested the hypothesis that carpal tunnel syndrome is associated with condition- and treatment-related plasticity in brain regions involved in somatosensation. We used quantitative sensory testing and clinical and pain questionnaires to assess sensory and pain function in 25 patients with carpal tunnel syndrome before  and after ( et al. report dysfunctional resting-state functional connectivity within the somatosensory system of patients with carpal tunnel syndrome which normalized following carpal tunnel release surgery. Treatment-related neuroplasticity was characterized by a reduction in functional connectivity between the primary somatosensory cortex and the thalamus and prefrontal cortex.Osborne   Central sensitization has been linked to worse short-term treatment outcomes in carpal tunnel syndrome.14 Quantitative sensory testing (QST) has identified multiple sensory phenotypes of carpal tunnel syndrome comprising thermal or mechanical hyperalgesia and sensory loss,16 which likely reflects heterogeneity in underlying nerve pathology and corresponding neuroplasticity throughout the somatosensory system.Carpal tunnel syndrome is the most common entrapment neuropathy, with a lifetime risk in the general population of 10%.18 In carpal tunnel syndrome, the S1 shows blurring of the digit representations of the affected hand19–22 and abnormal responses to hand stimulation,24 which can normalize after acupuncture26 and surgical27 treatment. Patients whose median nerve was transected and subsequently repaired exhibit abnormal responses to vibrotactile hand stimulation28 and tactile tasks29 in S130 and also in the secondary somatosensory, lateral parietal, premotor, inferior temporal, and prefrontal cortices. In addition to the S1,31–34 it is well known that the thalamus35–39 is impacted by chronic pain,40 and thalamocortical dysrhythmia41 is associated with chronic neuropathic pain.42 Resting-state functional connectivity (rsFC) represents the synchrony of oscillatory activity between brain areas and can be an indicator of the health of a neural pathway. Characterizing rsFC changes within the somatosensory system and between it and other brain regions in carpal tunnel syndrome may help to better understand its diverse patterns of on-going sensory symptoms and their alleviation with treatments such as carpal tunnel release surgery, which reduces symptoms in 70–90% of patients.Aberrant neural activity from a compressed peripheral nerve to the primary somatosensory cortex (S1) is thought to drive maladaptive central neuroplasticity.Here we evaluated carpal tunnel syndrome abnormalities and treatment-related plasticity in the rsFC of the somatosensory system, including the thalamus and S1, to answer three main questions: How does carpal tunnel syndrome and its treatment impact (i) functional connectivity (FC) of the hand area of S1?; (ii) thalamocortical FC?; and (iii) the brain–behaviour relationship of thalamocortical FC with TSP, a reflection of central sensitization? We predicted that, due to continuous abnormal sensory signals from the hand driving enhanced spontaneous synchronization between these two regions, FC between the thalamus and S1 hand area may be stronger in patients with carpal tunnel syndrome (before surgery) compared with healthy controls (HCs) and symptom-free postoperative (post-op) patients. We also predicted that pre-operatively, patients would show behavioural signs of central sensitization such as greater TSP responses compared with HCs. To test these hypotheses, we conducted a longitudinal study that used QST and fMRI to investigate rsFC in people with carpal tunnel syndrome before and after carpal tunnel release surgery, as compared with age- and sex-matched HCs.Additional methodological details are found in This study included 50 participants: 25 patients with carpal tunnel syndrome  and 25 sex-matched healthy controls . Patients were recruited from the Toronto Western Hospital Hand Program and HCs were recruited through advertisements posted throughout hospitals of the University Health Network in Toronto, Ontario, Canada. Recruitment and data collection took place from November 2017 to October 2020. All participants provided informed, written consent to the study procedures approved by the University Health Network Research Ethics Board.43 Although electrodiagnostic tests were not an inclusion criteria for patient recruitment, we do note that 16 (64%) patients had electrodiagnostic studies conducted, and the results supported their clinical CTS diagnoses. We included patients between the ages of 18 to 70 years with unilateral (right hand) or bilateral carpal tunnel syndrome whose symptoms were not alleviated with conservative management (defined as three consecutive months of nightly splint wearing) and who elected to undergo carpal tunnel release surgery by Dr. Anastakis. Exclusion criteria for