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Authors’ contributions | LZH was involved in the conception and design of the article, LZJ was involved in the supervision and critical review and editing of the manuscript, and ZAJ, XZ, and QGP were involved in discussions about the content of the manuscript. The author(s) read and approved the final manuscript. | PMC9979534 | ||
Funding | No.41310164 | This work was supported in part by the National Natural Science Foundation of China (No.41310164). | PMC9979534 | |
Availability of data and materials | All data generated or analyzed during this study are included in this published article. | PMC9979534 | ||
Declarations | PMC9979534 | |||
Ethics approval and consent to participate | Not applicable. | PMC9979534 | ||
Consent for publication | Not applicable. | PMC9979534 | ||
Competing interests | The authors declare no competing interests. | PMC9979534 | ||
References | PMC9979534 | |||
Purpose | knee arthroplasty, TKA | Personality traits, such as dispositional optimism and pessimism, have impact on a variety of health-related problems. Influence on outcome in total knee arthroplasty (TKA) could only be shown for other personality trait concepts, but not for dispositional optimism/pessimism. This study aims to examine the association of dispositional optimism/pessimism with pre-operative joint function and post-operative outcome in TKA. | PMC10435416 | |
Methods | Knee-osteoarthritis | REGRESSION | Data were acquired in a multicentre, cross-sectoral, prospective study (the PROMISE Trial). Patients were followed for 12 months post-operatively. Dispositional optimism/pessimism was measured pre-operatively via the revised Life Orientation Test (LOT-R), pre- and post-operative function was measured via the 12 Item Knee-osteoarthritis outcome Scores (KOOS-12). Log-linear regression models considering known confounders and t-test were carried out to show the association of LOT-R scores with pre- and post-operative KOOS-12 scores. | PMC10435416 |
Results | 740 patients were analyzed. Optimistic LOT-R was significantly positively associated to the mean scores of KOOS-12 pre- and post-operative, while pessimistic LOT-R was significantly associated negatively (pre-operative: optimistic | PMC10435416 | ||
Conclusion | Optimism was positively associated with pre-operative joint function and, more importantly, post-operative functional outcome in TKA, while pessimism was associated with the opposite. Assessing patients’ general personality traits prior to surgery to identify pessimistic patients, hence being at risk for poor outcome in TKA, should be considered to react to the patients’ special needs and possible pessimistic expectations, i.e., through a cognitive–behavioral intervention, to potentially increase optimism and hereby post-operative outcome in TKA. | PMC10435416 | ||
Level of evidence | Prognostic Level III. | PMC10435416 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10435416 | ||
Introduction | osteoarthritis, end stage, OA, pain | OSTEOARTHRITIS | While total knee replacement is an overall successful procedure for pain relief and improvement of mobility in patients suffering from end stage osteoarthritis (OA), literature still reports up to 30% of patients not being satisfied with their post-operative outcome [Other research has shown that certain personality constructs have positive or negative impact on the outcome in a variety of health problems and the overall mortality [ | PMC10435416 |
Materials and methods | All study data were derived from a multicenter, cross-sectoral, prospective healthcare research study (the PROMISE Trial) which was implemented in three different German hospitals, representing all levels of care. Sample size was chosen as available. Detailed methods descriptions (e.g., surgical techniques, rehabilitation procedures, patient education, etc.) are available via the published PROMISE Trial study protocol [ | PMC10435416 | ||
Criteria for inclusion and exclusion | After Institutional Review Board approval, all patients older than 18 years that met standardized criteria for surgery [ | PMC10435416 | ||
Data collection | ’ personality dimensions | Patients were followed for 12 months post-operatively during the regular administrative procedures of the participating hospitals. Evaluation started in 05/2018 and ended in 01/2021. Baseline data (age, age at surgery, sex, type of surgery, ASA score, BMI, marital status, education level and income) for the eligible patients were elicited before surgery. Patients’ personality dimensions were queried pre-operatively using the German version of the revised Life Orientation Test (LOT-R) (Fig. Revised Life Orientation Test (LOT-R)The surveys (LOT-R, KOOS-12) were handed to included patients after informed consent during the last visit at the outpatient clinic prior to surgery (range 1–8 weeks), and post-operative at the above-described follow-ups. Patients completed the surveys on their own, with qualified study nurses on-site on demand if questions arose. Collected data was pseudonymized and stored electronically. | PMC10435416 | |
Institutional Review Board approval | Approval from all ethics committees in the participating states in Germany was obtained prior to the study [Institutional Review Board approval: Submission No.: 837.533.17 (11367), Ethics Committee at the State Chambers of Physicians of Rhineland-Palatinate; B-F-2018-042, Ethics Committee at the State Chambers of Physicians of Baden-Wuerttemberg; MC 84/2018, Ethics Committee at the State Chambers of Physicians of Hesse]. | PMC10435416 | ||
