Brain functional connectivity changes on fMRI in patients with chronic pelvic pain treated with the Neuro Emotional Technique: a randomised controlled trial

Background: chronic pelvic pain is a substantial clinical challenge that profoundly impacts quality of life for many women. The neuro emotional Technique (ne T) is a novel mind-body intervention designed to attenuate emotional arousal of distressing thoughts and pain. This study evaluated functional connectivity changes in key areas of the brain in patients with chronic pelvic pain receiving the ne T intervention. The goal was to assess whether the ne T intervention was associated with functional connectivity (Fc ) changes in the brain related to reductions in emotional distress and pain, particularly in the limbic areas, sensory/pain regions, and cerebellum.

This is a prospectively designed study that included twenty-six patients with a diagnosis of chronic pelvic pain who were randomised to either the neT intervention or a waitlist control. To evaluate the primary outcome of neurophysiological effects, all participants received resting state functional blood oxygen level dependent (BolD) magnetic resonance imaging (rs-fMRI) before and after the neT intervention or waitlist control period. Pain, mood, anxiety, and quality of life also were assessed.

c ompared to the control group, the ne T group demonstrated significant improvements in pain interference and pain intensity, and in emotional measures such anxiety and depression. Functional connectivity in the ne T group compared to controls, was significantly decreased in the amygdala, cerebellum, and postcentral gyrus. There were also significant correlations between Fc changes and changes in clinical measures.

This study is an initial step towards describing a neurological signature of reducing emotional distress in women with chronic pelvic pain. Specifically, Fc changes between the cerebellum and the amygdala and sensory areas appears to be associated with a reduction in pain and the effects of that pain. Future, larger clinical trials are warranted to further evaluate these mechanisms and ne T as a potential therapeutic intervention in patients with chronic pelvic pain. PLAIN LANGUAGE SUMMARY chronic pelvic pain is a serious problem that can make everyday activities like sitting, driving, and even intimate moments very difficult. chronic pain can also lead to feelings of anxiety and depression, which can make the pain feel worse. The neuro emotional Technique (ne T) is a type of therapy focusing on emotional distress, often a big part of chronic pain that lowers quality of life. This study looked at whether ne T could help people with chronic pelvic pain by reducing their pain, lowering emotional distress, and improving how their brain handles pain. The results showed that people who had neT felt less anxious and depressed. They also had changes in the parts of their brain that deal with pain and emotions, and were linked to less pain and better emotional coping. This study suggests that ne T might be a helpful treatment for people dealing with chronic pelvic pain.

chronic pelvic pain ( cPP) in women is a well-known but poorly understood phenomenon. It affects approximately one quarter of all women worldwide and is usually treated by gynecological specialists ( a hangari 2014). cPP arises from several aetiologies, most commonly endometriosis, pudendal neuralgia, high tone pelvic floor dysfunction, and interstitial cystitis, with endometriosis one of the most common of these conditions (Raimondo et  al. 2023). The resultant cPP can be severely limiting and debilitating, affecting basic life activities such as sitting, driving, exercise, and importantly, sexual © 2025 t he a uthor(s). Published by i nforma uK limited, trading as taylor & f rancis Group CONTACT a ndrew b. newberg [email protected] t homas Jefferson university, 789 east lancaster a venue, suite 110, Villanova, P a 19085, usa. supplemental data for this article can be accessed online at https://doi.org/10.1080/01443615.2025.2472767. t his article has been corrected with minor changes. t hese changes do not impact the academic content of the article. https://doi.org/10.1080/01443615.2025.2472767 t his is an o pen a ccess article distributed under the terms of the c reative c ommons a ttribution license ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. t he terms on which this article has been published allow the posting of the a ccepted Manuscript in a repository by the author(s) or with their consent. ARTICLE HISTORY Received 10 July 2024 a ccepted 22 February 2025

