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Perception Abstract Previous studies have described the structure and function of the insular cortex in terms of spatially continuous gradients.

Here we assess how spatial features of insular resting state functional organization correspond to individual pain sensitivity. From a previous multicenter study, we included healthy participants, who underwent resting state functional MRI scans, T1-weighted scans and quantitative sensory testing on the left forearm.

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Thermal and mechanical pain thresholds were determined. Connectopic mapping, a technique using non-linear representations of functional organization was employed to describe functional connectivity gradients in both insulae. Partial coefficients of determination were calculated between trend surface model parameters summarizing spatial features of gradients, modal and modality-independent pain sensitivity.

The dominant connectopy captured the previously reported posteroanterior shift in connectivity profiles. The left insular gradient was not significantly associated with pain thresholds.

Our results highlight the functional relevance of gradient-like insular organization in pain processing. Considering individual variations in insular connectopy might contribute to understanding neural mechanisms behind pain and improve objective brain-based characterization of individual pain sensitivity.

Introduction The insular cortex is a functionally diverse brain region that is central to several aspects of pain processing, and shapes the subjective experience of the individual when encountering painful stimuli 12. Classically, it is thought to exhibit a dichotomous functional organization. The anterior part is more involved in the cognitive-emotional aspect of pain modulation, whereas the posterior part relates more to nociception, as it is able to encode the modality, intensity and location of a painful stimulus 1345.

The two parts exhibit a heterogeneous cytoarchitecture 6 and have different connections from the ascending spino-thalamo-cortical pathways as well 7. Váll alagút szindróma suggest a posteroanterior information propagation pattern, likely driven by the convergence segít e az akupunktúra ízületi fájdalmak esetén nociceptive inputs in the anterior insula after lower-level processing in the posterior part 3.

This concept is in line with the results of fMRI studies ascribing multisensory integration and higher-order pain modulation to the anterior insula 2. The anterior—posterior dichotomy osteoarthritis guidelines 2022 pdf has been challenged many times, and studies seeking an optimal functional partition describe numbers of subregions ranging from two to as many as 13 8.

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It seems that characterizing the organization of the insular cortex in terms of discrete subregions does not produce osteoarthritis guidelines 2022 pdf divisions, and recent studies showed that the distribution of both anatomical and functional connections in the insula can be better modeled as a spatially continuous, gradual change in connectivity profiles 9 These models exploit graph-based representations of functional connectivity profiles to construct similarity matrices, from which gradients of functional similarity can be derived using several dimensionality reduction techniques e.

The derived gradients can characterize axes of functional organization across the whole brain 13 or in pre-defined regions of interest; a prominent method employing the latter approach is connectopic mapping, which has also proven useful in extracting multiple overlapping gradients Gradient-based models have already been employed to relate insular organization to behavior, explaining a range of cognitive, affective and sensorimotor measures previously tied to the insula While initial evidence based on electrophysiological studies implies that pain-related activation follows a gradual, posteroanterior pattern that is driven by connectivity differences along the posteroanterior axis 3the gradient-like functional organization of the insula has not yet been directly linked to pain processing.

Such a link could push forward related research in two ways. First, describing insular connectivity in terms of functional gradients might reveal a clearer link between insula function and individual pain sensitivity, since subregions of the insula work together to influence the formation of a painful experience, possibly integrated by osteoarthritis guidelines 2022 pdf differences along the posteroanterior axis.

Although numerous other brain regions are involved in pain processing, the unique anatomical and functional organization of the insula lends itself well to gradient-based models. Second, it would render connectivity gradients as a novel, low dimensional component in predictive modelling approaches aiming at the development of imaging biomarkers of pain 1516 Therefore, we hypothesized that a gradient-based characterization of resting state functional organization in the insula is directly associated with individual pain sensitivity.

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In this study, we investigate whether features of connectivity gradients in the insula explain a significant part of individual pain sensitivity over and above known influencing factors, such as sex, age, and, in the case of women, the day of the menstruation cycle.

To assess the possibility of multiple overlapping, meaningful gradients, we employ the connectopic mapping approach. Furthermore, we link our findings to current integrative descriptions of the role the insula plays in pain processing, and discuss how low dimensional representations of functional connectivity in the insula might be osteoarthritis guidelines 2022 pdf into efforts searching for imaging markers of individual pain sensitivity.

