Does multimodal pain treatment affect neurotransmitter turnover and functional connectivity in the brain of patients with chronic pain?
Final Report Abstract
The primary objective of this collaborative project was a comprehensive investigation of neurochemical and functional changes in the salience brain network (SN), which are thought to reflect network reorganisation and disordered central nociceptive processing in the chronic pain state. In this regard, combined resting-state fMRI and edited 1H-MR spectroscopy were applied to 35 patients with manifest chronic back pain and 36 healthy subjects to assess deviations from functional integrity, oscillatory BOLD characteristics, and neurotransmitter levels (GABA+, glutamate+glutamine) in two key SN nodes, anterior insular and anterior mid-cingulate cortices (aInsR, aMCC). In addition, examinations were repeated in patients after a four week interdisciplinary multimodal pain treatment and in healthy subjects after four weeks to explore longitudinal, treatment-mediated changes in target variables. To minimize potential biases (different chronic pain conditions, medication or pain related comorbidities), we made special efforts to homogenize the patient cohort by considering multimodal clinical data from routine medical records. By applying network analysis on resting state BOLD signals from multiple SN hubs we found reduced network integration of the aInsR and aMCC nodes. This was accompanied by a shift of spectral BOLD power from a lower to a higher frequency band. These findings reflect a desynchronization of neuronal activity of aInsR and aMCC nodes and therefore are indicative for aberrant, spontaneous SN activations in the chronic pain state. By following the hypothesis that spontaneous SN activity in chronic pain state is provoked by an attenuated inhibition, we evaluated the GABA levels in InsR and MCC nodes but found no significant group differences in this variable between healthy subjects and chronic pain patients. However, without revealing GABA differences, patients alone showed significant positive associations between GABA levels and functional integrity in aInsR. This allows to suggest a stronger dependence of node synchronization on the inhibitory tone in the chronic pain state and might indirectly indicate an ongoing loss of inhibitory regulation of node activity in patients. However, this needs to be explored in future using MRS techniques that are more sensitive to detecting subtle neurotransmitter changes. Finally, despite distinct, treatment related improvements in patient-reported outcomes, patients did not exhibited any significant longitudinal changes in the MR variables studied. In our opinion, the lack of detection of these changes may be related to the timing of the follow up exam in our study, which was conducted immediately after therapy and may have been premature for monitoring ongoing network reorganization. Therefore, tracking long-term changes in future studies requires a more appropriate study design that includes multiple examinations after therapy. Our results encourage further, more detailed analyses on acquired data sets to obtain a deeper insight into the pathomechanisms, which are accompanying the manifestation of chronic pain. After initially having been focused on two nodes of the salience network, in the near future, we will expand our network analysis on other regions to explore chronic pain related changes of functional connectivity at the whole brain level. In addition, we are also planning to focus on acquired MP-RAGE data and use the voxel based morphometry approach to investigate the effects of functional deficits on long-term morphometric changes in the chronic pain state.
Publications
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Assessment of intra- and inter-regional interrelations between GABA+, Glx and BOLD during pain perception in the human brain - A combined (1)H fMRS and fMRI study. Neuroscience. 2017 Dec 4;365:125-136
Cleve M, Gussew A, Wagner G, Bär KJ, Reichenbach JR
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Difference optimization: Automatic correction of relative frequency and phase for mean non-edited and edited GABA 1H MEGA-PRESS spectra. J Magn Reson. 2017 Jun;279:16-21
Cleve M, Krämer M, Gussew A, Reichenbach JR
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Prefrontal glutamatergic emotion regulation is disturbed in cluster B and C personality disorders - A combined 1H/31P-MR spectroscopic study. J Affect Disord. 2018 Feb;227:688-697
Smesny S, Große J, Gussew A, Langbein K, Schönfeld N, Wagner G, Valente M, Reichenbach JR
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Neurometabolic patterns of an "at risk for mental disorders" syndrome involve abnormalities in the thalamus and anterior midcingulate cortex. Schizophr Res. 2020 May 19:S0920-9964(20)30228-0
Smesny S, Gussew A, Schack S, Langbein K, Wagner G, Reichenbach JR
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Alterations of neurometabolism in the dorsolateral prefrontal cortex and thalamus in transition to psychosis patients change under treatment as usual - A two years follow-up 1H/31P-MR- spectroscopy study. Schizophr Res. 2021 Feb;228:7-18
Smesny S, Berberich D, Gussew A, Schönfeld N, Langbein K, Walther M, Reichenbach JR
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Functional connectivity and neurotransmitter impairments of the salience brain network in chronic low back pain patients: a combined resting-state functional magnetic resonance imaging and 1H-MRS study. Pain 2022 Mar 10
Baumbach P, Meißner W, Reichenbach JR, Gussew A
