Co-producing research study recruitment strategies with and for children and young people for paediatric chronic pain studies.

Introduction: Children and young people experiencing chronic pain are at greater risk of inequitable and poor-quality pain management, which has implications for future management of pain in adulthood. Most chronic pain research is conducted with adults who are more likely to be middle-class, white and monocultured. Inclusive and diverse recruitment practices in paediatric pain research can be an area in which we can address this imbalance of representation. The aim of this current work was to explore these practices and to co-produce recommendations regarding recruitment strategies for paediatric pain research. Methods: The research team worked with Your Rheum, a United Kingdom young person's advisory group (ages 11-24 years) and diagnosed with rheumatic condition(s), the opportunity to input into rheumatology research. At a virtual Your Rheum meeting, eight young people (female = 7, male = 1, age range 12-24) took part in group discussions, sharing their experiences of taking part in research and their decision process. Online tools, including Mentimeter and Miro, were used to aid conversations and share ideas. Results: Most young people had experience of taking part in research as a study participant (n = 5). Recommendations synthesised included increased awareness of research in general. The young people discussed being open to hearing about research opportunities; they reflected that they are rarely exposed to these invitations or hear about current research. The clinic environment was highlighted as a "good and trustworthy" recruitment area - being approached by a member of the research team was considered ideal, even if it was someone they had not met previously. Many young people recalled little discussions of research at their clinical appointments. Deciding to participate in research included the following considerations: benefit/impact; connecting with others; research topic; which is then balanced against convenience, and reimbursement. The young people felt that taking part in research was empowering and helped them take ownership of their pain management. Conclusion: It is essential to understand the perspectives of potential study participants, to plan successful recruitment strategies. Ensuring we consider these factors when designing our studies and recruitment strategies is beneficial to all involved. Co-produced recruitment strategies would aid inclusive (and increased) research participation.

Decline in Processing Speed Tells Only Half the Story: Developmental Delay in Children Living with Sickle Cell Disease.

Children with sickle cell disease (SCD) may experience cognitive difficulties, including slowed processing speed. Thus, we investigated if processing speed changes over time. From 1992-2001, 103 participants with SCD aged 3-16 years (n ≤ 8.99 = 45; n ≥ 9.00 = 58) completed cognitive assessments. MRI was available for 54 participants. Between 1992-2002, 58 participants consented to one or two further assessments. A repeated measures regression using linear mixed-effects modelling determined longitudinal changes in processing speed index (PSI), examining the interaction between age (continuous variable) and timepoint (i.e., assessment 1 or 3) and controlling for MRI infarct status (i.e., no infarct, silent infarct, or stroke). Those aged ≤8.99 and ≥9.00 at first assessment experienced PSI decline. Declines were most prominent for the processing speed coding subtest, with a significant interaction between timepoint and age, t(31) = 2.64, p = 0.01. This decline may reflect a developmental delay, likely due to disease progression, with slower improvements in processing speed. Although there have been significant improvements in SCD treatments, mostly in high-income countries, processing speed still remains a target; thus, incorporating clinical monitoring of processing speed may help identify delay and allow for early intervention.

The sociocultural context of adolescent pain: portrayals of pain in popular adolescent media.

ABSTRACT: Research has consistently suggested that media consumption plays a vital role in children's socialization, including the socialization of painful experiences. Past research examining young children's popular media revealed worrisome trends in media depictions of pain; it consisted of narrow depictions of pain, gender stereotypes, and an overwhelming lack of empathy from observers, which could contribute to pain-related stigma. Research has not yet examined how pain is portrayed in adolescent media, despite adolescence being the developmental period when chronic pain often emerges. The current study extracted a cross-section of popular adolescent media selected based on popularity, including 10 movies and the first seasons of 6 TV shows. Pain instances were coded using 2 established observational coding schemes assessing sufferer pain characteristics and observer responses. Across 616 instances of pain, there was a preponderance of violence and injuries, whereas everyday, chronic-type, and medical/procedural pains were seldom represented. Individuals from marginalized (ie, gender diverse, girls) and minoritized groups (individuals with racialized identities) were underrepresented in pain instances. Furthermore, regardless of observed gender or "race," observers displayed a lack of empathy for sufferers and rarely engaged in prosocial behaviors. Popular media may serve as an agent of socialization in adolescence; thus, pain depictions may be a powerful force in propagating pain-related stigma and inequities. An opportunity exists to harness popular media to adaptively and accurately portray pain to adolescents.

Psychological challenges and quality of life in Pakistani parents of children living with thalassemia.