a mygdala functional connectivity; cerebellar functional connectivity; chronic pelvic pain; emotional trauma; functional magnetic resonance imaging; neuro emotional Technique 2 D. a. MonTI e T al. function ( acoG Practice Bulletin 2020). c ommon to cPP are emotional symptoms of anxiety and depression, or physical or sexual abuse (Meltzer-Brody et  al. 2007). Pain is a process that is mediated by the nervous system through changes that occur both peripherally and centrally (c ervero et  al. 1994). Using neuroimaging tools, researchers have begun exploring cnS changes induced by pain and the effects of various pain therapies ( a dler et  al. 1997, Kupers et  al. 2000). observations, including those from our group, have identified alterations in the brain’s pain matrix during chronic pain and its modulation through pharmacological and non-pharmacological therapies (newberg et  al. 2011, Støttrup et al. 2023). Key regions implicated in the pain matrix include the thalamus, amygdala, sensory areas, prefrontal cor - tex, and cerebellum. chronic pain also involves changes in the insular cortex and frontal lobes ( yang et  al. 2024). Specific pain conditions, such as cPP , are associated with disruptions in the salience network, anterior cingulate gyrus, and sensory regions (Kutch et  al. 2017). Functional connectivity (Fc ) in these networks is typically heightened, intensifying the inter - play between pain and emotional responses (Martucci et  al. 2015, a s-Sanie et  al. 2016). Patients with chronic pain frequently seek non-pharmacological and non-surgical management of their symptoms, with overall limited effectiveness (Urits et  al. 2021). This study explores a novel intervention, the neuro emotional Technique (neT), previ- ously shown to modulate autonomic nervous system function and affect emotional connectivity pathways in the brain that overlap with pain perception. The intervention combines emo - tional, cognitive, and motor processing in a standardised format designed to help patients reduce their psychophysiological reac- tivity to distressing memories, thoughts, and perceptions, includ- ing those related to pain. We have previously reported on brain responses to the ne T intervention in distressed cancer patients. Utilising functional magnetic resonance imaging (fMRI) signifi - cant changes in the brain’s reactivity to distressing stimuli were demonstrated (Monti et  al. 2017, 2018), as well as changes in Fc, including areas that overlap with pain regulation. Specifically, we have found changes in the amygdala, cerebellum, and prefrontal cortex associated with the neT intervention. Given the overlap between the brain areas previously observed to be affected by ne T and those involved with chronic pain, we wanted to assess whether ne T might have a clinical impact on patients with cPP . Given that chronic pain is often associated with heightened Fc in networks linking sensory, cer - ebellar, and emotional regions, we hypothesised that the inter - vention would result in decreased Fc between these regions. Furthermore, these reductions in connectivity were anticipated to be associated with improvements in pain and emotional symptoms in the treatment group. Thus, our primary outcome was the change in Fc based on MRI data, and the secondary outcomes were the self-reported clinical measures of pain per - ception and emotional status (e.g. anxiety and depression).

Participants The study was a prospectively designed study. Subjects enrolled were adult females with cPP of at least 3 months in duration. The specific cause of the pelvic pain was not exclu - sionary, but potential participants were excluded if they had pelvic surgery or any stimulators implanted. Patients were excluded if they had any history of significant and active medical or neurological conditions. Patients were excluded if they had any other major mental disorder or were actively participating in another emotional therapy. They were allowed to continue current treatments for their pelvic pain as long as there were no substantive changes in the three months prior to enrolling in the study. Patients were recruited through the Department of obstetrics and Gynaecology and from posted advertisements at the Sidney Kimmel c ancer c entre at Thomas Jefferson University. This study was also posted on clinicaltrials.gov (nc T03233594). a s an initial screening, potential participants were asked to describe their pain on a scale from 0 to 10 with 10 being the worst pain imaginable, and had to have a score of 7 or higher. This cut-off is at a level considered severe enough to significantly interfere with daily functioning which would establish the diagnosis of the patients and opti - mise the ability to evaluate the effect of the ne T intervention (Wolpe 1973, Boonstra et  al. 