Cognition and the Default Mode Network in Children with Sickle Cell Disease: A Resting State Functional MRI Study

Abstract

Cerebrovascular complications are frequent events in children with sickle cell disease, yet routinely used techniques such as Transcranial Doppler (TCD), Magnetic Resonance (MRI) and Angiography (MRA), insufficiently explain the cause of poor cognitive performances. Forty children with SS-Sβ° (mean age 8 years) underwent neurocognitive evaluation and comprehensive brain imaging assessment with TCD, MRI, MRA, Resting State (RS) Functional MRI with evaluation of the Default Mode Network (DMN). Sixteen healthy age-matched controls underwent MRI, MRA and RS functional MRI.Children with SCD display increased brain connectivity in the DMN even in the absence of alterations in standard imaging techniques. Patients with low neurocognitive scores presented higher brain connectivity compared to children without cognitive impairment or controls, suggesting an initial compensatory mechanism to maintain performances. In our cohort steady state haemoglobin level was not related to increased brain connectivity, but SatO2<97% was. Our findings provide novel evidence that SCD is characterized by a selective disruption of connectivity among relevant regions of the brain, potentially leading to reduced cognition and altered functional brain dynamics. RS functional MRI could be used as a useful tool to evaluate cognition and cerebral damage in SCD in longitudinal trials.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease

“…The 2 previously published pediatric studies differed in study design and technique, with Colombatti et al reporting increased connectivity within regions of the DMN with resting-state fcMRI and Sun et al reporting attenuated activation and deactivation in regions of the DMN in SCD with task-based fcMRI. 18,21 These 2 investigations were limited by a high prevalence of vasculopathy within the SCD cohort 18 and smaller sample size. 21 Although it has been shown that the hemodynamic response function (HRF) does not differ in patients with SCD compared with controls, 19 it remains unclear if the presence of vasculopathy affects the HRF, potentially impacting the interpretation of functional connectivity results in SCD cohorts that include participants with vasculopathy.…”

“…The disparate results of prior investigations into the impact of SCD on fcMRI are challenging to interpret due to the heterogeneity in study design and approach. [17][18][19][20][21][22][23][24] We aim to further our understanding of the pathophysiology of the cognitive complications of SCD using robust statistical analyses of fcMRI data, including homotopy (a global metric assessing the connectivity between the left and right hemispheres) 25 and large-scale networks specific to different neurocognitive functions. Using MRI to measure OEF and functional connectivity in a single session, we prospectively enrolled children with SCD and healthy controls to test our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, as measured by OEF, would have disrupted functional network connectivity.…”

Patients with sickle-cell disease exhibit greater functional connectivity and centrality in the locus coeruleus compared to anemic controls

“…Brain imaging studies (Balci et al, 2012; Chen et al, 2017; Schatz and Buzan, 2006; Scott Mackin et al, 2014) have shown atrophy of the corpus collosum, frontal lobes, thalamus, and basal ganglia, in addition to increased resting-state functional connectivity (RS-FC) of the default-mode network (DMN) in children, that was associated with cognitive decline (Chen et al, 2017; Colombatti et al, 2016; Schatz and Buzan, 2006; Scott Mackin et al, 2014). Increased amplitude of low-frequency fluctuations (ALFF) in the orbitofrontal cortex, anterior cingulate cortex (ACC) and posterior cingulate (PCC) compared to anemic controls has also been observed (Coloigner et al, 2017).…”

Contrasting resting-state fMRI abnormalities from sickle and non-sickle anemia

“…from sleep apnea, acute anemia) especially in light of diminished autoregulatory cerebrovascular flow reserve due to basal hyperemia [ 33 , 34 ]. Repeated ischemia-reperfusion injury may be responsible for decreased activity in watershed cortical areas [ 61 ]. Interestingly, we observed comparable loss of white matter in the ACTL group and SCD patients in the anterior and middle cerebral artery territories, consistent with chronic intermittent hypoxia in these regions.…”

“…Additionally, lower gyral white matter in watershed regions was previously reported in a study of SCD patients which may be indicative of preclinical white matter injury [ 12 ]. In [ 61 ], control temporal-concatenation group ICA analysis was not able to detect connectivity differences among SCD patients according to WMH volume. Contrary to this result, decreased ALFF was observed in small areas in the frontal pole and mSFG between patients with and without silent stroke.…”