PURPOSE: Children living with thalassemia experience psychological challenges, but despite significant psychosocial burdens, caregivers' psychological wellbeing and quality of life remain understudied, particularly in lower-and-middle-income countries. DESIGN AND METHOD: The current study evaluated these relationships in 100 male and female Pakistani caregivers (23-45 years; 61% female) using Ryff's Psychological Well-Being Scale and the Singapore Caregiver Quality of Life Scale. Caregivers completed questionnaires during regularly scheduled clinic visits for their child. RESULTS: We found that Pakistani caregivers in our sample generally had significantly lower (30-40 points) quality of life than a referent sample of caregivers of older adults (ps < 0.001). Self-acceptance and personal growth were consistently significant predictors across quality of life domains. Further, significant interactions were observed. Female caregivers with less self-acceptance had worse mental health and wellbeing and impact on daily life (p < .05). Male caregivers with less personal growth had worse physical health wellbeing (p < .05). CONCLUSIONS: Our results demonstrate the importance of considering how distinct aspects of psychological wellbeing, rather than just the overall score, relate to the specific quality of life domains among male and female caregivers. PRACTICE IMPLICATIONS: Pediatric nurses are at the frontline of service delivery for children and are in a prime position to observe caregivers who could be at high risk for psychological challenges. Given our findings, future clinical interventions should prioritize support services promoting personal growth and self-acceptance for Pakistani caregivers of children living with thalassemia.

Executive Function and Processing Speed in Children Living with Sickle Cell Anemia.

Executive function and processing speed difficulties are observed in children living with sickle cell anemia (SCA). The influence of processing speed on executive function is not well understood. We recruited 59 children living with SCA and 24 matched controls aged 8-18 years between 2010 and 2016 from clinics in the UK. Children completed tests in processing speed and cognitive flexibility, subdomains of executive function. MRI scans were conducted within one year of testing; oxygen saturation was obtained on the day of testing. Hemoglobin levels were obtained from medical records. Caregivers completed the executive function questionnaire. Hierarchical linear regressions found that hemoglobin, oxygen saturation, age, infarct status, and processing speed were not independent predictors for any model. However, for all cognitive flexibility tests, there was a significant interaction between infarct status and processing speed; children without silent cerebral infarction (SCI) with faster processing speed had better cognitive flexibility. Our findings indicate that, when interpreting executive function difficulties, it is important to account for the relationship between SCI status and processing speed. More research is needed to elucidate the mechanisms, but clinically, including executive function testing as part of clinic visits by embedding psychologists within the healthcare team would appear to be a critical step.

Mind the gap: trajectory of cognitive development in young individuals with sickle cell disease: a cross-sectional study.

Study objectives: Compared to typically developing children and young adults (CYA-TD), those living with Sickle Cell Disease (CYA-SCD) experience more cognitive difficulties, particularly with executive function. Few studies have examined the relative importance of silent cerebral infarction (SCI), haemoglobin and arterial oxygen content on age-related cognitive changes using cross-sectional or longitudinal (developmental trajectory) data. This study presents cohort data from a single timepoint to inform studies with multiple timepoints. Methods: We compared cross-sectional raw and scaled scores as age-related changes in cognition (trajectories) in CYA-SCD and age-and ethnicity-matched CYA-TD. We also compared cross-sectional age-related changes in cognition (trajectories) in CYA-SCD with and without SCI to CYA-TD. General cognitive abilities were assessed using Wechsler Intelligence Scales, including the Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) underpinning IQ. Executive function was evaluated using the Delis-Kaplan Executive Function System (D-KEFS) Tower subtest and the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire. SCI were identified from contemporaneous 3 T MRI; participants with overt stroke were excluded. Recent haemoglobin was available and oxygen saturation (SpO2) was measured on the day of the MRI. Results: Data were available for 120 CYA-SCD [62 male; age = 16.78 ± 4.79 years; 42 (35%) with SCI] and 53 CYA-TD (23 male; age = 17.36 ± 5.16). Compared with CYA-TD, CYA-SCD experienced a delayed onset in VCI and slower rate of development for BRIEF Global Executive Composite, Metacognition Index (MI), and Behaviour Regulation Index. The rate of executive function development for the BRIEF MI differed significantly between CYA-TD and CYA-SCD, with those with SCI showing a 26% delay compared with CYA-TD. For CYA-SCD with SCI, arterial oxygen content explained 22% of the variance in VCI and 37% in PRI, while haemoglobin explained 29% of the variance in PRI. Conclusion: Age-related cognitive trajectories of CYA-SCD may not be impaired but may progress more slowly. Longitudinal studies are required, using tests unaffected by practice. In addition to initiation of medical treatment, including measures to improve arterial oxygen content, early cognitive intervention, educational support, and delivery of extracurricular activities could support cognitive development for CYA-SCD.Graphical Abstract.