2016). a total of 26 participants met the full criteria for participa - tion in the study ( Figure 1 and Table 1), a number consistent with our prior study of ne T in cancer patients which showed significant findings in Fc (Monti et  al. 2018). The subjects were randomised using a permuted block design into two parallel groups (IBM SPSS Statistics) that were not significantly different. The randomisation was performed by the one of the investigators ( aBn) and provided to the study coordinator who placed subjects into their respective treatment arms upon enrolment. Thirteen subjects were assigned to the ne T intervention group (average age of 43.0 ± 15.7 years) and thir - teen were assigned to the waitlist control condition (average age of 42.8 ± 13.6 years). The mean BMI for the ne T group was 22.5 ± 3.9 and for the control group was 26.9 ± 6.6. Patients had four potential diagnoses – endometriosis, pudendal neu - ralgia, high tone pelvic floor dysfunction, and interstitial cys - titis. once enrolled, subjects received a battery of psychological and pain measures (see below) and the initial MRI scan with rs-fMRI. Ethical approval This study was approved (17D.163) by the Institutional Review Board of Thomas Jefferson University. a ll procedures per - formed in this study involving human participants were in accordance with the ethical standards of the Institutional Review Board of Thomas Jefferson University and with the 1964 Helsinki declaration. Participating women signed an informed consent form at the first study visit. NET intervention The ne T intervention consisted of five sessions which were approximately one hour in length, typically one per week. a ll sessions were led by a ne T-certified, licenced psychologist (aT). o ur previous work suggests that five sessions usually are sufficient for the intervention to address the distress of a BRaIn FUnc TIon cHanGeS In cHR onIc Pel VIc PaIn TReaTeD WITH ne T 3 given situation (Monti et  al. 2017). The focus of the sessions was on the subjective experience of the pain and its distress - ing effects on all dimensions of life. During the desensitisa - tion aspect of the protocol, while thinking about the distressing aspects of the pain experience and the cognitions and emotions associated with it, participants were asked to do simple breathing exercises. The intervention integrates the use of acupressure points on the wrists that are thought to correlate with specific emotional qualities in the Traditional chinese Medicine system. Targeted acupressure has shown promise for relieving stress and anxiety ( cho et  al. 2021). The focus of the ne T sessions was on the experience of chronic pain with an emphasis on stress-related aspects of the pain. In summary, the ne T protocol for this study targeted the emotions, cognitions, energy, and autonomic activation related to stressful aspects of the pain experience. The participants underwent the same battery of clinical and fMRI evaluations after the ne T intervention that they underwent prior to the intervention. The participants who were placed in the waitlist control group continued usual care for the cPP between the two scans, and all were offered the opportunity to undergo the ne T intervention after the study period. The waitlist period with standard care is also used to try to balance the patient’s expectation of therapeu - tic improvement since it is not clear what would be an ade - quate placebo condition that would match the elements of ne T without providing a specific therapeutic benefit. Figure 1. consort flow sheet diagram of the study participants. Table 1. d emographics for the two study groups. demographic data c ontrol net Mean ± sd Mean ± sd age 42.8 ± 13.6 43.0 ± 15.7 body mass index 26.9 ± 6.6 22.5 ± 3.9 diagnoses ic-5; eM-2; Ht -4; Pn-8 ic-4; eM-5; Ht -5; Pn-6 back depression inventory 15.9 ± 12.9 13.6 ± 11.0 Physical function 16.2 ± 3.7 16.5 ± 3.9 ic = i nterstitial cystitis; eM = endometriosis; Ht = High tone pelvic floor dys - function; Pn = Pudendal neuralgia; sd = s tandard deviation. 