Statistical analysis | REGRESSION | To quantify the possible impact of LOT-R optimism/pessimism on post-operative outcomes, several linear regression models were fitted, in which the respective outcomes (KOOS-12 post-operative) were regressed on the study variable LOT-R optimism/pessimism. In addition to the respective study variable, each regression model included the possible confounders: age, ASA score, BMI, pre-operative KOOS-12 at baseline, EQ5D score, HSS expectation score, education background (low vs. high) and sex as covariates.To obtain the regression equation for the association of LOT-R pessimism with the respective KOOS-12 score, the LOT-R- optimism score was replaced with the LOT-R-pessimism score of a given patient.To prevent an attrition bias, all regression models were based on 10 datasets that were obtained by means of multiple imputation (using predictive mean matching as the imputation method). The imputation model included all recorded variables that were significantly correlated with LOT-R optimism/pessimism and the KOOS-variable.All statistical analyses were performed using R [R version 3.5.1, Core Team (2017)] [ | PMC10435416 | |
Results | PMC10435416 | |||
Personality traits | Mean LOT-R optimism was 10.5 (SD 2.12). Mean LOT-R pessimism was 9.4 (SD 2.03). Distributions of LOT-R optimism and LOT-R pessimism are shown in Figs. Total distribution of LOT-R optimism in the cohort. Point value > 10 indicates “very optimistic”, 7–9 indicates “somewhat optimistic”, and < 7 “not optimistic”Total distribution of LOT-R pessimism in the cohort. Point value > 10 indicates “not pessimistic”, 7–9 “rather pessimistic”, and < 7 “pessimistic” | PMC10435416 | ||
Mean functional scores | Mean KOOS Scores for pre- and post-operative follow-ups in association with the respective optimistic and pessimistic categories are shown in Tables Mean KOOS-12 scores in LOT-R optimistic valuesMean KOOS-12 scores in LOT-R pessimistic values | PMC10435416 | ||
Pre-operative function and association with dispositional optimism/pessimism | REGRESSION | Optimistic patients showed significantly higher pre-operative KOOS-12 scores compared to their not optimistic counterparts (Association between the LOT-R-optimism values and the pre-operative KOOS-12 values in the cohort. Hexagons indicate patient clusters with lighter colors indicating a higher number of patients. The continuous line indicates the slope of a univariate regression model, while the surrounding, transparent area corresponds to the standard error of the slope coefficientAssociation between the LOT-R-pessimism values and the pre-operative KOOS-12 values in the cohort. Hexagons indicate patient clusters with lighter colors indicating a higher number of patients. The continuous line indicates the slope of a univariate regression model, while the surrounding, transparent area corresponds to the standard error of the slope coefficient | PMC10435416 | |
Post-operative function and association with dispositional optimism/pessimism | Associations of LOT-R optimism and LOT-R pessimism scores with absolute post-operative KOOS-12 scores (3, 6 and 12 months) in the multivariate analysis are shown in Table Association of optimism and pessimism with 3, 6 and 12 months post-operative absolute KOOS-12 scores, when adjusting for the confounders (i.e., KOOS-12 baseline value)**Indicates statistical significanceAssociation of LOT-R optimism and pre- and post-operative absolute KOOS-12 valuesAssociation of LOT-R pessimism and pre- and post-operative absolute KOOS-12 valuesAssociation of optimism and pessimism with 3, 6 and 12 months post-operative absolute KOOS-12 scores without adjusting for confounders**Indicates statistical significance | PMC10435416 | ||
Discussion | hip arthroplasty, TKA | DISORDERS | The most important findings of this study were the significant positive/negative association of dispositional optimism/pessimism with post-operative functional outcome after TKA measured via the KOOS-12 score. Optimistic patients showed significant higher KOOS-12 scores pre-operative as well as 3, 6 and 12 months post-operative, while pessimistic patients had significant lower scores at all survey points compared to their respective counterparts.The findings of higher post-operative function in optimistic than in pessimistic patients are in line with other literature, showing better outcome in optimistic patients after total hip arthroplasty [Nevertheless, the significant higher post-operative functional scores in optimistic patients could be derived by the influence of pre-operative functional score levels on post-operative score values as this has been shown previously [Besides the overall higher satisfaction in life and after surgery in optimists [Even though the KOOS-12 is a widely used instrument in patient-reported outcome measurements (PROMs), one has to take into consideration that PROMs might not be the right instrument when measuring outcome in optimists and pessimists. Scherer et al. [When considering the study results, the question about the practical significance for orthopedic surgeons remains, especially as the MCID of the KOOS-12 was not reached at every post-operative survey point in this study, probably due to the large sample size. Nevertheless, our findings suggest considering every patient’s individual personality traits when he or she is admitted to surgery. This would allow the treating physicians to detect pessimistic patients, who tend to have worse outcomes and potentially react to their special needs and pessimistic expectations prior to surgery. A redirection of these pessimistic patients to a cognitive–behavioral intervention or an intervention on pessimism-predicting variables (e.g., preexisting mental disorders, lack of social support) prior to surgery could help to reduce pessimism and increase optimism and optimistic expectations in those patients, and thus could improve post-operative outcome. | PMC10435416 |