Tele-neuropsychological Assessment of Children and Young People: A Systematic Review.

The coronavirus pandemic identified a clinical need for pediatric tele-neuropsychology (TeleNP) assessment. However, due to limited research, clinicians have had little information to develop, adapt, or select reliable pediatric assessments for TeleNP. This preliminary systematic review aimed to examine the feasibility of pediatric TeleNP assessment alongside (1) patient/family acceptability, (2) reliability, and (3) the quality of the literature. Between May 2021 and November 2022, manual searches of PubMed, PsycINFO, and Google Scholar were conducted using terms related to "pediatric" and "tele-neuropsychology." After extracting relevant papers with samples aged 0-22 years, predefined exclusion criteria were applied. Quality assessment was completed using the AXIS appraisal tool (91% rater-agreement). Twenty-one studies were included in the review, with reported qualitative and quantitative data on the feasibility, reliability, and acceptability extracted. Across included studies, TeleNP was completed via telephone/video conference with participants either at home, in a local setting accompanied by an assistant, or in a different room but in the same building as the assessor. Pediatric TeleNP was generally reported to be feasible (e.g., minimal behavioral differences) and acceptable (e.g., positive feedback). Nineteen studies conducted some statistical analyses to assess reliability. Most observed no significant difference between in-person and TeleNP for most cognitive domains (i.e., IQ), with a minority finding variable reliability for some tests (e.g., attention, speech, visuo-spatial). Limited reporting of sex-assigned birth, racialized identity, and ethnicity reduced the quality and generalizability of the literature. To aid clinical interpretations, studies should assess underexamined cognitive domains (e.g., processing speed) with larger, more inclusive samples. Supplementary Information: The online version contains supplementary material available at 10.1007/s40817-023-00144-6.

School Challenges and Services Related to Executive Functioning for Fully Included Middle Schoolers with Autism.

The educational services available for fully included middle schoolers with autism spectrum disorder (ASD) in the general education setting are not well known. Even less is known about how the executive functioning (EF) deficits of such youth are addressed in the classroom. The current study sought to identify the challenges, including EF, that middle schoolers with ASD face and the services that they receive on their Individualized Education Program (IEP), and also explore specific strategies used to build EF skills at school. A convenience data sample was obtained from focus groups with educational personnel (n = 15), and qualitative analyses of IEPs were conducted in middle schoolers with ASD with EF deficits (n = 23). Results confirmed that social communication and EF challenges are common. Multiple services and accommodations were identified, although EF challenges were rarely targeted on IEPs. Factors that may facilitate the success of EF strategies in the classroom are discussed.

Psychologists as leaders in equitable science: Applications of antiracism and community participatory strategies in a pediatric behavioral medicine clinical trial.

Psychologists have an ethical responsibility to advance health equity and can play a significant role in improving health care experiences for families racialized as Black, including those with sickle cell disease (SCD), a group of genetic blood disorders primarily affecting communities of color. Parents of children with SCD report experiences of stigma and discrimination due to racism in the health care system. The current commentary describes the application of antiracism and participatory strategies to the research design, implementation, and dissemination of a behavioral medicine clinical trial (Engage-HU; NCT03442114) of shared decision-making (SDM) for pediatric patients with SCD, including (a) the development of a research question to promote justice for racialized groups; (b) a focus on "redressing imbalances" through SDM and a multidisciplinary, inclusive research team led by a Black psychologist; (c) community participatory approaches through the integration of stakeholder feedback across the study; and (d) centering context by attending to structural realities in response to the COVID-19 and racism pandemics. With attention to the fact that most primary caregivers of children with SCD are Black women, an intersectionality lens was applied. Implications and considerations for psychologists working to advance health equity in medical settings are also discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Racism exposure and trauma accumulation perpetuate pain inequities-advocating for change (RESTORATIVE): A conceptual model.

