Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease.
Sickle cell disease (SCD) is a hemoglobinopathy that affects more than 100,000 individuals in the United States. The disease is characterized by the presence of sickle hemoglobin and recurrent episodes of pain. Some individuals with SCD experience frequent hospitalizations and a high burden of pain. The role of central mechanisms in SCD pain has not been explored. Twenty-five adolescents and young adults with SCD underwent functional magnetic resonance imaging. Participants were stratified into groups with high pain or low pain based on the number of hospitalizations for pain in the preceding 12 months. Resting state functional connectivity was analyzed using seed-based and dual regression independent component analysis. Intrinsic brain connectivity was compared between the high pain and low pain groups, and association with fetal hemoglobin, a known modifier of SCD, was explored. Patients in the high pain group displayed an excess of pronociceptive connectivity such as between anterior cingulate and default mode network structures, such as the precuneus, whereas patients in the low pain group showed more connectivity to antinociceptive structures such as the perigenual and subgenual cingulate. Although a similar proportion of patients in both groups reported that they were on hydroxyurea, the fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to antinociceptive structures. These findings support the role of central mechanisms in SCD pain. Intrinsic brain connectivity should be explored as a complementary and objective outcome measure in SCD pain research.


CONCLUSIONS
Altered connectivity patterns associated with high pain experience in patients with sickle cell disease suggest a possible role of central mechanisms in sickle cell pain. Resting state brain connectivity studies should be explored as an effective methodology to investigate pain in SCD.
Division of Hematology, Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC; Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: ddarbari@childrensnational.org.
Deepika S
DS
Darbari
Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
Johnson P
JP
Hampson
Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
Eric
E
Ichesco
Department of Radiology, Boston University Medical Center, Boston, Massachusetts.
Nadja
N
Kadom
Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Diagnostic Imaging and Radiology, Children's National Health System, Washington, District of Columbia.
Gilbert
G
Vezina
Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Department of Diagnostic Imaging and Radiology, Children's National Health System, Washington, District of Columbia.
Iordanis
I
Evangelou
Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
Daniel J
DJ
Clauw
Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
James G
JG
Taylor Vi
Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
Richard E
RE
Harris
D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000453:epidemiology / Q000503:physiopathology* / Q000628:therapy*; D000986:Antisickling Agents / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D001931:Brain Mapping; D002648:Child; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010146:Pain / Q000453:epidemiology / Q000503:physiopathology*; D059408:Pain Management / Q000379:methods / Q000706:statistics & numerical data*; D010865:Pilot Projects; D012146:Rest; D012720:Severity of Illness Index; D055815:Young Adult
D000986:Antisickling Agents; D005319:Fetal Hemoglobin; D006918:Hydroxyurea
Sickle cell disease; brain network connectivity; functional neuroimaging; pain