Limitations | depression, TKA, anxiety | This study has some limitations. First, other psychological variables known to interfere with post-operative outcome, such as depression and anxiety [However, due to the multi-center design, a large study sample size matching the general population of TKA patients in Germany [ | PMC10435416 | |
Conclusions | Dispositional optimism is positively associated with pre-operative joint function and, more importantly, post-operative functional outcome in TKA, whereas the opposite applies for pessimism. Assessing patients’ general personality traits prior to surgery to identify pessimistic patients, hence being at risk for poor outcome in TKA, should be considered to react to the patients’ special needs and possible pessimistic expectations, i.e., through a cognitive–behavioral intervention, to potentially increase optimism and hereby post-operative outcome in TKA. | PMC10435416 | ||
Author contributions | PD | FW participated in the design of the study, performed surgery, carried out data collection and abstraction, and drafted the manuscript. LE participated in the design of the study, performed surgery, carried out data abstraction and helped to draft the manuscript. RK performed statistical analysis. PD and TK conceived the study and participated in its design and coordination, performed surgery, acquired the funding, and helped to draft the manuscript. PD, YA and EW coordinated the data collection in the different centers, carried out data abstraction, and helped to draft the manuscript. JGK participated in the study design, and helped to draft the manuscript. All authors read and approved the final manuscript. | PMC10435416 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. This work was supported by the grant from the German Federal Joint Committee (01NVF16015). | PMC10435416 | ||
Data availability | The data that support the findings of this study are available on request from the corresponding author, FW. The data are not publicly available due to the German privacy laws in the medical sector. | PMC10435416 | ||
Declarations | PMC10435416 | |||
Conflict of interest | The authors declare that they have no competing interest. | PMC10435416 | ||
Ethical approval | Submission No.: 837.533.17 (11367), Ethics Committee at the State Chambers of Physicians of Rhineland-Palatinate. Submission No.: B-F-2018–042, Ethics Committee at the State Chambers of Physicians of Baden-Wuerttemberg. Submission No.: MC 84/2018, Ethics Committee at the State Chambers of Physicians of Hesse. | PMC10435416 | ||
Informed consent | Informed consent was obtained from all individual participants included in the study. | PMC10435416 | ||
References | PMC10435416 | |||
Background | depression | The study was designed to investigate effects of single intravenous injection of esketamine on the incidence of postpartum depression (PPD) after labor analgesia and explore the potential mechanisms. | PMC10668401 | |
Methods | inflammation | INFLAMMATION | A total of 120 women who underwent labor analgesia by epidural analgesia pump were enrolled and divided into two groups randomly. Esketamine at a dose of 0.2 mg/kg was intravenously injected after fetal disengagement in the test group and placebo was administered in the control group. The occurrence of PPD and side effects after delivery were recorded. Some indicators related to stress and inflammation were measured before labor analgesia and at 24 h, 1 week, and 6 weeks after delivery in this study. Data were analyzed by independent t-test, repeated measures analysis of variance and Chi-square test in SPSS software (version 25.0). It was considered statistically significant since a p value less than 0.05. | PMC10668401 |
Results | The incidence of PPD was significantly decreased both for one week and six weeks after delivery by using of esketamine (3.4% vs. 15.3%, p = 0.004 and 5.2% vs. 18.6%, p = 0.006, respectively). There were also significant differences between the stress and inflammation-related indicators in different time points in this study, while the side effects for 48 h after delivery were similar between the two groups. | PMC10668401 | ||
Conclusions | depression | INFLAMMATION | Single intravenous injection of esketamine after delivery in participants underwent labor analgesia can decrease the occurrence of postpartum depression for one week and six weeks after delivery, while the side effects were not increased. The antidepressant effects of esketamine may be related to the reduction of stress response and inflammation. | PMC10668401 |