our study were as follows: (i) polyneuropathy/other peripheral neuropathy ; (ii) atypical innervation of the hand (e.g. Martin-Gruber or Riche-Cannieu anastomoses); (iii) previous carpal tunnel release surgery; (iv) rheumatoid arthritis or degenerative osteoarthritis in the hand; (v) diabetes mellitus, renal disease or metabolic disorder; (vi) neurodegenerative disorders; (vii) other chronic pain conditions, (viii) psychiatric disorders other than depression and anxiety and (ix) pregnancy, claustrophobia and contraindications for MRI. Initial pre-screening identified 254 potentially eligible patients; subsequent screening excluded 164 patients according to the criteria mentioned above, with an additional 16 patients not interested in the study, 19 patients whose conservative management course did not finish before the study’s end date, and 28 individuals who did not attend their clinical appointments. A total of 27 patients completed the preoperative (pre-op) study visit, two of which were not included in the present analyses because they had unilateral CTS on the left hand, and 16 patients returned for the post-op visit. HCs were included in the study if they were between the ages of 18 and 70 and excluded if they had any of the nine criteria above. Additional exclusion criteria for HCs were as follows: (i) current acute pain or diagnosis of a chronic pain condition and (ii) diagnosis of depression and anxiety.A diagnosis of carpal tunnel syndrome was based on clinical examination and in some cases also electrodiagnostic tests.The study protocol in the patient group included a pre-op assessment prior to surgical release of one or both of their carpal tunnels. HCs were assessed in a single visit. In each assessment we acquired neuroimaging, QST, and questionnaire data. Post-op assessments were also done for 16 of the patients, at least three months after surgery to allow time for the median nerve to regenerate. If a patient had surgery on both hands, the post-op visit was collected after the second surgery.We determined mechanical, vibration, warm, cool, heat, and cold pain detection thresholds at the volar aspect of the distal phalanx (fingertip) of D2 (index finger) on the patient’s most symptomatic hand and from the right index finger in a subset of 10 HCs. We determined each participant’s ‘Pain50’ as the temperature that elicited a verbal pain rating of 50/100 .44 Five patients and five HCs were excluded from the TSP analyses because they did not have pain evoked by the first three stimuli.TSP was assessed with a 30 mm × 30 mm Peltier thermode  set at the participant’s Pain50 temperature. A series of 10 consecutive 1 s thermal stimuli were applied manually at 0.33 Hz to the right volar forearm (15 cm from the wrist). Participants verbally rated the pain (0–100) after each stimulus. A practice run was done before the series used to determine TSP. The TSP effect was calculated as the percentage change in pain from the first stimulus to the peak pain rating within the series as done previously.46 that contains two subscales. The symptom severity scale contains 11 questions about the occurrence and duration of sensations such as pain, numbness, and tingling. Each item is rated one-five, with one representing a ‘normal’ response (no symptoms) and five indicating ‘very serious’ or constant symptoms. The numerical responses to each question are summed, and the total divided by the number of questions (11) to calculate the symptom score. The functional status scale consists of eight questions that assess hand function. Each item is rated 1–5 and the numerical responses are summed and divided by eight to obtain the functional score. Because a ‘normal’ response is indicated by a one, a symptom-free hand would have a symptom severity score of one (1 × 11/11) and a functional status score of one (1 × 8/8), and therefore a total BCTQ score of two. The most severe BCTQ score possible is 10. Here we report the BCTQ for the right hand only. Symptom distribution was delineated with the Katz Hand Diagram,47 assessed (by N.R.O.), and classified as indicating either a ‘median nerve’ or ‘extra-median nerve’ symptom distribution. An extra-median distribution could include areas innervated by the radial or ulnar nerve (e.g. little finger) or ‘whole hand’ i.e. ‘glove distribution’.7Participants self-identified their sex in a socio-demographic questionnaire with the binary options of male and female. The severity of carpal tunnel syndrome was assessed with the patient-completed Boston Carpal Tunnel Questionnaire (BCTQ), a validated tool48 was used to measure the likelihood of the presence of neuropathic pain. The Brief Pain Inventory49 (BPI) was used to assess pain severity at present, average pain, and pain at its worst and least in the past 24 h.50 The BPI assesses pain from 0 (no pain) to 10 (pain as bad as you can imagine). Here