Experiences of racism occur across a continuum from denial of services to more subtle forms of discrimination and exact a significant toll. These multilevel systems of oppression accumulate as chronic stressors that cause psychological injury conceptualized as racism-based traumatic stress (RBTS). RBTS has overlapping symptoms with posttraumatic stress disorder (PTSD) with the added burden that threats are constantly present. Chronic pain is a public health crisis that is exacerbated by the intersection of racism and health inequities. However, the relationship between RBTS and pain has not yet been explored. To highlight how these phenomena are interlinked, we present Racism ExpoSure and Trauma AccumulatiOn PeRpetuate PAin InequiTIes-AdVocating for ChangE (RESTORATIVE); a novel conceptual model that integrates the models of racism and pain and demonstrates how the shared contribution of trauma symptoms (e.g., RBTS and PTSD) maintains and perpetuates chronic pain for racialized groups in the United States. Visualizing racism and pain as "two halves of the same coin," in which the accumulative effects of numerous events may moderate the severity of RBTS and pain, we emphasize the importance of within-group distinctiveness and intersectionality (overlapping identities). We call on psychologists to lead efforts in applying the RESTORATIVE model, acting as facilitators and advocates for the patient's lived experience with RBTS in clinical pain care teams. To assist with this goal, we offer suggestions for provider and researcher antiracism education, assessment of RBTS in pain populations, and discuss how cultural humility is a central component in implementing the RESTORATIVE model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of regional brain volumes on cognition in sickle cell anemia: A developmental perspective.

Background and objectives: Cognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA. Methods: Data from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available. Results: One hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8-64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls. Discussion: Increasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials.

Using the consolidated framework for implementation research to identify recruitment barriers and targeted strategies for a shared decision-making randomized clinical trial in pediatric sickle cell disease.

BACKGROUND/AIMS: Recruitment is often a barrier in clinical trials that include minoritized populations, such as individuals with sickle cell disease. In the United States, the majority of people with sickle cell disease identify as Black or African American. In sickle cell disease, 57% of the United States trials that ended early did so due to low enrollment. Thus, there is a need for interventions that improve trial enrollment in this population. After lower-than-expected recruitment during the first 6 months of the Engaging Parents of Children with Sickle Cell Anemia and their Providers in Shared-Decision-Making for Hydroxyurea trial, a multi-site study for young children with sickle cell disease, we collected data to understand barriers and used the Consolidated Framework for Implementation Research to categorize them and guide the development of targeted strategies. METHODS: Study staff used screening logs and coordinator and principal investigator calls to identify recruitment barriers that were then mapped onto Consolidated Framework for Implementation Research constructs. Targeted strategies were implemented during Months 7-13. Recruitment and enrollment data were summarized before (Months 1-6) and during the implementation period (Months 7-13). RESULTS: During the first 13 months, 60 caregivers (M = 30.65 years; SD = 6.35) enrolled in the trial. Most caregivers primarily self-identified as female (n = 54, 95%) and African American or Black (n = 51, 90%). Recruitment barriers mapped onto three Consolidated Framework for Implementation Research constructs: (1) Process barriers (i.e. no identified "site champion" and poor recruitment planning at several sites); (2) Inner setting barriers (i.e. limited communication, low relative study priority at several sites); and (3) Outer setting barriers (i.e. poor patient attendance at clinic appointments). Targeted strategies to improve recruitment included (1) principal investigator site visits and retraining on recruitment procedures to address process barriers; (2) increased frequency of communication through all coordinator, site principal investigator, and individual site calls to address inner setting barriers; and (3) development and implementation of no-show procedures for clinic appointments to address outer setting barriers. After implementation of the recruitment strategies, the number of caregivers identified for pre-screening increased from 54 to 164, and enrollment more than tripled from 14 to 46 caregiver participants. CONCLUSION: Consolidated Framework for Implementation Research constructs guided the development of targeted strategies that increased enrollment. This reflective process reframes recruitment challenges as the responsibility of the research team rather than characterizing minoritized populations as "difficult" or "hard to reach." Future trials including patients with sickle cell disease and minoritized populations may benefit from this approach.

Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia.

In sickle cell disease, the relative importance of reduced hemoglobin (Hb) and peripheral oxygen saturation on brain structure remains uncertain. We applied graph-theoretical analysis to diffusion magnetic resonance imaging data to investigate the effect of structural brain connectivity on cognitive function, alongside the presence or absence, number, and volume of silent cerebral infarction. In patients, we investigated the relationships between network properties, blood oxygenation, and cognition (working memory and processing speed indices). Based on streamline counts and fractional anisotropy, we identified a subnetwork with weakened connectivity in 92 patients with sickle cell disease (91 homozygous for HbS [HbSS], 1 heterozygote with HbSß0 thalassemia; 49 males; aged 8.0 to 38.8 y), compared with 54 control subjects (22 males; aged 6.7 to 30.6 y). Multiple regression analyses showed a significant effect of Hb on full-network edge density (P < .05) and of peripheral oxygen saturation on streamline-weighted subnetwork efficiency (P < .01). There were effects of fractional anisotropy-weighted full-network and subnetwork efficiency on working memory index (both P < .05), and of streamline-weighted subnetwork efficiency on processing speed index (P = .05). However, there were no effects of presence, number or volume of silent cerebral infarcts. Streamline-weighted efficiency was progressively lower with lower oxygen saturation, with a downstream effect on the processing speed index. In path analysis, indirect relationships between blood oxygenation and cognition, mediated by network properties, were better supported than direct alternatives, with an indirect relationship between low oxygen saturation and processing speed index in patients, mediated by structural connectivity efficiency in a subnetwork of the brain differing from control subjects. Our findings are consistent with the notion that cognitive impairment is primarily mediated by hypoxic-ischemic effects on normal-appearing white matter and highlight the utility of network-based methods in providing biomarkers of cognitive dysfunction in patients with sickle cell disease.

Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia.

Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8-30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24-42% in patients, and 4-23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue.

Considerations for Selecting Cognitive Endpoints and Psychological Patient-Reported Outcomes for Clinical Trials in Pediatric Patients With Sickle Cell Disease.

Pediatric patients with sickle cell disease (SCD) experience a range of medical complications that result in significant morbidity and mortality. Recent advances in prophylactic and curative treatment approaches have highlighted the need for sensitive and clinically-meaningful trial endpoints. The detrimental effects of cognitive and psychological difficulties on social and economic mobility are well described. Although numerous reviews have assessed cognitive outcomes in other rare genetic disorders, SCD has not received the same focus. This review describes the cognitive (i.e., executive function and processing speed) and psychological domains (i.e., depression and anxiety) that are consistently associated with SCD pathology and, therefore, may be of particular interest as clinical trial endpoints. We then discuss corresponding well-validated and reliable cognitive tests and patient-reported outcomes (PROs) that may be appropriate for clinical trials given their robust psychometric properties, ease of administration, and previous use in the SCD population. Further, we provide a discussion of potential pitfalls and considerations to guide endpoint selection. In line with the move toward patient-centered medicine, we identify specific tests (e.g., NIH Toolbox Cognition Module, Wechsler Cancellation Test) and psychological PROs (e.g., PROMIS depression and anxiety scales) that are sensitive to SCD morbidity and have the potential to capture changes that are clinically meaningful in the context of patients' day to day lives. In particularly vulnerable cognitive domains, such as executive function, we highlight the advantages of composite over single-test scores within the context of trials. We also identify general (i.e., practice effects, disease heterogeneity) and SCD-specific considerations (i.e., genotype, treatment course, and disease course, including degree of neurologic, pain, and sleep morbidity) for trial measures. Executive function composites hold particular promise as trial endpoints that are clinically meaningful, amenable to change, relatively easy to collect, and can be incorporated into the routine care of patients with SCD in various settings and countries.

Individual Watershed Areas in Sickle Cell Anemia: An Arterial Spin Labeling Study.

Previous studies have pointed to a role for regional cerebral hemodynamic stress in neurological complications in patients with sickle cell anemia (SCA), with watershed regions identified as particularly at risk of ischemic tissue injury. Using single- and multi-inflow time (TI) arterial spin labeling sequences (ASL) in 94 patients with SCA and 42 controls, the present study sought to investigate cerebral blood flow (CBF) and bolus arrival times (BAT) across gray matter, white matter with early arrival times, and in individual watershed areas (iWSAs). In iWSAs, associations between hemodynamic parameters, lesion burden, white matter integrity, and general cognitive performance were also explored. In patients, increases in CBF and reductions in BAT were observed in association with reduced arterial oxygen content across gray matter and white matter with early arrival times using both sequences (all p < 0.001, d = -1.55--2.21). Across iWSAs, there was a discrepancy between sequences, with estimates based on the single-TI sequence indicating higher CBF in association with reduced arterial oxygen content in SCA patients, and estimates based on the multi-TI sequence indicating no significant between-group differences or associations with arterial oxygen content. Lesion burden was similar between white matter with early arrival times and iWSAs in both patients and controls, and using both sequences, only trend-level associations between iWSA CBF and iWSA lesion burden were observed in patients. Further, using the multi-TI sequence in patients, increased iWSA CBF was associated with reduced iWSA microstructural tissue integrity and slower processing speed. Taken together, the results highlight the need for researchers to consider BAT when estimating CBF using single-TI sequences. Moreover, the findings demonstrate the feasibility of multi-TI ASL for objective delineation of iWSAs and for detection of regional hemodynamic stress that is associated with reduced microstructural tissue integrity and slower processing speed. This technique may hold promise for future studies and treatment trials.