4 D. a. MonTI e T al. Psychological assessments a ll assessments were conducted in the same office environ - ment and were collected and managed using the computer based ReDc ap electronic data capture tools hosted at yale University (Harris et  al. 2009, 2019), so that the assessor is not involved in acquiring this data. a ll participants completed the Beck Depression Index (Beck et  al. 1961), Spielberger State Trait a nxiety Index Spielberger 1983), and PR oMIS ( c ella et  al. 2010, a mtmann et  al. 2010) which is a clinical scale that eval - uates physical function, anxiety, depression, fatigue, sleep quality, pain interference, and pain intensity. fMRI Imaging protocol Resting-state fMRI data was obtained using the similar pro - tocol as we have used in prior studies (Monti et  al. 2018, Vedaei et  al. 2021). Briefly, all patients were scanned using a 3 T Siemens Biograph mMR Pe T-MR scanner with a 32-channel head coil. Initially, an anatomical T1-image was obtained for all subjects to check for any radiological find - ings of brain abnormality or injury, and for further segmen - tation and registration steps during data pre-processing. next, a resting state BolD scan was collected using an e cho Planar Imaging (ePI) sequence to examine intrinsic Fc of the brain regions. The following imaging parameters were used: FoV = 23.6 cm; voxel size = 3 × 3 × 4 mm3; TR = 2.0 s; Te = 30 ms; slice thickness = 4 mm; number of slices = 34; number of volumes = 180; and acquisition time = 366 s. During rs-fMRI, the subjects were instructed to close their eyes, keep their heads still, and rest quietly without thinking about anything. Data processing MRI processing was performed in a manner similar to our prior studies evaluating Fc with ne T (Monti et  al. 2018, Vedaei et  al. 2021). a ll rs-fMRI data were preprocessed using Data Processing & a nalysis for Resting-State Brain Imaging (DPaBI, V5.1_201201; http://rfmri.org/dpabi) based on Statistical Parametric Mapping (SPM12; http://www.fil.ion.ucl.ac.uk/spm) running on M aTlaB R2020b (The Maths Works, Inc., natick, M a, USa ). The pre-processing steps are summarised here and are similar to our prior studies of the ne T. each individual T1-weighted struc- tural image was co-registered to the mean of the realigned ePI images. a fter this step, all resting-state data were spatially nor - malised to the ePI template in Montreal neurological Institute (MnI) space with a resampling voxel size of 3 × 3 × 3 mm. c orrection for head motion was applied (Vedaei et  al. 2022). Then, signal from white matter and cerebrospinal fluid were regressed out and filtered with a temporal band-pass of 0.01– 0.08 Hz to reduce the effects of low-frequency drifts and high-frequency respiratory and cardiac noise. Functional connectivity analysis Seed-based voxel-wise Fc analysis was carried out after band-pass filtering of 0.01–0.08 Hz. The seed regions were cre - ated as a spherical 5-mm region of interest (R oI) around the centre of mass coordinates. The seeds used included the follow- ing that were based on prior studies of the ne T as well as regions expected to be involved with chronic pain (Monti et  al. 2018): a mygdala, a nterior cingulate, c erebellum c rus, cerebellum, Hippocampus, Insula, Postcentral, Precentral, Supplementary motor area; all left and right sides. Fc was mea - sured using Pearson’s correlation coefficient between time series of the seeds and the rest of the time series in the gray matter area. For standardisation purpose, a Fisher’s z-transform was applied to change Fc to Z values and standardised Fc maps were obtained. These converted z-score maps of Fc are referred to as the Pearson correlation coefficient maps (Vedaei et al. 2022). Statistical analysis Statistical analyses are performed in an automated manner with the subjects separated by groups. o ur primary outcome was the change in Fc based on MRI data, and the secondary outcomes were the self-reported clinical measures of pain perception and emotional status (e.g. anxiety and depres - sion). a nalysis of covariance ( ancoV a ) analysis was executed to estimate group-by-time interaction between treatment and control groups and baseline and follow-up scans. Gaussian Random Field (GRF) was applied for correction of multiple comparison with p-value voxel < 0.05 and the minimum clus - ter size was defined 200 voxels. The motion parameters and age were used as covariates. Partial correlation analysis was conducted to estimate the correlation between the neuropsychological scores and the rs-fMRI metrics, controlling for age and gender as the covari - ates. The clusters showing significant differences from ancoV a analysis were selected as regions of interest (R oIs). The mean of Fc was extracted over the mask of R oIs. Spearman’s rank correlation coefficients between the mean values of seed-based Fc and neurophysiological scores were generated for all the patients within the nutrition and the control groups. The linear correlation being considered signif - icant if p value was less than 0.05. For the secondary outcomes related to clinical and psycho - logical measures, a paired t-test was used to compare within group differences between the pre and post evaluation time points, and a repeated measures anoV a was used to deter - mine the group vs time differences (IBM SPSS Statistics).