we report the average of these four ratings as patient’s ‘average pain severity’.We used two questionnaires to assess chronic pain: The painDETECT questionnaire1-weighted anatomical scan  as did the pain ratings . The BCTQ scores also improved post-operatively .All three indicators of pain and pain-related impact were improved after surgery (see n = 10) to the patients’ pre-op state (n = 22) showed that patients had significantly  higher mechanical detection thresholds (6.6 ± 21.3 mN) than the HCs (0.69 ± 0.7 mN). Pre-operatively, patients (n = 20) also had significantly higher vibration detection thresholds than HCs (n = 11) . However, these patients did not differ pre-operatively from HCs in terms of their group average warm detection thresholds (patients (n = 15): 36.8 ± 2.5°C; HCs (n = 10): 35.93 ± 2.5°C, Mann–Whitney two-tailed test, P = 0.30), cool detection thresholds (patients (n = 14): 24.1 ± 7.3°C; HC (n = 10): 27.6 ± 5.4°C, Mann–Whitney two-tailed test, P = 0.07), heat pain thresholds , or cold pain thresholds .The somatosensory thresholds in the HCs and the most affected digit  of the most affected hand in the carpal tunnel syndrome group before and after surgery are shown in P = 0.032) from a geometric mean of 6.6 ± 21.2 mN pre-op (n = 22) to 1.0 ± 1.0 mN post-op (n = 14);  from 4.7 ± 3.0 V  to 3.0 ± 1.1 V . Heat pain thresholds also decreased significantly  from 45.8 ± 4.0°C pre-op (n = 15) to 44.1 ± 4.4°C post-op (n = 14), and cold pain thresholds increased significantly  from 9.0 ± 11.2°C pre-op (n = 14) to 13.3 ± 10.5°C post-op (n = 13). However, the warm thresholds (pre-op (n = 15): 36.8 ± 2.5°C, post-op (n = 14): 37.6 ± 3.1°C, one-tailed paired t-test, P = 0.4849) and cool thresholds (pre-op (n = 14): 24.1 ± 7.3, post-op (n = 13): 26.9 ± 3.6, Wilcoxon matched-pairs signed-rank test, one-tailed, P = 0.2129) were not significantly different before and after surgery.After surgery, patients’ mechanical and vibration detection thresholds were significantly lower compared to their pre-op levels  in the average temperature that elicited a pain rating of 50 in pre-op patients (44.9 ± 2.7°C) compared with HCs (45.8 ± 1.9°C), nor in post-op average pain50 temperatures (44.1 ± 3.1°C) compared with HCs . Prior to surgery, the patients exhibited significantly less TSP compared with HCs , 199% ± 273 in HCs (n = 20), Mann–Whitney two-tailed test, P = 0.048]. Patient’s pre-op TSP responses were not correlated  with their average pain scores (BPI). After surgery, the average TSP response  decreased from the pre-op average, but not significantly .There was no significant difference  had lower FC between the left S1 hand area seed and a cluster that included the right somatosensory association cortex, specifically the supramarginal gyrus (Broadman Area (BA) 40) and angular gyrus . We found that FC between the S1 hand area and the prefrontal cortex was attenuated after surgery, specifically in BA 9 and 46, corresponding to the right dorsolateral prefrontal cortex . Post-op patients also had decreased S1 FC with bilateral primary visual cortices , and a cluster (P = 0.02) including the left middle and superior temporal gyri (BA 21 & 22) and angular gyrus (BA 39) . There were no differences in thalamic FC with the somatosensory mask between post-op patients and HCs , primary motor cortex (BA 4), sensory association cortex (BA5) and visual motor area (BA 7) compared to patients pre-operatively ( and HCs .n = 25) and HCs  or post-operatively (n = 16) and HCs . See The seed-to-seed analyses of FC between the thalamus and S1 BA3a did not reveal any significant differences between patients pre-operatively (n = 22) in patients  or in HCs  Before surgery, patients have abnormally low rsFC between the hand area of S1 and the contralateral somatosensory association cortex, specifically in regions associated with pain and discerning somatosensory stimuli. Then, FC of S1 (corresponding to the operated hand) with the contralateral somatosensory association cortex normalized after surgery that relieved pain and somatosensory symptoms, but S1 FC with the ipsilateral somatosensory cortex was abnormally low. (ii) After surgery, the S1 FC was attenuated from pre-op levels with the DLPFC, a region associated with attentional and emotional modulation of pain, as well as with the primary visual cortex. (iii) FC between the thalamus and S1 (as well as M1) was also attenuated after surgery. These findings suggest that thalamocortical FC reflects the presence (and subsequent reduction) of pain, numbness, and paraesthesia in carpal tunnel syndrome, and supports the proposition that persistent abnormal peripheral input from the hand can drive functional changes throughout the somatosensory system21 and larger and slower S1 responses to stimulation may reflect increased afferent drive from the hand or coactivation of neighbouring digits’ cortical