Connectopic mapping The average dominant connectopy across all participants showed a rostrocaudal gradient of connectivity profiles in the insula on both sides. Connectivity changes along the main axis were similar in the bilateral insulae and exhibited the previously reported profiles. The anterior insula mainly showed the strongest connections to dorsolateral prefrontal, anterior cingulate areas and inferior parietal lobules, whereas the posterior part was connected to the parietal operculum and somatosensory areas see Fig.

We observed no significant connectivity differences between the left and right insula. Figure 1 Average connectopy of the insular cortex.

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A Average connectopic maps overlaid on the MNI template, displayed in neurological orientation. Bilateral insular cortices show a similar posteroanterior trajectory of change in functional connectivity profiles. Full size image The second and third connectopies were highly variable and inconsistent across participants, and did not show any association to modal pain thresholds and composite pain sensitivity. Individual coefficients did not correlate with pain sensitivity scores.

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Regarding the left insula, connectopy features did not explain significant amounts of variance in either pain threshold. Figure 2 Connectopy of the right osteoarthritis guidelines 2022 pdf is associated with pain sensitivity scores. Apart from posterioanterior steepness, differences in finer spatial variation also contribute to the effect. B Differences of the connectopy curve in participants with high and low composite pain sensitivity. C Bar plot showing the contribution of trend surface model parameters to pain sensitivity scores.

Resting-state functional heterogeneity of the right insula contributes to pain sensitivity

TSM parameters of the dominant connectopy did not differ significantly between males and females after correcting for multiple comparisons. Discussion In this study, osteoarthritis guidelines 2022 pdf showed that individual spatial patterns of the dominant connectopy in the insula explain a significant amount of variance in both thermal and composite pain sensitivity measured on the contralateral forearm, over and above established biological factors that contribute to pain sensitivity age, sex and day of the menstrual cycle in women.

On a group level, spatial features of the dominant connectopy explained 7. Consequently, the layout of functional connectivity in the insula might provide additional information that might improve current resting-state fMRI-based predictions of subjective pain thresholds. The dominant connectopy in our sample exhibits a rostrocaudal main axis that falls in line with previous descriptions of anatomical and functional organization in the insula 9 Earlier studies also show that differential connections along the topology of the insula scale in strength with pain-relevant behavioral variables, e.

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This is consistent with the idea of anterior and posterior dominant individuals in terms of insular connectivity described in However, single TSM osteoarthritis guidelines 2022 pdf did not explain significant amounts of variance in pain sensitivity scores on their own, suggesting that finer spatial variation is also important on top of a simple posteroanterior connectivity gradient.

As depicted in Fig. Since previous studies describe a posteroanterior convergence of pain-related information in the osteoarthritis guidelines 2022 pdf 3the link between spatial features of connectivity change and pain sensitivity could suggest that the dominant connectopy captures at least in part the functional organization of this system.

In our sample, larger stepwise connectivity changes in the anterior part were associated with lower pain sensitivity.

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Consistently with this, participants exhibiting a steeper diversity curve in the anterior insula scored higher on measures of positive affect, osteoarthritis guidelines 2022 pdf and emotion recognition in the study by Tian and Zalesky 10which, in light of our results, might represent more effective mechanisms of coping with the painful experience that results in lower sensitivity to painful stimuli e.

Current opinions indicate that a subjective experience of pain arises from the integration of nociceptive, cognitive and emotional information The anterior insula connects to prefrontal and anterior cingulate cortices, which are implicated in cognitive pain modulation 1523and these connections were shown to be important features in predicting individual pain sensitivity Additionally, in our recent study we found that morphological and functional network properties of the posterior insula are also associated with pain sensitivity Based on this, the anterior-dominant connectopy might represent a more effective connectivity layout in terms of top-down pain modulation.

Our finding that the modality-independent composite pain sensitivity is also explained by the dominant connectopy supports this further. A possible link between the layout of functional connectivity in the insula and pain sensitivity might be further supported by studies reporting functional and structural reorganization of the insula in osteoarthritis guidelines 2022 pdf pain conditions.