Clinical results The clinical data demonstrated significant improvements in the neT group between the pre and post time points in specific measures related to anxiety, depression, fatigue, pain percep - tion, and pain interference (Table 2). The results with (*) indicate significant difference between the ne T and control group. Functional connectivity results There were significant changes observed in Fc in the ne T group compared to the control group between the pre and BRaIn FUnc TIon cHanGeS In cHR onIc Pel VIc PaIn TReaTeD WITH ne T 5 post scan conditions. These are shown in Table 3 with repre - sentative examples shown in Figure 2( a –e). Correlational analysis The correlation between changes of resting-state Fc (in the significant clusters found from ancoV a ) was measured with changes of clinical scores ( Table 4).

This study evaluated brain Fc in patients with cPP who received ne T to address both the pain itself as well as the distressing emotional elements of pain that may contrib - ute to suffering. The results suggest that the ne T inter - vention was clinically useful in patients with cPP , with specific improvements in pain intensity, pain interference, depression, and anxiety symptoms. clinical improvement was associated with Fc changes in both affective and pain regions of the brain. This data is an important step in understanding the mechanism of treatment effect when addressing the emotional distress associated with chronic pain. There were a number of significant changes observed in patients treated with the ne T intervention compared to controls including cerebellar regions, post-central sensory Table 2. d ifferences in clinical measures in the net and waitlist control group showing significant improvements in the net group with * representing significance between the net and control groups. neuropsychological tests c ontrol net baseline f ollow-up Group p-value baseline f ollow-up Group p-valueMean ± sd Mean ± sd Mean ± sd Mean ± sd state trait anxiety inventory state anxiety 44.5 ± 11.0 45.6 ± 8.7 0.362 40.7 ± 9.0 38.1 ± 8.2 0.180 trait anxiety 49.8 ± 7.5 50.0 ± 8.1 0.468 46.0 ± 8.2 42.5 ± 5.4 0.045 back depression inventory 15.9 ± 12.9 17.2 ± 11.2 0.174 13.6 ± 11.0 8.8 ± 8.5 0.032* ProMis -29 Physical function 16.2 ± 3.7 15.4 ± 4.2 0.130 16.5 ± 3.9 16.3 ± 5.0 0.349 a nxiety 9.76 ± 2.8 15.4 ± 2.8 0.169 10.0 ± 4.5 7.9 ± 3.2 0.015* depression 9.7 ± 4.4 10.2 ± 4.5 0.200 7.1 ± 3.5 6.2 ± 3.0 0.080 f atigue 12.5 ± 3.6 13.4 ± 4.3 0.198 14.1 ± 3.7 10.6 ± 4.0 0.002* sleep quality 11.6 ± 3.1 11.4 ± 3.6 0.390 11.2 ± 4.4 9.9 ± 4.2 0.152 Pain interference 14.3 ± 4.2 12.3 ± 5.3 0.030 12.1 ± 4.6 9.8 ± 5.8 0.021 Pain intensity 5.7 ± 2.4 5.4 ± 2.5 0.183 6.5 ± 1.9 5.2 ± 2.4 0.005* Abbreviations: sd: s tandard d eviation; net : neuroemotional technique. Table 3. ancoV a analysis, interaction effect (group-by-time) showing the functional connectivity that was significantly different between the pre and post scans when the net group was compared to the control group. seed brain region Voxels Peak Mni coordinates f score (peak value) c erebellum c rus r Postcentral r 435 39 − 24 39 16.57 c erebellum c rus r c alcarine r 207 15 − 75 9 14.08 c erebellum l Postcentral r 882 51 − 21 60 21.25 c erebellum l Postcentral l 641 −54 − 27 57 16.99 c erebellum r Postcentral r 959 42 − 21 45 19.57 c erebellum r Postcentral l 391 −54 − 27 57 12.20 a mygdala l c ingulate_Mid r 422 −21 − 24 81 15.56 a mygdala l f rontal_inf_t ri l 280 −36 30 15 14.63 a mygdala l Parietal_inf l 204 −60 − 42 39 9.43 a mygdala r f rontal_sup_Medial r 325 6 39 45 15.14 a mygdala r supraMarginal r 287 42 − 39 42 22.77 a mygdala r c ingulate_Mid l 248 −15 − 54 36 13.18 a mygdala r Precentral l 239 −57 − 3 42 14.27 a mygdala r temporal_Pole_sup r 221 60 12 − 9 16.07 a mygdala