sites.23 A study of S1 rs-fMRI activity reported increased FC with the ipsilateral, and decreased FC with the contralateral, hemisphere in patients compared to HCs, including lower S1 FC with the contralateral supramarginal gyrus.57 They also found decreased amplitude of low frequency fluctuation (ALFF) in S1, which they proposed reflected lower local activity that led to desynchronization with the contralateral S1 and subsequent cortical disinhibition19 that facilitated the ipsilateral FC.57There are several proposed mechanisms of S1 plasticity in carpal tunnel syndrome. Hebbian neuroplasticity driven by abnormally enhanced temporal synchrony of signals from paraesthesias emanating from the fingers may cause S1’s digit maps to blur,58 and there is right-lateralized processing of bilateral painful and non-painful stimuli in BA40.59 As part of the somatosensory association cortex, the supramarginal gyrus is thought to be involved in integrating visual and tactile stimuli,60 as well as proprioception,61 and stroke-induced damage to this area has been linked with proprioceptive difficulties63 and tactile agnosia.64 Lesions to the left angular gyrus can lead to ‘finger agnosia’, which is defined as a loss of the ability to distinguish, name, recognize, and even selectively move fingers.65 Transcranial magnetic stimulation to the angular and supramarginal gyri can temporarily induce finger agnosia in healthy adults.66 Therefore, decreased left hand area S1 rsFC to the right somatosensory association cortex could reflect a patient’s reduced tactile acuity and sensitivity, and functional difficulties associated with their hand. Abnormally low brain activation in BA40 in response to vibrotactile hand stimulation has been shown in patients whose median nerves were transected and subsequently repaired and may be linked to incomplete nerve regeneration and persistent impairments in mechanical and vibration detection.28 Interestingly, although left S1 FC with the right somatosensory association cortex normalized in patients after surgery, they showed abnormally low left S1 FC with the left supramarginal and angular gyri compared with HCs. It is unclear what is driving persistent abnormalities between the left S1 hand area and its ipsilateral somatosensory association cortex in patients whose right hand symptoms had resolved, although it is possible mild symptoms in the untreated left hand could contribute to aberrant bilateral processing in somatosensory association areas.Our study also identified abnormally low static rsFC between the left S1 and the right somatosensory association cortex  in carpal tunnel syndrome patients before surgery. Bilateral tactile hand stimulation has been shown to activate the right supramarginal gyrus,68 and top-down cognitive engagement of descending pain modulation, as well as reducing the emotional unpleasantness of pain. Alterations in DLPFC structure and function, including abnormally strong FC with the S1,33 are reported in chronic pain.70 Non-invasive brain stimulation of the DLPFC can reduce somatosensory cortical excitability in sustained pain,71 and a dynamic causal model of pain processing found an additional forward and backward connection between S1 and right DLPFC in chronic pain but not HCs, which they proposed could reflect increased attention to and catastrophizing of pain.72 Although we did not find any correlation of the S1-DLPFC FC with symptom or pain scores pre-operatively, it is possible that such a relationship may exist with other individual factors such as pain catastrophizing. Therefore, it is possible that enhanced S1-DLPFC FC before surgery reflects greater attention to abnormal sensory signals from the hand.One of our key findings was the reduction of S1 rsFC with the DLPFC following surgery. The DLPFC is associated with attentional modulation of tactile processing and memory,22 as proposed to occur in patients whose median nerves were transected and subsequently repaired.29 A rodent model of chronic nerve constriction found enhanced thalamic-S1 FC during the development of neuropathic pain,73 and stronger thalamic-S1 rsFC compared with HCs has been reported in other chronic pain conditions74–76 including upper extremity neuropathic pain, where stronger thalamic-S1 FC was associated with lower tactile acuity and weaker FC was linked with higher pain scores.77 Conversely, diabetic-neuropathy patients show reduced thalamic-S1 FC, particularly those with mechanical hyperalgesia.38 Interpreting the directionality of plasticity in thalamocortical connections is challenging when assessed with rs-fMRI, particularly in conditions that have heterogeneous (i.e. positive and negative) sensory and pain profiles.15 Contrary to our predictions, we found no differences in thalamocortical FC between patients pre-operatively and HCs. The heterogeneous pain and symptom scores in the