Trial registration | The trial was registered at the Chinese Clinical Trial Registry on 5/30/2022 (CTRI registration number—ChiCTR2200060387). URL of registry: | PMC10668401 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s40360-023-00705-7. | PMC10668401 | ||
Keywords | PMC10668401 | |||
Introduction | Due to the particularity of physiology, maternal perinatal safety has been a special concern. At present, the labor analgesia is gradually recommended on the premise of ensuring maternal and fetal safety [Nowadays, medication combined with psychological counseling are mainly used for the treatment of PPD. However, long-term medication may have side effects for lactating women on the infant’s motional, behavioral and neurological development [ | PMC10668401 | ||
Methods | PMC10668401 | |||
Study design | This randomized, double-blinded, controlled trial was conducted at the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China, from 6/1/2022 to 2/28/2023, which performed in accordance with the declaration of Helsinki. The Consolidated Standards of Reporting Trials (CONSORT) recommendations were followed in this study [ | PMC10668401 | ||
Study participants | Anxiety, organic or pharmacogenic depression, mental disorder, Self-rating Depression | COAGULATION DISORDERS | One hundred and twenty primiparous women who underwent labor analgesia, aged 22 to 38, with American society of Aneshesiologists (ASA) physical status II, with 1 fetal 0 labor, pregnancy time greater than 38 weeks and less than 42 weeks, and single term pregnancy, were enrolled. The exclusion criteria were as follows: not suitable for transvaginal delivery; combined with coagulation disorders; having mental disorder; organic or pharmacogenic depression before delivery; the Self-rating Anxiety Scale (SAS) ≥ 50 or the Self-rating Depression Scale (SDS) ≥ 0.5 [ | PMC10668401 |
Sample size estimation | Based on the results of our pre-experiment (10 participants in each group), the incidence of PPD at 6 weeks after delivery can be reduced by 12% in the tested group. Power analysis showed that a reduction rate of 15% with
CONSORT flow diagram. In the study, a total of 120 participants were enrolled initially and three participants were excluded during the trial. Finally, There were 117 participants included in the statistical analysis (58 in Group E and 59 in Group C, respectively). CONSORT: the Consolidated Standards of Reporting Trials | PMC10668401 | ||
Randomization and allocation concealment | Participants were randomly assigned to one of two groups. Random tables were generated by SPSS 20.0. One hundred and twenty sealed envelopes were prepared by a statistician who did not participate in the study. The study was performed with neither patients’ nor observers’ awareness of the group to which each patient belonged. To assure concealment of allocation, numbers were kept in sealed and opaque envelopes, which were opened by an anaesthesiologist who was not involved in the study. | PMC10668401 | ||
Study interventions | After entering the delivery room, peripheral venous access was opened in all participants, maternal heart rate, noninvasive blood pressure measurement, electrocardiography and pulse oximetry were monitored. All women were received oxygen for 3 L/min by transnasal catheter. Epidural anaesthesia were operated between L | PMC10668401 | ||
Outcome measurements | depression, nausea, peripheral venous blood before labor, vomiting | SIDE EFFECTS, POSTPARTUM HEMORRHAGE | The primary outcomes of the study were the incidence of PPD at one week and six weeks after delivery. The diagnosis of postpartum depression was based on the reference [Ramsay sedation score before analgesia (TAll women were tested levels of norepinephrine (NE), epinephrine (E) ,C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-10 (IL-10) in peripheral venous blood before labor analgesia (when the woman was quiet in the ward), at 24 h, 1 week, and 6 weeks after delivery. Serum concentrations of IL-6 and IL-10 were determined by enzyme linked immunosorbent assay (ELISA).The duration of the first and second stage of labor, the Apgar score of fetus at delivery, and the volume of postpartum hemorrhage was calculated for 24 h after delivery. Side effects such as nightmares, drowsiness, nausea and vomiting were measured for 48 h after delivery as well. | PMC10668401 |
Statistical analysis | The statistical analysis were performed using SPSS software package (version 25.0; IBM, Inc., Chicago, IL, USA). The continuous data were presented as mean (M) ± standard deviation (SD) and examined by independent t-test. The categorical data were shown as n(%) and examined with a Chi-square test. It was considered statistically significant since a p value < 0.05. | PMC10668401 | ||
Results | PMC10668401 | |||
Patient recruitment | failure of epidural puncture | In the study, a total of 120 participants were enrolled initially and three participants were excluded during the trial. One case was excluded for failure of epidural puncture, and another one was for changed to cesarean section in Group E, while one participant was excluded for failure of epidural puncture in Group C. Finally, There were 117 participants included in the statistical analysis (58 in Group E and 59 in Group C, respectively. Figure | PMC10668401 | |