r Precentral r 212 54 3 24 18.11 a nterior c ingulate l Parietal_inf r 271 36 − 48 54 10.76 a nterior c ingulate r Precuneus l 211 −12 − 51 42 17.17 Hippocampus l f rontal_sup l 324 −21 45 36 13.15 insula l f rontal_inf_t ri l 272 −54 15 39 13.15 insula l Precuneus l 258 −15 − 54 36 24.13 Postcentral l c erebellum l 459 −30 − 63 − 27 19.67 Postcentral r c erebellum l 1848 −30 − 63 − 27 24.71 Precentral l temporal_sup r 398 57 0 − 9 18.84 Precentral l Putamen l 379 −18 12 9 24.97 Precentral l acc_pre l 260 −3 39 6 24.04 Precentral l temporal_Mid l 255 −54 − 21 − 6 14.20 Precentral r f rontal_sup r 239 18 48 48 12.29 Precentral r Pallidum l 205 −21 − 3 −3 12.60 supplementary Motor a rea l Putamen l 288 −21 − 3 3 15.07 supplementary Motor a rea r f rontal_inf_t ri l 283 −48 27 15 13.82 t he values are Grf corrected for a voxel p < 0.05, minimum cluster size of 200 voxels, and corrected for motion parameters and age. Abbreviations: l: l eft; r: r ight; i nf: i nferior; sup: superior; Mid: Middle; f rontal_inf_t ri: i nferior frontal gyrus, triangular part; acc: a nterior c ingulate c ortex; Mni: Montreal neurological i nstitute. 6 D. a. MonTI e T al. regions, the amygdala, the cingulate gyrus, as well as sev - eral frontal regions. The decreased Fc from the ne T inter - vention among several motor and pre-motor regions, particularly with several dopaminergic areas and the fron - tal regions, may explain some of the clinical effects seen. o ther studies have revealed heightened connectivity in these regions in chronic pain patients ( c oppieters et  al. 2021; Dorado et  al. 2024). Therefore, reducing this connec - tivity, could arguably be associated with decreased pain perception. In addition, studies of placebo interventions Figure 2. (a–e) r epresentative figures of the findings in the table 2 are provided below showing areas that had significant differences in functional connectivity between the pre and post scans in the net and waitlist control group. ( a bbreviations: l: l eft; r: r ight; i nf: i nferior; sup: superior; Mid: Middle; f rontal_inf_tri: inferior frontal gyrus, triangular part; acc: a nterior c ingulate c ortex). BRaIn FUnc TIon cHanGeS In cHR onIc Pel VIc PaIn TReaTeD WITH ne T 7 have typically revealed increased Fc ( a shar et al . 2024). Thus, the present findings seem more specific for the ne T intervention. fMRI studies have revealed that the motor cortex is acti - vated in response to painful stimuli (Peyron et  al. 2000). For example, when subjects are exposed to noxious heat or elec - trical shocks, regions within the motor cortex, including the supplementary motor area (SM a ) and premotor cortex (PMc ), show increased activity (Peyron et  al. 2007). Beyond activa - tion, the motor cortex also has been shown to modulate pain perception (eccleston and c rombez 1999). Motor imagery, the mental simulation of movement without actual execution, can reduce pain perception (Moseley and Flor 2012). The motor cortex is connected to descending pain modulation pathways that inhibit pain signals at the spinal cord level (Fields 2004). Reducing the connectivity between the motor cortex and these regions, as found in the present study, may allow the inhibitory pathways to function more actively reducing the pain signals. This study also implicates the cerebellum with the ther - apeutic effects of ne T. This is consistent with our prior study of ne T in distressed cancer patients where it was demonstrated that the cerebellum appears to play an important role in the modulation of negative or traumatic emotions. The potential role of the cerebellum in modu - lating emotions and autonomic reactivity has been sup - ported by clinical and neuroimaging data (Stoodley and Schmahmann 2009, 2010). Relevant to the present study, prior fMRI studies show that negative emotional stimuli activate the cerebellum, pos - terior cingulate, and fusiform gyrus (Park et  al . 