present patient cohort may correspond with different compensatory or maladaptive changes throughout the somatosensory pathway. At the level of the peripheral nerve, multiple pathophysiological mechanisms likely interact, including mechanical forces, ischaemic compression, inflammation, oedema, and hypoxic injury,78 resulting in progressive axonal loss and deafferentation that affects both large (Aβ) and small (Aδ and C) sensory fibres.3 In the brain, S1 and M1 cortical thickness dissociates carpal tunnel syndrome patients with primarily paraesthesia versus pain symptoms.79 The amount of afferent drive from the hand in the present patient group likely differed depending on their symptoms and degree of nerve impairment, and the different symptom subtypes in carpal tunnel syndrome may require stratification when comparing with HCs to detect specific FC abnormalities.Another key finding in our study is that of decreased thalamocortical FC post-operatively involving S1 and M1 compared to pre-op levels. We suggest that thalamic-S1 FC reflects and is maintained by on-going aberrant input from the median nerve. We propose its reduction post-operatively occurs because this afferent input is attenuated, as signified by the symptom relief following surgery. Alternately, stronger rsFC could reflect cortical disinhibition, a compensatory mechanism to magnify weaker sensory input from a damaged nerve to maintain sensory perception in the hand,44 higher TSP responses were not correlated with increased thalamic-S1 BA3a FC in either patients or HCs. Enhanced pain facilitation80 and TSP has been reported in carpal tunnel syndrome.13 These behaviours are considered experimental characteristics of central sensitization, and increased TSP is frequently  reported in chronic pain conditions with ‘centralized’ pain.81 Contrary to our hypothesis, we found significantly less thermal TSP in both pre- and post-op patients compared with HCs. Significantly lower wind-up ratio (a measure similar to TSP) was also found in carpal tunnel syndrome versus HCs.15 While the area of the forearm where our TSP paradigm was performed is innervated by the lateral and medial antebrachial cutaneous nerve, some patients reported pain and paraesthesia symptoms extending up their volar forearm, which may have influenced TSP responses. Indeed, the patient group in this study had clinical characteristics of central sensitization, with 19 indicating proximal symptom spread, and seven showing extra-median symptom patterns.Unlike our previous study in healthy young adults,et al.82 The heterogeneity in sensory thresholds, extra-median versus median symptom distribution, and average pain and symptom scores likely reflects different carpal tunnel syndrome ‘subtypes’. Current clinical guidelines recommend that patients with ‘non-classical’ symptoms  undergo painful electrophysiological testing to rule out involvement of other peripheral nerves.83 These tests are associated with increased costs and delays to surgery,84 which is linked with worse outcomes.85 Establishing the role of central plasticity and sensitization in carpal tunnel syndrome, particularly in non-classical symptoms, could reduce diagnostic uncertainty in these cases and perhaps even contribute to stratification of symptom subtypes for more personalized treatments.1 Characterizing altered cortical functioning in carpal tunnel syndrome could inform physiotherapy designed to target neuroplasticity, such as sensory re-learning, which has variable effectiveness.86–88 We recently demonstrated that abnormal rsFC of a node of the descending anti-nociceptive system, the subgenual anterior cingulate cortex (sgACC), was influenced by sex,89 as well as treatment-related plasticity in carpel tunnel syndrome.90 Thus, in addition to an impaired descending pain modulation system in chronic pain,91 the present study findings of altered thalamic-S1 and S1-to-whole brain FC help provide a more complete picture of the CNS aberrations in carpal tunnel syndrome.Clinically, the carpal tunnel syndrome patients mostly had improved or resolution of pain and other sensory symptoms. However, there may be incomplete healing of the median nerve in line with Kennedy 92 As demonstrated by Kennedy et al.,15 healthy threshold data collected at the more common site of the thenar eminence are not suitable as a reference for finger thresholds. Therefore future studies of similar hand conditions could contribute to a shared database of QST measures performed on the fingers. Our sex-disaggregated analyses revealed that sex may influence carpal tunnel related-abnormalities in S1 FC, as it does in the descending anti-nociceptive system,90 however our sample of men may have been too small to detect the abnormally low S1-right somatosensory association cortex FC seen in the women only and main analyses (93 Future studies with larger sample sizes