Summary: Sickle cell disease (SCD) is commonly viewed as a blood disorder, but new research shows it also reshapes brain network organization. Using high-resolution MRI and advanced directional analyses adapted from economics, researchers found that adult brains with SCD reorganize their networks to compensate for chronic reductions in oxygen delivery.
Although many patients perform daily tasks comparably to healthy people, their brains recruit additional attention-related systems and work harder to preserve higher-level cognitive abilities such as decision-making. These results underline the need for targeted neurological care for adults living with SCD, a population that often lacks consistent access to specialized adult clinics.
Key Facts
- Compensatory Network Recruitment: The executive control network (ECN), which supports decision-making and other executive functions, recruits input from attention networks in people with SCD—a pattern not observed in healthy controls.
- Adaptation Varies with Severity: Patients with milder SCD complications show increased influence from the dorsal attention network (DAN), which supports focused attention. Patients with more severe disease show greater reliance on the ventral attention network (VAN), which responds to salient or unexpected stimuli.
- Accuracy Preserved, Speed Reduced: Many patients match healthy controls in task accuracy, but their behavioral and neural response times are slower, reflecting the extra effort and circuit reorganization required to maintain performance.
- Directional Connectivity Applied: This study is the first to use Granger causality–based effective connectivity in SCD, an approach borrowed from economics that reveals the direction and influence of information flow between brain regions.
- Equity and Adult Care: The findings emphasize the need for more neurologically informed adult SCD care, especially given that this disease predominantly affects underserved communities and adult neurology services are often limited.
Source: Carnegie Mellon University
Sickle cell disease is commonly associated with blood-related complications, but the Wood Neuro Research Group’s study provides measurable evidence that SCD can alter how brain networks communicate and reorganize.
Prior neuroimaging work used functional connectivity to show altered communication among brain networks in adults with SCD, suggesting compensatory changes linked to reduced oxygen delivery. Functional connectivity, however, does not reveal which networks are driving others. To address this gap, the research team applied effective connectivity analysis—specifically Granger causality—to determine directionality and influence among networks.
“Sickle cell alters the shape and function of red blood cells that carry oxygen to the brain, which reduces oxygen delivery across regions and can lead to long-term functional changes,” said Nahom Mossazghi, a biomedical engineering Ph.D. student and the study’s first author.
“To compensate, the brain recruits additional regions during cognitive processing—an adaptation not seen in people without the disease.”
The team combined ultra-high-field 7T MRI with statistical tools adapted from economics to study effective connectivity. Unlike functional connectivity, effective connectivity estimates the directional influence of one network or region over another, allowing the researchers to identify which systems are supplying extra input to the executive control network.
Results revealed that the ECN receives increased afferent influence from attention networks in patients with SCD. In milder cases, the dorsal attention network provides much of that support; in more severe cases, the ventral attention network plays a larger role. This pattern suggests different compensatory strategies depending on disease severity.
“The brain appears to reorganize its network architecture to preserve function in the face of chronic oxygen shortages,” Mossazghi explained.
These findings also help explain why cognitive impacts in adults with SCD are frequently underrecognized. “People may function well enough on the surface, but their brain wiring is different,” said Sossena Wood, assistant professor of biomedical engineering. “Accuracy on tasks can be preserved, yet slower response speeds and altered neural routes reveal an unseen cognitive cost.”
Historically, SCD care focuses on pediatric hematology, and comprehensive adult clinics are scarce in many regions. Pittsburgh hosts one of the few adult SCD centers in the United States. The new evidence supports expanding neurology involvement in adult SCD care and raises awareness about cognitive effects that influence daily living, education, and work—issues closely tied to health equity.
Looking ahead, the Wood Neuro Research Group plans to examine how these network interactions occur during specific cognitive tasks by combining MRI with simultaneous EEG. Identifying the precise circuits working overtime may enable development of noninvasive interventions, such as targeted stimulation, to improve processing efficiency and reduce cognitive fatigue.
“This line of research could change adult care for people with SCD and shed light on how the brain compensates for chronic systemic conditions more generally,” Mossazghi added.
Supported by NIH and institutional funding, the study is the first to apply Granger causality–based effective connectivity in adults with SCD. It offers a new framework for interpreting compensatory brain dynamics and lays groundwork for future research focused on improving quality of life.
Key Questions Answered:
A: Because the brain requires a steady supply of oxygen. Sickle-shaped red blood cells are less efficient at delivering oxygen, so the brain compensates by rerouting processing through additional networks—essentially “calling for backup” from attention systems to support thinking and decision-making.
A: Not necessarily. Many people with SCD achieve similar accuracy on cognitive tasks as healthy individuals. The difference is that their brains often use different pathways and more resources to reach the same outcome, which typically results in slower response times and greater cognitive effort.
A: By pinpointing the specific neural circuits that compensate for disease-related changes, clinicians may be able to design noninvasive interventions—such as targeted brain stimulation or cognitive rehabilitation—to make processing more efficient and reduce mental fatigue. The findings also support integrating neurological evaluation and care into adult SCD services.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff editors.
About this sickle cell disease and neurology research news
Author: Sara Pecchia
Source: Carnegie Mellon University
Contact: Sara Pecchia – Carnegie Mellon University
Image: The image is credited to Neuroscience News
Original Research: Open access.
Title: Investigating Disruptions in Information Flow due to Sickle Cell Disease Using Granger Causality by Nahom Mossazghi, Helmet T. Karim, Nadim Farhat, Tales Santini, Enrico M. Novelli, Tamer Ibrahim, Sossena Wood. Human Brain Mapping
DOI:10.1002/hbm.70407
Abstract
Investigating Disruptions in Information Flow due to Sickle Cell Disease Using Granger Causality
Sickle cell disease (SCD) is an inherited disorder caused by a mutation in the beta-globin gene that leads to chronic complications, including cognitive changes—particularly in executive functions.
Neuroimaging studies have identified structural and functional abnormalities associated with SCD, but the directional flow of information between brain networks and how disruptions in those flows contribute to cognitive deficits has been unclear.
This study used Granger causality (GC) analysis to evaluate effective connectivity and information flow between brain regions and resting-state networks with ultra-high-field 7T MRI in adults with SCD (n = 51) and age-, sex-, and race-matched controls (n = 44).
Researchers performed whole-brain network analysis and targeted examinations of regions within the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), and ventral attention network (VAN). For each comparison, they measured both the magnitude and direction of information flow to capture strength and causal influence among regions.
Patients with SCD showed greater overall magnitude of information flow at the regional level, and markedly increased afferent flow from DAN and VAN to ECN compared with controls. Subtype analysis revealed that patients with severe SCD displayed higher information-flow magnitude than those with mild SCD and controls, with subtype-specific differences in which attention network provided input to ECN.
Multiple regression analyses relating information flow to cognitive performance indicated that controls exhibited higher model fit values (R²) than patients with SCD, suggesting reduced network efficiency in the patient group.
This work is the first to apply GC-based effective connectivity analysis in SCD, revealing distinct patterns of information exchange that likely reflect compensatory mechanisms for disease-related structural and functional disruptions. These findings provide new insight into how SCD affects brain network organization and cognitive function and support further investigation of network-level dynamics in this population.