Chronic sleep deficiency and its impact on pain perception in healthy females.

Acute sleep deprivation in experimental studies has been shown to induce pain hypersensitivity in females. However, the impact of natural sleep deficiency and fluctuations across the week on pain perception remains unclear. A sleep-monitoring headband and self-reports were utilized to assess objective and subjective sleep in longer (> 6 hr) and short sleepers (< 6 hr). Pain sensitivity measures including heat, cold, pressure pain thresholds, pain inhibition (conditioned pain modulation) and facilitation (tonic pain summation) were assessed on Mondays and Fridays. Forty-one healthy young (23.9 ± 0.74 years) women participated. Short sleepers slept on average 2 hr less than longer sleepers (297.9 ± 8.2 min versus 418.5 ± 10.9 min) and experienced impaired pain inhibitory response (mean = -21.14 ± 7.9°C versus mean = 15.39 ± 9.5°C; p = 0.005). However, no effect was observed in pain thresholds and pain summation (p > 0.05). Furthermore, pain modulatory responses differed between Mondays and Fridays. Chronic sleep deficiency (< 6 hr) compromises pain responses, notably on Mondays. Maintaining a consistent sleep pattern with sufficient sleep (> 6 hr) throughout the week may protect against pain sensitization and the development of chronic pain in females. Further research is needed, especially in patients with chronic pain.

Modulation of the Association Between Corticospinal Tract Damage and Outcome After Stroke by White Matter Hyperintensities.

BACKGROUND AND OBJECTIVES: Motor outcomes after stroke relate to corticospinal tract (CST) damage. The brain leverages surviving neural pathways to compensate for CST damage and mediate motor recovery. Thus, concurrent age-related damage from white matter hyperintensities (WMHs) might affect neurologic capacity for recovery after CST injury. The role of WMHs in post-stroke motor outcomes is unclear. In this study, we evaluated whether WMHs modulate the relationship between CST damage and post-stroke motor outcomes. METHODS: We used data from the multisite ENIGMA Stroke Recovery Working Group with T1 and T2/fluid-attenuated inversion recovery imaging. CST damage was indexed with weighted CST lesion load (CST-LL). WMH volumes were extracted with Freesurfer's SAMSEG. Mixed-effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment, controlling for age, days after stroke, and stroke volume. RESULTS: A total of 223 individuals were included. WMH volume related to motor impairment above and beyond CST-LL (ß = 0.178, 95% CI 0.025-0.331, p = 0.022). Relationships varied by WMH severity (mild vs moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (ß = 0.888, 95% CI 0.604-1.172, p < 0.001) with a CST-LL × WMH interaction (ß = -0.211, 95% CI -0.340 to -0.026, p = 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 0.299, 95% CI 0.008-0.590, p = 0.044), but did not significantly relate to CST-LL or a CST-LL × WMH interaction. DISCUSSION: WMHs relate to motor outcomes after stroke and modify relationships between motor impairment and CST damage. WMH-related damage may be under-recognized in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

White matter hyperintensities modify relationships between corticospinal tract damage and motor outcomes after stroke.

Motor outcomes after stroke relate to corticospinal tract (CST) damage. Concurrent damage from white matter hyperintensities (WMHs) might impact neurological capacity for recovery after CST injury. Here, we evaluated if WMHs modulate the relationship between CST damage and post-stroke motor impairment outcome. We included 223 individuals from the ENIGMA Stroke Recovery Working Group. CST damage was indexed with weighted CST lesion load (CST-LL). Mixed effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment. WMH volume related to motor impairment above and beyond CST-LL (ß = 0.178, p = 0.022). We tested if relationships varied by WMH severity (mild vs. moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (ß = 0.888, p < 0.001) with a CST-LL x WMH interaction (ß = -0.211, 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 0.299, p = 0.044), but did not significantly relate to CST-LL or a CST-LL x WMH interaction. WMH-related damage may be under-recognised in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

Neurobiology of osteoarthritis: a systematic review and activation likelihood estimation meta-analysis.

Osteoarthritis (OA) affects 240 million people worldwide. Neuroimaging has been increasingly used to investigate brain changes in OA, however, there is considerable heterogeneity in reported results. The goal of this systematic review and meta-analysis was to synthesise existing literature and identify consistent brain alterations in OA. Six databases were searched from inception up to June, 2022. Full-texts of original human studies were included if they had: (i) neuroimaging data by site of OA (e.g. hand, knee, hip); (ii) data in healthy controls (HC); (iii) > 10 participants. Activation likelihood estimation (ALE) was conducted using GingerALE software on studies that reported peak activation coordinates and sample size. Our search strategy identified 6250 articles. Twenty-eight studies fulfilled the eligibility criteria, of which 18 were included in the meta-analysis. There were no significant differences in brain structure or function between OA and healthy control contrasts. In exploratory analysis, the right insula was associated with OA vs healthy controls, with less activity, connectivity and brain volume in OA. This region was implicated in both knee and hip OA, with an additional cluster in the medial prefrontal cortex observed only in the contrast between healthy controls and the hip OA subgroup, suggesting a possible distinction between the neural correlates of OA subtypes. Despite the limitations associated with heterogeneity and poor study quality, this synthesis identified neurobiological outcomes associated with OA, providing insight for future research. PROSPERO registration number: CRD42021238735.