should explore the effects of handedness and unilateral versus bilateral carpal tunnel syndrome symptoms on somatosensory FC.There are limitations to our study, namely a small post-op patient sample size and insufficient healthy control sensory threshold data to enable us to definitively calculate sensory gain or loss in carpal tunnel syndrome patients relative to normal.analyses . FinallyIn conclusion, we provide novel evidence that carpal tunnel syndrome is associated with altered FC in cortical areas associated with somatosensory and pain processing, and that surgical treatment can normalize some of these connectivities. Our findings of neuropathy- and treatment-related brain plasticity provide a window into potential mechanisms underlying the resolution of symptoms, and possible targeted treatments to complement hand surgery or provide relief for those with poor post-surgical outcomes.fcac237_Supplementary_DataClick here for additional data file.


After laparoscopic cholecystectomy (LC), pain is still a significant concern leading to extended hospital stays or readmissions. A standardized strategy is needed to offer effective pain relief postoperatively. The pain in the early postoperative period is mainly due to elimination of intraperitoneal surface tension. The aim of this study is to evaluate the restoration of intraabdominal surface tension and the use of bupivacaine‐soaked tachosil to control parietal abdominal pain at the port sites to optimize postoperative pain management.Between March 2020 to December 2021, 816 patients undergoing LC were randomized into two groups after exclusion of 12 patients: Group A—interventional contained 402 patients; Group B—control contained 402 patients. Data to be compared were made in terms of operative time, shoulder pain, upper abdominal pain, and number of analgesic doses and hospital stay. Pain intensity was assessed by using the visual analog scale.P < .05.There was no significant variation in the demographic data between the two groups. There was significant statistical difference between Groups (A) and (B) regarding severity of shoulder pain and port site pain and number of analgesic doses and hospital stay in favor of Group (A). The results were evaluated within 95% confidence intervals and significance was determined as 2 as possible at the end of laparoscopic cholecystectomy via the epigastric port route, as well as the use of bupivacaine‐soaked tachosil to control parietal abdominal pain at the port sites; both steps significantly improved postoperative pain management, reduced the number of analgesic doses, and decreased the length of hospital stay.The restoration of intraabdominal surface tension by absorbing as much CO The cornerstone of treatment for symptomatic gallbladder stones is laparoscopic cholecystectomy. Pain is the commonest cause of extended hospital stay. Disturbance of liver—diaphragm surface tension is the main cause of pain. Retained CO2 is a major concern post laparoscopic cholecystectomy. Port sites pain is another contributor of the post laparoscopic cholecystectomy pain After a laparoscopic cholecystectomy, pain is still a significant concern, leading to extended hospital stays or readmissions. Because analgesic procedures vary widely, a standardized strategy is needed to offer effective pain relief.The pain that patients experience following laparoscopic cholecystectomy may be classified into three categories based on its origin: parietal, visceral, and shoulder pain.The parietal or somatic type of pain is generated by the abdomen wall being traumatized upon trocar insertion. The visceral type of pain is a result of the surgical dissection and manipulation of the gall bladder bed. Shoulder tip pain has been observed often, ranging from 35% to 63%, but the severity is significantly less severe following laparoscopic cholecystectomy than other types of laparoscopic surgery.Numerous techniques have been attempted to alleviate postoperative pain, including gasless procedures, low‐pressure pneumoperitoneum, saline washout, subdiaphragmatic instillation of a local anesthetic agent, and local anesthetic infiltration at the port site wounds.The cause of the shoulder pain is unknown; proposed causes include neuropraxia of the phrenic nerve, stretching of the subdiaphragmatic fibers due to the pneumoperitoneum, increased stretch on the liver's diaphragmatic attachments attributable to a decrease in visceral surface tension, and peritoneal injury as a result of chemical, ischemia, or traumatic injury.22.1This study has been reported in line with Consolidated Standards of Reporting Trials (CONSORT) Guidelines.2.2This study was carried out in two big centers .2.3March 2020 to December 2021.2.4Patients admitted with clinical diagnosis of symptomatic gall bladder stones.2.5A total of 816 patients with a clinical diagnosis of symptomatic gall bladder stones