Discussion | TRD, Pain, inflammation, ’ mood, pain, infection, hallucination, depression | INFLAMMATION, INFECTION | Pain in the perinatal period is one of the factors leading to the development of PPD. The symptoms of PPD are more prominent in women who experience frequent pain during childbirth [The traditional treatment for depression is to increase the amount of serotonin in the synaptic space to achieve the effect of alleviating depression, but these antidepressants are slow to act, generally taking three to six weeks to achieve therapeutic effects [Another retrospective analysis have showed that both esketamine’s approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, though the efficacy of esketamine compared to racemic ketamine remained unclear [As endocrine hormones, NE and E can affect the bodies’ mood by modulating the sensitivity of neuronal synapses and neurotransmitters [As a non-specific inflammatory marker, CRP reflects the stress and inflammation response of the human body. When infection and injury take place, CRP rises sharply in the plasma [Studies have shown the brain causes negative emotions by the clustering of the lateral halterate nucleus, where the excitatory transmitter is the N-methyl-D-aspartate (NMDA) receptor of the glutamate-gated ion channel [Esketamine has been used clinically for many years as an anesthetic drug, which is now also widely concerned as a new antidepressant. Considering the possible side effects such as nightmare, hallucination and abusement [There were some limitations in this study, such as the strong subjectivity of the PPD evaluation by EPDS. To minimize the subjective differences, the PPD valuator in this study was the same physician who did not participate in the specific study. Furthermore, the objective indicators such as levels of, NE, E, CRP, IL−6 and IL−10 were also combined in the study, which could better reflect maternal depression. Furthermore, the severity of PPD was not measured in this study, which would be content of next studies. | PMC10668401 |
Conclusions | depression | INFLAMMATION | In conclusion, single intravenous injection of esketamine (0.2 mg/kg) after delivery in participants underwent labor analgesia can decrease the occurrence of postpartum depression for one week and six weeks after delivery, while the side effects were not increased. The antidepressant effects of esketamine may be related to the reduction of stress response and inflammation. | PMC10668401 |
Authors’ contributions | BL, YZ, HX, HC and WW designed the study. QWsupervised the practical carrying out of the clinical trial. WY participated in the study’s conceptualization and sampling. ZY and HX analyzed the data. BL, YZ and WW wrote the manuscript. All authors read and approved the final manuscript. | PMC10668401 | ||
Funding | No funding was received for conducting this study. | PMC10668401 | ||
Data Availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Wei Wang, e-mail: wangwei2024@163.com. | PMC10668401 | ||
Declarations | PMC10668401 | |||
Ethics approval and consent to participate | The study was performed in accordance with the declaration of Helsinki. Ethical approval for this study (2021-03-031-K01) was provided by the Institutional Ethics Committee of the Affiliated Jiangning Hospital of Nanjing Medical University. The registration of this study was approved in the Chinese Clinical Trial Registry on 5/30/2022 (CTRI registration number—ChiCTR2200060387). All volunteers involved were informed of the proposal and gave their written, informed consent. | PMC10668401 | ||
Consent for publication | Not Applicable. | PMC10668401 | ||
Competing interests | The authors declare no conflict of interests. | PMC10668401 | ||
Abbreviations | Depression | postpartum depressionAmerican society of Anesthesiologistsconsolidated standards of reporting trialsthe Self-rating Anxiety Scalethe Self-rating Depression ScaleEdinburgh Postpartum Depression ScalenorepinephrineepinephrineC-reactive proteininterleukin-6interleukin-10N-methyl-D-aspartate | PMC10668401 | |
References | PMC10668401 | |||
Background | breathlessness, COPD, Chronic breathlessness | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD | Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. | PMC10447378 |
Methods | COPD | COPD | Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. | PMC10447378 |
Results | breathlessness | Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). | PMC10447378 | |
Conclusions | chronic breathlessness, breathlessness | BRAIN | Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain’s expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness. | PMC10447378 |
WHAT IS ALREADY KNOWN ON THIS TOPIC | chronic breathlessness, breathlessness, COPD | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD | Pulmonary rehabilitation is an effective treatment for many, but not all people with chronic obstructive pulmonary disease (COPD who suffer from chronic breathlessness in COPD. Baseline patient characteristics predicting improvements in breathlessness are unknown. | PMC10447378 |
WHAT THIS STUDY ADDS | breathlessness, prerehabilitation breathlessness | This is the first study to identify a model capable of predicting changes in breathlessness over pulmonary rehabilitation at the individual patient level. The study shows that prerehabilitation breathlessness expectation related brain activity is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. | PMC10447378 | |
