Elevated Posterior Insula Glutamate in Patients with Sickle Cell Disease

Xiaopeng Zhou; Eric Ichesco; Andrew Q Pucka; Ziyue Liu; Andrew Rw O'Brien; Steven E Harte; Richard E Harris; Ying Wang

doi:10.1016/j.jpain.2024.104743

Elevated Posterior Insula Glutamate in Patients with Sickle Cell Disease

J Pain. 2024 Nov 28:104743. doi: 10.1016/j.jpain.2024.104743. Online ahead of print.

Authors

Xiaopeng Zhou¹, Eric Ichesco², Andrew Q Pucka³, Ziyue Liu⁴, Andrew Rw O'Brien⁵, Steven E Harte², Richard E Harris⁶, Ying Wang⁷

Affiliations

¹ School of Health Sciences, Purdue University, West Lafayette, IN, USA.
² Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA; Susan Samueli Integrative Health Institute, School of Medicine, University of California at Irvine, Irvine, CA, USA; Department of Anesthesiology and Perioperative Care, School of Medicine, University of California at Irvine, Irvine, CA, USA.
⁷ Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: ywa12@iu.edu.

PMID: 39615812
DOI: 10.1016/j.jpain.2024.104743

Abstract

Sickle cell disease (SCD) is an inherited hemolytic disorder accompanied by chronic pain and recurrent acute painful episodes known as vaso-occlusive crises (VOCs). Increased Glx (glutamate+glutamine) and lowered insula GABA concentration has been reported in the insula of patients with fibromyalgia, a nociplastic chronic pain condition, and may affect the pathophysiology of pain-related syndromes. Therefore, proton magnetic resonance spectroscopy (¹H-MRS) was conducted to measure levels of Glx and other brain metabolites using a single voxel (size: 2×3×3 cm³) in the right posterior insula cortex (PIC) in 17 individuals with SCD and 17 ethnicity-, age- and sex-matched healthy controls (HCs). The frequency of VOCs in the preceding 12 months was recorded. The concentration of Glx (p=0.019) and the ratio of Glx to tCr (total creatine, p=0.035) in the PIC were significantly higher in patients with SCD as compared to matched HCs (n=17). Secondary analyses with the unpaired full sample of 24 SCD also showed a significantly higher level of Glx/tCr than HCs (n=19), with a positive correlation between the level of Glx/tCr and the number of VOCs (p=0.034, r=0.476), as well as a negative correlation between Glx and sensory sensitivity assessed by tonic pressure pain in gastrocnemius area of the non-dominant leg (p=0.040, r=-0.462). The unpaired full sample additionally revealed a significant difference in sensory sensitivity (p=0.050). Altered metabolites such as GABA and myoinositol were also observed between SCD and HCs. These results suggest that elevated excitatory neurotransmission in the insula might contribute to nociplastic pain in SCD. PERSPECTIVE: Our work highlighted the innovative finding of elevated levels of the excitatory neurotransmitter glutamate with glutamine in patients with SCD compared to healthy controls. The trend of positive relationship between Glx/tCr and the frequency of VOCs suggests that an excitatory brain neurotransmitter imbalance may be involved in VOCs.

Keywords: (1)H-MRS; brain metabolites; glutamate; pain; sickle cell disease; vaso-occlusive crisis.