Prof. Dr. Rainer Spanagel

Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University

Prof. Dr. Dr. Heike Tost

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University

PD Dr. Jonas Tesarz

Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg University

Dr. Sebastian Wieland

Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg University

Translational studies in pain chronicity: role of corticothalamostriatal pathway in stress-sensitisation and comorbidity development

Psychiatric comorbidities, such as depression, anxiety and alcohol abuse are a major medical challenge in chronic pain, especially in female pain patients with adverse childhood experiences. However, it is unknown whether these comorbidities are caused by specific brain circuit alterations. A brain area that is strongly activated by pain and mediates motivational and affective behaviors is the paraventricular thalamic nucleus (PVT). PVT neurons project to nucleus accumbens (NAc) and anterior cingulate cortex (ACC) – both key nodes of motivational and affective processing. Current knowledge highlights that plasticity alterations in NAc and ACC may cause comorbidities related to chronic pain. Our translational project in humans and mice aims to understand whether plasticity in PVT-to-NAc/-ACC projections causally mediates pain comorbidities and whether adverse childhood experiences and gender have significant influence on these circuit alterations.

In adult mice, we will mechanistically disentangle the role of plasticity in PVT-to-NAc/ACC projections for development of comorbidities during chronic stages of neuropathic pain using patch-clamp electrophysiology and fiber photometry in combination with neurobehavioral testing and opto-/chemogenetics.

In patients suffering from chronic musculoskeletal pain, we will cross-sectionally investigate structural and functional alterations of PVT-to-NAc/ACC projections using high-resolution neuroimaging, diffusion tensor imaging, fMRI and fiber tracking analysis and determine their correlations to motivational/ affective alterations in daily life and to biomarkers for allosteric load. Both in humans and in rodents, we will investigate whether early childhood adversity especially in female subjects significantly sensitizes these circuit alterations.

For the future, we aim to modulate PVT activity by targeted neurofeedback- or TMS/tDCS and hence test, whether PVT circuitry can be a novel target region for therapy of chronic pain-related motivational deficits and anxiety.

Our translational study will unravel novels mechanistic insights in higher-order processing of chronic pain and may open up the door for specific therapy of one of the major challenges in chronic pain.

Human part – A Deterministic fiber tracking from a probabilistic mask of the human PVT to sgACC/vmPFC, VS and amygdala (targets). B Anatomical connection probability of PVT to target regions. C Brain responses during reward processing (MID). Rodent part – D TdTomato expression after injection of HSV-Cre in NAc of ROSA26-tdTomato reporter mouse. MD mediodorsal thalamus E Two single unit recordings in PVT upon capsaicin hindpaw injection in anesthetized mouse. Small inserts: unit waveform (10 µV, 0,5 ms) (with AG Groh ↔B10).