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY | chronic breathlessness | Manipulation of the brain’s expectation pathways (either pharmacological or non-pharmacological) merits further testing in the treatment of chronic breathlessness. | PMC10447378 | |
Introduction | chronic breathlessness, cognitive behavioural, breathlessness, depression, COPD | CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD | Chronic breathlessness is a key feature of chronic obstructive pulmonary disease (COPD) with symptoms often persisting despite maximal medical therapy. Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPDBreathlessness severity is often poorly explained by objective clinical measures.Between-subject variability in therapeutic response is increasingly recognised as a confounder in clinical trials. A personalised medicine approach aims to identify subgroups of patients that respond to a specific therapy. In psychiatry, brain-derived metrics using functional neuroimaging have taken similar approaches to identifying subtypes of depression that may respond to bespoke therapies.In this study, we aimed to predict improvements in breathlessness during pulmonary rehabilitation by analysing baseline data from a longitudinal experimental medicine study of D-cycloserine on breathlessness during pulmonary rehabilitation. We selected D-cycloserine, which is a partial agonist at the NMDA receptor in the brain, for its action on neural plasticity and influence on brain expectation mechanisms associated with cognitive behavioural therapies. | PMC10447378 |
Methods and materials | A brief overview of materials and methods is presented here with full details included within
| PMC10447378 | ||
Participants | Seventy-one participants (18 female, median age 71 years (46–85 years)) ( | PMC10447378 | ||
Study protocol | Data for this analysis were acquired at baseline assessment held at the start of a pulmonary rehabilitation course, and following completion of the pulmonary rehabilitation at 6–8 weeks. At each study visit, identical measures were collected. Following the first visit, participants were randomised in a double-blind procedure to receive either 250 mg oral D-cycloserine or a matched placebo. Participants received a single dose on four occasions 30 min prior to the onset of the first four pulmonary rehabilitation sessions. | PMC10447378 | ||
Self-report questionnaires | Depression, breathlessness, Anxiety, Fatigue | All questionnaires (List of measures included within each of the three models (indicated by ‘X’)Drug ID labels corresponded to whether the participant received D-cycloserine or placebo.BCS, breathlessness catastrophising scale; BMI, body mass index; BORG, rating of perceived exertion; CES-D, Centre for Epidemiologic Studies Depression Scale; D12, Dyspnoea-12; FEV1, forced expiratory volume; FSS, Fatigue Severity Scale; FVC, forced vital capacity; HR, heart rate; MRC, Medical Research Council; MSWT, Modified Shuttle Walk Test; SGRQ, St George’s Respiratory Questionnaire; SPO2, oxygen saturation; TRAIT, Trait Anxiety Inventory. | PMC10447378 | |
Physiological measures | Spirometry and two Modified Shuttle Walk Tests (MSWT) were collected using standard protocols. | PMC10447378 | ||
MRI measures | PMC10447378 | |||
Image acquisition | MRI of the brain was carried out using a Siemens 3T MAGNETOM Trio. A T1-weighted (MPRAGE) structural scan (voxel size: 1×1 × 1 mm) was collected and used for registration purposes. A T2*-weighted, gradient echo planar image (EPI) scan sequence (TR, 3000 ms; TE 30 ms; voxel size: 3×3×3 mm) was used to collect functional imaging data during the word cue task. | PMC10447378 | ||
Word cue task | fearful breathlessness, breathlessness | Given sufficient fearful breathlessness exposures, the suggestion alone of the situation can be sufficient to drive a top-down neural cascade and produce breathlessness in the absence of afferent inputs. We drew on this link to probe the neural responses of breathlessness-related expectation by examining the activity of brain regions responding to breathlessness-related word cues. | PMC10447378 | |
Analysis | PMC10447378 | |||
Regions of interest | Fifteen regions of interest were selected a priori (Region of interest map showing 15 brain areas. | PMC10447378 | ||
Brain imaging analysis | BRAIN | Image processing was carried out using the Oxford Centre for Functional MRI of Brain Software Library (FMRIB, Oxford, UK; FSL V.5.0.8; | PMC10447378 | |
Preprocessing and single subject models | Data were preprocessed according to standard protocols which included motion correction and physiological noise removal, before being entered into single subject general linear models. These models captured brain activity during the periods in which the breathlessness-related word cues were presented allowing us to examine expectation-related processes ( | PMC10447378 | ||
Definition of response to pulmonary rehabilitation | breathlessness | REGRESSION | Responsiveness to pulmonary rehabilitation was defined as a change in D12 score, a well-validated clinical measure of breathlessness, of three or more points, consistent with the minimal clinically important difference.Logistic regression coefficients for predictive power of the computationally derived brain-behaviour model (model prediction labels), and baseline D12 on pulmonary rehabilitation outcome, measured as a change in D12 score above the minimal clinical important differenceSignificance is expressed as false discovery rate (FDR)—corrected p values.D12, Dyspnoea-12. | PMC10447378 |