were included in this study. Patients were randomly assigned to one of two groups: Group (A)—includes 408 patients as the intervention group (the group to whom our technique was applied); Group (B)—includes 408 patients as the control group.2.6Simple random sample with a balance.2.72 volume.Taking the level of significance to be 5% and the power of the study to be acceptable at 80% with a confidence level of 95%, the sample size calculation was based on pain scores in similar studies in which patients were subjected to interferences to decrease the port site pain and reduce the residual CO2.8Patients were randomly allocated using a random sequence generator. Random allocations were sequentially numbered in sealed opaque envelopes, which were opened before surgery. Patients, clinicians, and researchers following the patients postoperatively and collecting data were blinded to the assigned group. Process of randomization was carried out by the registration office.2.9Patients who were having symptoms consistent with biliary colic, had ultrasound evidence of gall stones, and were classified as American Society of Anesthesiology (ASA) I and II and with ages ranging from 18 to 65 years.2.10Patients who refused to give consent, were pregnant, had a history of drug abuse, had CBD stones, acute cholecystitis, acute pancreatitis, previous abdominal surgery, a history of peritonitis, or had carcinoma of the gall bladder.2.11After obtaining approval for the procedure, all patients in this research gave consent and operated on by the two experienced surgical teams, one in each center, and were anesthetized by two anesthesiologist teams who adhered to a predetermined procedure, one in each center. Vital signs were monitored in accordance with clinical norms. The postoperative assessment was performed by two independent clinician teams, one in each center.2 was the gas used for abdominal insufflation, using low flow rate of 2 L/min intraabdominal pressure was adjusted to 12 mmHg in both groups. After the formal triangle of Calot's dissection was performed and the cystic duct and artery were controlled, the gallbladder was removed via the epigastric port. The gallbladder bed is thoroughly inspected for bleeding or biliary leakage then:In the control group (B), all ports were removed under vision, cessation of insufflation was carried out, the umbilical port valve was opened, and the abdomen was gently squeezed to drain the retained CO2. The fascia of the epigastric port was closed with vicryl 0, and the skin of the four ports was closed with prolene 3/0.In the interventional group (A), the epigastric port was removed, and its site was inspected for bleeding, then reinserted and the laparoscopic suction device was introduced and left above the upper surface of the right liver lobe under the diaphragm. Then the midclavicular port and anterior axillary line port were removed under vision. Cessation of insufflation was done and the patient was kept in Trendelenburg position then the abdomen was gently squeezed to drain the retained CO2, the suction device was activated and sucked all the remaining CO2 from the celomic cavity till we met resistance (not liable to be blocked by omentum) leading the restoration of the liver‐diaphragm surface tension and the surface tension between the abdominal wall and viscera. Then the suction device was removed, and the epigastric port was blindly removed and the fascia of the epigastric port was closed with Vicryl® 0. Then four pieces of Tachosil® (one piece of 1 × 1 cm and three pieces of 0.5 × 0.5 cm) were impregnated with Bupivacaine® 0.5%w/v solution and applied in the subcutaneous region of each wound, and, lastly, the skin of the four ports was closed with Prolene® 3/0. Pain medications used postoperatively were pethidine 1 mg/kg intramuscular Q4HPRN and paracetamol 1 gm iv Q6HPRN in a unified sequenced alternative pattern. Statistical analysis was done using MedCalc® version 20.026.All cases were performed via four ports. One 5‐mm port was placed via the umbilicus (camera), one 10‐mm port in the epigastrium at the level of the lower border of the right liver lobe and two 5‐mm ports were placed one in the right hypochondrial region in the midclavicular line 2 cm below the costal margin and one in the anterior axillary line at the level of the umbilicus. COPostoperative data to be compared were made in terms of operative time, shoulder pain, upper abdominal pain , number of analgesic doses, hospital stay, and number of days required to return to normal activity. Pain intensity was assessed by using the visual analog scale (VAS).3P‐value >.05). The mean operative time in group (B) is slightly shorter, at (55.96 ± 9.43) minutes, than in group (A), which is (57.54 ± 9.56) minutes . The mean total hospital stay was statistically significantly lower in Group (A) at (1.2 ± 0.23) days than in Group (B) at (1.74 ± 0.54) days . Return to normal daily activity was statistically significantly lower in Group (A) at (5.27 ± 1.25) days than in Group (B) at (5.93 ± 1.43)   (n = 408) or the control group (Group B) (n = 408). Six patients were excluded from group (A)  and six patients were excluded from group (B) . Finally, 804 patients completed the study . There was no significant variation in the demographic data between the two groups, regarding age, sex, and body mass index (BMI) distribution , While the median and the range of the registered score of VAS for the other two areas (left shoulder and interscapular areas) showed non‐significant difference between the two groups  Table Due to the spread out of the data from the mean value we faced, we used the median value and the range to express and test the differences between the two groups. The median and the range of the registered score of VAS for patients in Group (A) at 6,12,18, and 24 hours were statistically significantly lower than those registered for group (B) for two of the assessed areas of pain perception (right shoulder and port sites) .The mechanism behind shoulder tip discomfort and diaphragmatic irritation is unknown and is believed to be complex. The duration of the pneumoperitoneum, the rate of gas insufflations, the peak intraperitoneal pressure, and the gas temperature have all been investigated. Distension, acidification of the intra‐abdominal environment, or temperature variations all tend to stimulate intraperitoneal nerve endings, which appear to be the common denominators. Insufflations may also trigger a localized inflammatory reaction that stimulates nerve endings and causes pain as a result of the original stimulation.2. The study evaluated abdominal X‐rays to determine the amount of gas volume in the right subdiaphragmatic region. They found statistically significant relationships between the volume of retained gas and the intensity of the pain, indicating that leftover gas may be a substantial source of post‐laparoscopy pain.Jackson et al investigated the relationship between post‐laparoscopy pain and pre‐discharge residual COOne study found that using a drain to remove leftover gas during the postoperative period reduced pain by 50%, but this result did not achieve statistical significance.2 from the celomic cavity till we met resistance (it is not susceptible to be blocked by omentum), leading to the restoration of the liver‐diaphragm surface tension and the surface tension between the abdominal wall and viscera, just like the same principle of using the intercostal tube to treat pneumothorax and restoring the normally present surface tension between the visceral and parietal pleurae. We also got a statistically significant reduction in the median and the range of the pain score and a decrease in the mean number of analgesic doses in our interventional group (A) as compared to the control group (B). Also, there was a statistically significant reduction in the mean days of hospital stay decreasing the overall cost of the procedure and the mean days required to return to normal activities in our Group (A) as compared to our control Group (B). Also, the number of cases operated as day cases in Group (A) was statistically significantly higher than in Group (B), which had an additive positive economic impact. Our findings matched the results of Koray Das et al.However, in our study, the suction device was inserted via the epigastric port (the last port to be removed) and sucked all the remaining COIn Tables Aman et al2 as possible at the end of laparoscopic cholecystectomy via the epigastric port route, as well as the use of bupivacaine‐soaked tachosil to control parietal abdominal pain at the port sites. These two final steps improved postoperative pain management, reduced the number of analgesic doses, decreased the length of hospital stay and the overall cost. We strongly recommend ending every case of laparoscopic cholecystectomy with these two final steps.In conclusion, the restoration of intraabdominal surface tension was carried out by absorbing as much CO4.1Further studies with larger sample size are recommended to support our findings and other studies are recommended to study the exact causes of postoperative shoulder pain in patients undergoing laparoscopic surgery in general.Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.Conflict of Interest: The authors declare no conflicts of interest for this article.Approval of the Research Protocol: The protocol for this research project has been approved by a suitably constituted Ethics Committee of our university hospital (ZU‐IRB #6534/15‐2‐2020).Informed Consent: All informed consent was obtained from the subject(s) and/or guardian(s).https://clinicaltrials.gov/ct2/show/NCT05214157.Registration at clinicaltrials.gov protocol registration quality control review criteria NCT05214157