A recent fMRI study employing graph theoretical techniques in a fibromyalgia cohort found that hub topology was different in fibromyalgia patients, with insular regions becoming prominent, functionally central hubs scaling with clinical pain and glutamate levels Another study reported that the altered connectivity of the right anterior insula was central to changes in brain network connectivity in painful knee osteoarthritis patients In our recent study, we found altered temporal dynamics osteoarthritis guidelines 2022 pdf connectivity in the right insula of migraine patients that scaled with headache frequency Further studies are needed to investigate whether these alterations are reflected in the dominant insular connectopy in chronic pain osteoarthritis guidelines 2022 pdf.

Remarkably, in the current study, only the connectopy of the contralateral insula is connected to pain sensitivity, which is consistent with the organization of supraspinal nociceptive pathways and the known right hemispheric dominance in pain-related processing 28 In accordance, previous studies involving direct electrical stimulation of the insular cortex in epilepsy patients reported painful sensations in response to the stimulation, contralateral to the stimulated side Conversely, electrical potentials elicited by painful laser-based heat stimuli were picked up in the insular cortex both contralateral and ipsilateral to the stimulation site, although evoked potentials in the ipsilateral insular cortex were recorded after a short latency Although touch sensation and mechanical pain is also processed in the insula osteoarthritis guidelines 2022 pdfwe did not find a significant association between mechanical pain sensitivity and the dominant connectopy.

Prior studies using intracerebral EEG recordings in epilepsy patients reported low-frequency phase-locked local field potentials and gamma-band oscillations which are considered a közös kenőcs recept királyi gyalogosoktól of supramodal activity in the insula on both sides in response to mechano-nociceptive stimulation, however, the amplitude and latency of LFPs and GBOs were different from those elicited by thermal painful stimuli Additionally, an fMRI study of somatotopic representations for heat and mechanical painful stimuli in the insula found multiple, overlapping representations for osteoarthritis guidelines 2022 pdf modalities 5.

In light of these reports, it is possible that there are modality-dependent differences in the processing of painful stimuli that are reflected in the functional organization of the insula. However, a lack of association between the dominant connectopy and mechanical pain sensitivity might also be related to the osteoarthritis guidelines 2022 pdf noise inherent in the measurement of mechanical pain thresholds.

There are aspects of our study that prompts for further studies. The effects of preprocessing on the estimation of cortical gradients have not yet been fully investigated. Here we employed a preprocessing pipeline similar to that in the original paper, and repeated the analysis with a different, more stringent pipeline which yielded similar results see Supplementary material.

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Since we only measured pain sensitivity unilaterally, more studies are needed to ascertain the laterality of the link between insular functional organization and pain sensitivity. Finally, pain is a complex phenomenon involving many regions of the brain, and here we use only one of them to characterize pain sensitivity.

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Future studies might examine and relate functional heterogeneity in multiple brain regions to pain sensitivity to get better predictions and complement current imaging markers of individual pain thresholds. Conclusions Characterizing insular connectivity in terms of a low-dimensional representation, such as functional gradients, provides a parsimonious description that can be used to explain both modal and modality-independent contralateral pain sensitivity.

This provides a more direct link between insular connectivity and subjective pain sensitivity, and supports earlier accounts of anterior and posterior dominance in terms of insular connectivity.

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Therefore, functional gradients of the insula might be utilized as complementary markers in objectively predicting individual pain thresholds. Methods Participants To osteoarthritis guidelines 2022 pdf the relationship between functional organization in the insula and pain thresholds, we used our dataset published in 17which contains data from young healthy participants collected at three centers University of Szeged, Hungary, Ruhr University Bochum and University Hospital Essen, Germany.

Any participants with neuropsychiatric or chronic pain conditions e. Participants were asked to refrain from consuming alcohol both before the MRI and QST measurements and on the previous day.

MRI measurements and quantitative sensory testing took place on different dates, with an average difference of 2. Here we give a brief summary of the procedure.

Sensory measurements were carried out on the left palmar forearm.

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The thresholds were determined using a method of limits, meaning the application of increasing and decreasing temperatures to the skin via a modular sensory analyzer MSA thermal stimulator Somedic, Hörby, Sweden in the Bochum sample and Pathway thermal stimulators Medoc Ltd.