Predictive models | PMC10447378 | |||
Physiological measures | confusion | Spirometry and two MSWT were collected using standard protocols.Models were programmed using R V.3.6.1 (2019-07-05). Modelling procedure remained the same for each of the three models (A schematic of the modelling procedure adapted from an illustration by Chekroud and colleagues.All measures were centred and scaled. Checks were performed to determine whether any measures were highly correlated (R>0.8) or linear combinations of each other.To correct for imbalance in the number of responders/non-responder a resampling procedure. Imbalanced classes can affect classifier performance. Random OverSample Examples (ROSE) was carried out. ROSE, an R package, creates an artificially balanced sample using a smoothed bootstrap approach.An elastic net procedure was used to identify the number most relevant features for inclusion into the model. Elastic net procedure was selected for its ability to regularise, improve data sparsity via feature selection and cluster correlated measures together (for more details see Model training parameters—C, kappa and sigma were selected based on an internal repeated cross-validation procedure (10-fold cross validation repeated 3 times). In all instances automated tuning parameter selection for the values, with a tune length of 5, was used within R’s caret package. Train test data were kept separate across folds, with the algorithm never having access to the entire dataset. The best tuning parameters were selected automatically by R’s caret package from across cross validation folds.These parameters were used to train a Support Vector Classifier with radial kernel to predict outcomes in the entire dataset.Model performance was assessed internally using accuracy, sensitivity, specificity and area under the curve. Full confusion matrices are presented along with calibration curves. Model significance was assessed with a one-tailed binomial test of model accuracy compared with the null information rate. | PMC10447378 | |
Results | PMC10447378 | |||
Participants | breathlessness | At baseline the median MRC breathlessness score of the 71 participants was 3 (IQR 1), median FEV1/FVC (forced expiratory volume/ forced vital capacity) was 0.55 (IQR 0.15), median FEV1% predicted was 58 (IQR 21). | PMC10447378 | |
Responders and non-responders | A total of 41/71 participants in the primary dataset met the criteria of a change in D12 score of three or more points to be considered a responderAverage scores on questionnaire and behavioural measures before and after pulmonary rehabilitationVariance is expressed as IQR.Significance is reported as exploratory uncorrected p values and as family wise error (*p<0.05) corrected values.D12, Dyspnoea-12; MSWT, Modified Shuttle Walk Test. | PMC10447378 | ||
Feature selection: brain imaging only model | The elastic net procedure identified 13 of 15 brain-derived metrics and drug as relevant for model inclusion ( | PMC10447378 | ||
Feature selection: brain and non-imaging measure model | The elastic net procedure identified 12 of 15 brain-derived metrics, 13 of 20 non-imaging measures including drug as relevant for model inclusion ( | PMC10447378 | ||
Feature selection: non-imaging measures model | Of the 20 questionnaire and physiological features available, only D12 survived the feature selection process ( | PMC10447378 | ||
Model results: internal validation | CORTEX | Three models with variables selected by the elastic net procedure were assessed for their ability to discriminate responders from non-responders (Model statistics for brain imaging only, brain and non-imaging measure models and non-imaging measures only modelAll models contained drug ID as an additional term.P value is expressed as the result of a one-tailed binomial test of model accuracy compared with the null information rate.*p<0.05AUC, area under the curve.The combination of brain and behaviour metrics produced the best classification performance (accuracy—0.83 (95% CI 0.75 to 0.90); sensitivity—0.88; specificity—0.77; p<0.001) and was well calibrated (Schematic representation of the best predictive model. Predictive brain imaging and non-imaging measures are shown linked to treatment response by weighted lines, indicating variable importance. ACC, anterior cingulate cortex; BMI, body mass index; D12, Dyspnoea-12; HR, heart rate; MRC, Medical Research Council; MFG, middle frontal gyrus; MSWT, Modified Shuttle Walk Test; SMG, supramarginal gyrus; SpO2, oxygen saturation. | PMC10447378 | |
Discussion | PMC10447378 | |||
