Altered connectivity in ACC-insula circuitry in small fiber neuropathy: a dynamic causal model study
Poster No:
2052
Submission Type:
Abstract Submission
Authors:
Pia Klabunn1, Thilo Kellermann1, Ute Habel1, Timo Hottel1, Han-Gue Jo2, Maike Dohrn3, Angelika Lampert4, Roman Rolke5, Marc Spehr6, Sebastian Scheliga1
Institutions:
1Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen, Aachen, Germany, 2Kunsan National University, Department of AI Convergence, Gunsan, Korea, Democratic People's Republic of, 3Department of Neurology, Medical Faculty Uniklinik RWTH Aachen, Aachen, Germany, 4Institute of Neurophysiology, Medical Faculty Uniklinik RWTH Aachen, Aachen, Germany, 5Department of Palliative Medicine, Medical Faculty Uniklinik RWTH Aachen, Aachen, Germany, 6Department of Chemosensation, Institute for Biology, RWTH Aachen University, Aachen, Germany
First Author:
Pia Klabunn
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Co-Author(s):
Thilo Kellermann
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Ute Habel
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Timo Hottel
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Han-Gue Jo
Kunsan National University, Department of AI Convergence
Gunsan, Korea, Democratic People's Republic of
Kunsan National University, Department of AI Convergence
Gunsan, Korea, Democratic People's Republic of
Angelika Lampert
Institute of Neurophysiology, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Institute of Neurophysiology, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Roman Rolke
Department of Palliative Medicine, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Palliative Medicine, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Marc Spehr
Department of Chemosensation, Institute for Biology, RWTH Aachen University
Aachen, Germany
Department of Chemosensation, Institute for Biology, RWTH Aachen University
Aachen, Germany
Sebastian Scheliga
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty Uniklinik RWTH Aachen
Aachen, Germany
Introduction:
Small Fiber Neuropathy (SFN) is clinically defined by neuropathic pain and autonomic dysfunction (Hoeijmakers et al., 2012). Although traditionally seen as a peripheral nerve disorder, neuroimaging studies increasingly link SFN to altered central processing (e.g. Hsieh et al., 2015; Tseng et al., 2015; Chao et al., 2021). Pain perception can be modulated by olfaction (Jo et al., 2021; Villemure et al., 2003). Nociceptive and olfactory inputs exhibit substantial overlap in brain activation patterns, including the amygdala, insular cortex, and anterior cingulate cortex, suggesting potential multisensory interactions (Lötsch et al., 2016; Villemure & Bushnell, 2009). However, multisensory processing in SFN remains poorly understood. To address this, we applied a cross-modal fMRI approach using general linear models (GLM) to assess functional activity and potential multisensory interactions. Dynamic Causal Modeling (DCM) was used to analyze connectivity patterns in key regions under thermal and olfactory stimulation.
Methods:
Twenty-five patients with a diagnosis of idiopathic SFN and 27 age- and sex-matched healthy controls were included. Individually calibrated warm or painfully hot thermal stimuli were combined with pleasant, unpleasant, or neutral olfactory stimuli. Behavioral data, including ratings of thermal intensity and odor pleasantness, were collected using an 11-point visual analog scale. Thermal stimuli were administered with the Pain & Sensory Evaluation System (PATHWAY model; Medoc, Israel). Olfactory stimuli were delivered via a computer-controlled, 16-channel MR-compatible olfactometer (Lundström et al., 2010). For each participant, parameter estimates reflecting blood-oxygen-level-dependent (BOLD) signal changes were calculated using GLM. Dynamic causal modeling (DCM) was applied within a predefined 10-model space to identify the connectivity properties of three regions of interest: the right amygdala, right anterior insula, and right dorsal anterior cingulate cortex (rdACC) under thermal and olfactory stimuli.
Results:
Whole-brain GLM analyses revealed significantly higher neural activation in the right insula, left superior frontal gyrus, and right postcentral gyrus in response to painfully hot stimuli in SFN patients compared to controls. Furthermore, exposure to both olfactory conditions revealed higher activation in the right amygdala among SFN patients. Importantly, no significant interaction effects between thermal and olfactory stimuli were observed at the behavioral or neural level. Further, Bayesian model selection for DCM revealed group differences in the modulatory impact of pain on the rdACC-right anterior insula connection. As shown in Figure 1, the favored model (model 1) in patients indicated a significant inhibitory pain-related effect, while in controls (model 4), no such effect was observed. This effect significantly differed between groups, with an effect size (rate of change in Hertz, Hz) of -0.296 Hz in patients and 0.119 Hz in controls, t(50) = 2.40, p = 0.020.