2010, Schraa-Tam et  al. 2012). The mechanism is based in part on Figure 2. c ontinued. 8 D. a. MonTI e T al. how regions of the cerebellum are activated by negative or aversive stimuli independent of regulation of motor or auto - nomic processes (Utz et  al. 2015). The vermis appears to be involved in forming emotional memories including how memories are acquired (Supple and Kapp 1993), how they are stored and retrieved (Sacchetti et  al. 2007), and how they dissipate (Dempesy et al . 1983). o f particular relevance to the present study, Fc between the cerebellum and emo - tional regions such as the insula has been correlated with more intense pain in patients with endometriosis (Szabo et  al. 2022). Thus, reducing such connections may help reduce the overall salience of the pain signals, and also enable more effective modulation of pain pathways via inhibitory processes. Using MRI techniques similar to the current study, studies have found functional coherence between the cerebellum and amygdala, hippocampus, hypothalamus, insula, and ante - rior cingulate ( a llen et  al. 2005, Seeley et  al. 2007, Sang et  al. 2012). The ne T intervention may be of particular value in helping people regulate negative emotions and associated memories because the mechanism of action of this technique likely affects motor, emotional, and sensory processing. This relationship is further exemplified by correlations between the change in Fc in the aforementioned brain areas and changes on various clinical measures. Fc between the amygdala and frontal regions was associated with improvements in pain intensity along with improvements in various measures of negative emotions. The change in negative emotions was also correlated with Fc changes between the amygdala and cingulate gyrus, frontal lobe including the precentral region, and parietal lobe struc - tures. The Fc between the frontal lobes and both the insula and hippocampus were similarly correlated with improve - ments in negative emotions. Thus, ne T appears to be asso - ciated with widespread changes in Fc in a number of brain areas that support pain perception, motor function, and emotional processing. Regarding limitations, the current study was exploratory and the sample size will need to be expanded to confirm the clinical and Fc changes observed in these patients. Future, larger studies should include an analysis of covariables such as age, duration of chronic pain, gender, and other factors. We used a waitlist control group, however, the next level of investigation should include an active control group that accounts for attention and therapeutic time to mitigate expectation effects. The results of this study represent the first investigation into both the Fc changes and clinical effects of neuro emotional Technique (ne T) in patients with cPP . The findings suggest that a short course of ne T not only alters brain Fc Figure 2. c ontinued. BRaIn FUnc TIon cHanGeS In cHR onIc Pel VIc PaIn TReaTeD WITH ne T 9 but that these changes are directly associated with improve - ments in clinical symptoms. a practical implication of this research is that ne T may serve as a valuable therapeutic intervention, particularly because it targets emotional distress, which is a common contributor to chronic pain conditions. This initial study is encouraging and emphasises the need for larger scale clinical and neurophysiological trials of this poten - tially important therapeutic approach for patients with cPP . a n important goal would be to corroborate the present find - ings and establish the generalisability of the ne T intervention in this patient population. Author contributions a ll