Key findings | breathlessness, post-traumatic stress disorder, anxiety, pain | Using supervised machine learning, this study successfully identified markers that predict clinically relevant improvements in breathlessness over a course of pulmonary rehabilitation. The best model combined brain-imaging markers of breathlessness-expectation, self-report questionnaires and physiology measures, and demonstrated high sensitivity and specificity. Whether or not a participant received D-cycloserine was a significant feature in this model. Our findings demonstrate the first predictive model of change in breathlessness across pulmonary rehabilitation and, for the first time, the clinical relevance of expectation-related brain activity as a therapeutic target in the treatment of breathlessness.To date, no study has produced a model capable of predicting an individual’s change in breathlessness over pulmonary rehabilitation from baseline traits.Expectation has been linked with symptom severity across conditions including breathlessness and pain,Fear and anxiety are key components of expectation, which recent research suggests may play a key role in the mechanisms and maintenance of breathlessness.In this study, we focused on brain activity changes within a set of pre-selected regions of interest associated with breathlessness-expectation and body and symptom perception.Using data-driven techniques, 13 of the 15 brain-derived metrics (and drug) were identified as relevant for model inclusion. Selected brain areas spanned the components of relevant body and symptom perception and emotional salience networks. The resulting brain-only model, while statistically significant (p=0.02) and possessing good sensitivity (0.93), did not distinguish responders from non-responders with sufficient specificity (0.40).By, enriching the brain-only models with questionnaire and physiology measures improved performance considerably. In this enriched model, 12 brain-derived metrics and 13 non-imaging-derived metrics, which included self-report questionnaire measures, physiology and drug, were identified as relevant for model inclusion. Measures of accuracy (0.83), sensitivity (0.88) and specificity (0.77) all suggest this model was able to significantly (p<0.001) predict pulmonary rehabilitation outcome.Within the non-imaging measure only model, D12 alone was selected by the elastic net and was not found to be significantly (p=0.09, sensitivity=0.68, specificity=0.20) predictive of pulmonary rehabilitation outcome. No other of the 13 non-imaging-derived metrics available was found to contribute to the model. That only D12 was selected suggests that the remaining measures, which were important predictors of rehabilitation outcome in the enriched model, interact strongly with brain activity. These results highlight the value of approaching breathlessness from a multimodal data perspective.The retained brain activity features implicate a range of brain networks encompassing functions of cognitive control, symptom perception and sensory integration. Activity within these regions has been shown to predict outcome to cognitive behavioural therapy in social anxiety disorderD-cycloserine has been shown to augment changes to expectation, boosting the therapeutic effects in trials examining anxiety, post-traumatic stress disorder and other mental health conditions, | PMC10447378 | |
Limitations and future work | breathlessness | EVENTS | The major limitation of this study is the lack validation of the model in an external dataset. While some studies hold out a proportion of the original data to create an external validation dataset, this technique was not possible here due to restrictions of sample size. To address these limitations, we used a cross validation approach to provide an indication of out of sample transferability in which the support vector machine was exposed to multiple iterations of the sub-sampled dataset during model training, and therefore never ‘saw’ the entire dataset until the test phase. Models with a large number of measures compared with events (responder or non-responder) risk overfitting and demonstrate poor generalisability to novel datasets. Our dataset contained 35 potential features and therefore was at risk of overfitting. To address this issue, we reduced the number of data-dimensions via feature selection, employed cross-validation and used an automated tuning of the regularisation parameter ‘C’. However, while these techniques may ameliorate some of the risk of overfitting, a future study with larger sample size, or independently collected datasets, would take the next steps to externally validate the brain-behaviour model and allow assessment of generalisability.A key feature of support vector machines is that they fit high-dimensional discriminatory planes between multiple measures to predict an outcome. This multivariate approach affords greater sensitivity in distinguishing between non-separable distributions along a single dimension. The additional use of a non-linear kernel also enables us to capture relationships between highly disparate biological features which often demonstrate non-linear profiles and as a result predict changes in breathlessness. Although this technique leads to less intuitive interpretations of feature weightings, the methods used are the first to successfully demonstrate a relationship between breathlessness expectation related brain activity and changes to reported breathlessness over pulmonary rehabilitation. To reconcile these challenges and move towards eventual clinical application, we suggest that this model form the basis for further studies scrutiny via first an external validation dataset and then further interventional studies.While larger sample sizes are now required to translate these mechanistic models into clinical relevance, the data provides evidence that breathlessness expectation related brain activity at baseline strongly influences how patients respond to treatment in a predictable manner. | PMC10447378 |
Data availability statement | Data are available on reasonable request. | PMC10447378 | ||
Ethics statements | PMC10447378 |
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