Conclusions:
Comparing SFN patients and controls, we observed elevated functional activity in response to multisensory stimulation in patients, which may indicate a sensitized CNS (Wang & Frey-Law, 2023). Further, we identified altered effective connectivity between the rdACC and the right anterior insula in SFN patients, characterized by an inhibitory effect of acute pain on this connection. This reduced connectivity may reflect cortical neuroplasticity as a compensatory response to peripheral nerve damage. The uncoupling of key pain-processing regions in SFN has previously been described and interpreted as the formation of 'isolated islands' (Hsieh et al., 2015). Contrary to expectations, no interaction effects between thermal and olfactory stimulation were observed. Future research is needed to clarify how these two sensory modalities interact in SFN patients.
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI)
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 2
Perception, Attention and Motor Behavior:
Perception: Pain and Visceral 1
Keywords:
FUNCTIONAL MRI
Pain
Perception
Peripheral Nerve
Plasticity
Smell
Other - Small Fiber Neuropathy (SFN)
1|2Indicates the priority used for review
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1. Chao, C.-C., Tseng, M.-T., Lin, Y.-H., Hsieh, P.-C., Lin, C.-H. J., Huang, S.-L., Hsieh, S.-T., & Chiang, M.-C. (2021). Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: Altered thalamic connectome and its associations with skin nerve degeneration. Pain, 162(5), 1387–1399. https://doi.org/10.1097/j.pain.0000000000002155
2. Hoeijmakers, J. G., Faber, C. G., Lauria, G., Merkies, I. S., & Waxman, S. G. (2012). Small-fibre neuropathies—Advances in diagnosis, pathophysiology and management. Nature Reviews Neurology, 8(7), 369–379. https://doi.org/10.1038/nrneurol.2012.97
3. Hsieh, P.-C., Tseng, M.-T., Chao, C.-C., Lin, Y.-H., Tseng, W.-Y. I., Liu, K.-H., Chiang, M.-C., & Hsieh, S.-T. (2015). Imaging signatures of altered brain responses in small-fiber neuropathy: Reduced functional connectivity of the limbic system after peripheral nerve degeneration. Pain, 156(5), 904–916. https://doi.org/10.1097/j.pain.0000000000000128
4. Jo, H.-G., Wudarczyk, O., Leclerc, M., Regenbogen, C., Lampert, A., Rothermel, M., & Habel, U. (2021). Effect of odor pleasantness on heat-induced pain: An fMRI study. Brain Imaging and Behavior, 15(3), 1300–1312. https://doi.org/10.1007/s11682-020-00328-0
5. Lötsch, J., Hähner, A., Gossrau, G., Hummel, C., Walter, C., Ultsch, A., & Hummel, T. (2016). Smell of pain: Intersection of nociception and olfaction. Pain, 157(10), 2152–2157. https://doi.org/10.1097/j.pain.0000000000000599
6. Lundström, J. N., Gordon, A. R., Alden, E. C., Boesveldt, S., & Albrecht, J. (2010). Methods for building an inexpensive computer-controlled olfactometer for temporally-precise experiments. International Journal of Psychophysiology: Official Journal of the International Organization of Psychophysiology, 78(2), 179–189. https://doi.org/10.1016/j.ijpsycho.2010.07.007
7. Tseng, M.-T., Kong, Y., Chiang, M.-C., Chao, C.-C., Tseng, W.-Y. I., & Hsieh, S.-T. (2015). Brain imaging signatures of the relationship between epidermal nerve fibers and heat pain perception. NeuroImage, 122, 288–297. https://doi.org/10.1016/j.neuroimage.2015.08.021
8. Villemure, C., & Bushnell, M. C. (2009). Mood Influences Supraspinal Pain Processing Separately from Attention. Journal of Neuroscience, 29(3), 705–715. https://doi.org/10.1523/JNEUROSCI.3822-08.2009
9. Villemure, C., Slotnick, B. M., & Bushnell, M. C. (2003). Effects of odors on pain perception: Deciphering the roles of emotion and attention. Pain, 106(1–2), 101–108. https://