authors meet the IcMJe criteria for authorship. Disclosure statement a ll authors have no conflict of interest to declare. Funding This study was funded by a grant from the Marcus Foundation. Table 4. Pearson correlation analysis results between clinical measures and structures found to have significant changes in functional connectivity (interaction effect (group*time), showing the correlations that were significantly different between the pre and post scans when the net group was compared to the control group. seed brain region clinical test Pearson’s r p-Value a mygdala l c ingulate_Mid r state a nxiety 0.752 0.012 a mygdala l c ingulate_Mid r depression 0.797 0.006 a mygdala l c ingulate_Mid r a nxiety 0.666 0.035 a mygdala l f rontal_inf_t ri l state a nxiety 0.784 0.007 a mygdala l f rontal_inf_t ri l f atigue 0.683 0.030 a mygdala l f rontal_inf_t ri l sleep Quality 0.865 0.001 a mygdala l f rontal_inf_t ri l Pain i ntensity 0.720 0.019 a mygdala l Parietal_inf l state a nxiety 0.826 0.003 a mygdala l Parietal_inf l trait a nxiety 0.666 0.036 a mygdala l Parietal_inf l sleep Quality 0.793 0.006 a mygdala r f rontal_sup_Medial r trait a nxiety 0.690 0.027 a mygdala r f rontal_sup_Medial r depression 0.636 0.048 a mygdala r f rontal_sup_Medial r f atigue 0.732 0.016 a mygdala r f rontal_sup_Medial r a nxiety 0.643 0.045 a mygdala r supraMarginal r state a nxiety 0.792 0.006 a mygdala r supraMarginal r depression 0.772 0.009 a mygdala r supraMarginal r f atigue 0.688 0.028 a mygdala r supraMarginal r a nxiety 0.779 0.008 a mygdala r c ingulate_Mid l trait a nxiety 0.709 0.022 a mygdala r c ingulate_Mid l f atigue 0.746 0.013 a mygdala r c ingulate_Mid l a nxiety 0.787 0.007 a mygdala r Precentral l state a nxiety 0.838 0.002 a mygdala r Precentral l trait a nxiety 0.656 0.039 a mygdala r Precentral l depression 0.694 0.026 a mygdala r Precentral l f atigue 0.696 0.026 a mygdala r Precentral l a nxiety 0.673 0.033 a mygdala r Precentral l sleep Quality 0.745 0.013 a mygdala r temporal_Pole_sup r depression 0.717 0.020 a mygdala r temporal_Pole_sup r a nxiety 0.640 0.460 a mygdala r Precentral r state a nxiety 0.761 0.011 a mygdala r Precentral r trait a nxiety 0.689 0.027 a mygdala r Precentral r depression 0.680 0.030 a mygdala r Precentral r depression 0.773 0.009 c erebellum c rus r c alcarine r Pain i nterference 0.637 0.048 c erebellum r Postcentral r depression 0.768 0.010 Hippocampus l f rontal_sup l depression 0.717 0.020 insula l inf f ront l state a nxiety 0.852 0.002 insula l inf f ront l trait a nxiety 0.697 0.025 insula l inf f ront l depression 0.728 0.017 insula l inf f ront l depression 0.860 0.001 insula l inf f ront l a nxiety 0.712 0.021 insula l inf f ront l sleep Quality 0.666 0.035 insula l Precuneus l depression 0.664 0.036 insula l Precuneus l a nger 0.677 0.031 Precentral r Pallidum l state a nxiety 0.706 0.023 Precentral r Pallidum l trait a nxiety 0.692 0.027 Precentral r Pallidum l depression 0.767 0.010 suppl Motor a rea l Putamen l trait a nxiety 0.770 0.009 suppl Motor a rea l Putamen l depression 0.759 0.011 suppl Motor a rea l Putamen l f atigue 0.639 0.047 suppl Motor a rea l Putamen l a nxiety 0.733 0.016 suppl Motor a rea r inf f ront l state a nxiety 0.648 0.043 suppl Motor a rea r inf f ront l trait a nxiety 0.704 0.023 suppl Motor a rea r inf f ront l depression 0.670 0.034 t he values are Grf corrected for a voxel p < 0.05, a minimum cluster size of 200 voxels, and corrected for motion parameters, and age. Abbreviations: l: l eft; r: r ight; i nf: i nferior; sup: superior; Mid: Middle; f rontal_inf_t ri: i nferior frontal gyrus, triangular part. 10 D. a. MonTI e T al. Data availability statement Data can be made available upon reasonable request.

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