RESUMO
BACKGROUND: Pain is a non-motor symptom that impairs quality of life in Parkinson's patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla (RVM). Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in the STN. METHODS: The study was carried out on the 6-OHDA rodent model of Parkinson's disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioral tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons. RESULTS: STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, As with L-Dopa, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice. CONCLUSION: Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson's disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibers, as shown in the DREADDs experiment.
RESUMO
Paget's disease of the bone (PDB) is a benign osteodystrophy of the elderly characterized by excessive remodeling of bone tissue, mainly in the pelvis, femur, and skull. Its neurological manifestations are numerous and affect both the central and peripheral nervous systems. As headaches are often reported, epileptic seizures remain exceptional. We report the case of a 75-year-old female patient with a history of chronic worsening headache who was admitted to the emergency department for the first episode of a seizure. Brain imaging revealed heterogeneous bone thickening and circumscribed skull osteoporosis. Bone scintigraphy showed pagetoid lesions restricted to the skull and face. Alkaline phosphatases increased. The rest of the biological work-up and the cerebrospinal fluid study ruled out other metabolic causes or central nervous system infections. The patient was treated with bisphosphonates and anti-convulsive treatment. The evolution was satisfactory, with progressive improvement in headache and seizure control, even several months after discontinuation of anti-seizure medication. Our case report highlights the importance of exploring chronic headaches in the elderly, not only in search of lesions of the cerebral parenchyma but also of the structures containing them, in this case, the skull.