The impact of sleep disturbance on pain perception: A systematic review examining the moderating effect of sex and age.

Females have increased pain sensitivity and are more vulnerable to chronic pain conditions. Sleep disturbances are comorbid with chronic pain and exacerbate pain symptoms. Different types of sleep disturbance affect pain perception distinctly, but it is not clear if these effects are equal in men and women. This systematic review investigated potential differences in how sleep disturbance affects pain in males and females. We searched EBSCO, MEDLINE, Psych INFO, Science Direct, and Web of Science from January 2001 to November 2022 and found 38 studies with 978 participants. Separate random-effects models were used to estimate the pooled effect sizes based on standardized mean differences (SMDs) of experimental sleep disturbance paradigms on various pain outcomes. Sex moderated the effect of sleep disturbance on pain facilitation (SMD = 0.13; 95%CI: 0.004 to 0.022; p=.009) and pain inhibition (SMD = 0.033; 95%CI: 0.011 to 0.054; p=.005), with increased facilitation and decreased inhibition in females, but the opposite effect in males. Further, age moderated the effects of total sleep deprivation (SMD = -0.194; 95%CI -0.328 to -0.060; p=.008) on pain sensitivity and fragmented sleep (SMD = -0.110; 95%CI: 0.148 to -0.072; p<.001) on pain threshold. While the moderating effect of sex and age on the sleep-pain relationship was small, these factors need to be considered in future sleep-pain research.

When knowledge hurts: humans are willing to receive pain for obtaining non-instrumental information.

Humans and other animals value information that reduces uncertainty or leads to pleasurable anticipation, even if it cannot be used to gain tangible rewards or change outcomes. In exchange, they are willing to incur significant costs, sacrifice rewards or invest effort. We investigated whether human participants were also willing to endure pain-a highly salient and aversive cost-to obtain such information. Forty participants performed a computer-based task. On each trial, they observed a coin flip, with each side associated with different monetary rewards of varying magnitude. Participants could choose to endure a painful stimulus (low, moderate or high pain) to learn the outcome of the coin flip immediately. Importantly, regardless of their choice, winnings were always earned, rendering this information non-instrumental. Results showed that agents were willing to endure pain in exchange for information, with a lower likelihood of doing so as pain levels increased. Both higher average rewards and a larger variance between the two possible rewards independently increased the willingness to accept pain. Our results show that the intrinsic value of escaping uncertainty through non-instrumental information is sufficient to offset pain experiences, suggesting a shared mechanism through which these can be directly compared.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

Neural correlates of verbal fluency revealed by longitudinal T1, T2 and FLAIR imaging in stroke.

Diffusion-weighted imaging has been widely used in the research on post-stroke verbal fluency but acquiring diffusion data is not always clinically feasible. Achieving comparable reliability for detecting brain variables associated with verbal fluency impairments, based on more readily available anatomical, non-diffusion images (T1, T2 and FLAIR), enables clinical practitioners to have complementary neurophysiological information at hand to facilitate diagnosis and treatment of language impairment. Meanwhile, although the predominant focus in the stroke recovery literature has been on cortical contributions to verbal fluency, it remains unclear how subcortical regions and white matter disconnection are related to verbal fluency. Our study thus utilized anatomical scans of ischaemic stroke survivors (n = 121) to identify longitudinal relationships between subcortical volume, white matter tract disconnection, and verbal fluency performance at 3- and 12-months post-stroke. Subcortical grey matter volume was derived from FreeSurfer. We used an indirect probabilistic approach to quantify white matter disconnection in terms of disconnection severity, the proportion of lesioned voxel volume to the total volume of a tract, and disconnection probability, the probability of the overlap between the stroke lesion and a tract. These disconnection variables of each subject were identified based on the disconnectome map of the BCBToolkit. Using a linear mixed multiple regression method with 5-fold cross-validations, we correlated the semantic and phonemic fluency scores with longitudinal measurements of subcortical grey matter volume and 22 bilateral white matter tracts, while controlling for demographic variables (age, sex, handedness and education), total brain volume, lesion volume, and cortical thickness. The results showed that the right subcortical grey matter volume was positively correlated with phonemic fluency averaged over 3 months and 12 months. The finding generalized well on the test data. The disconnection probability of left superior longitudinal fasciculus II and left posterior arcuate fasciculus was negatively associated with semantic fluency only on the training data, but the result aligned with our previous study using diffusion scans in the same clinical population. In sum, our results presented evidence that routinely acquired anatomical scans can serve as a reliable source for deriving neural variables of post-stroke verbal fluency performance. The use of this method might provide an ecologically valid and more readily implementable analysis tool.

Changes in White Matter Microstructure Over 3 Years in People With and Without Stroke.

BACKGROUND AND OBJECTIVES: Cerebral white matter health can be estimated by MRI-derived indices of microstructure. White matter dysfunction is increasingly recognized as a contributor to neurodegenerative disorders affecting cognition and to functional outcomes after stroke. Reduced indices of white matter microstructure have been demonstrated cross-sectionally in stroke survivors compared with stroke-free participants, but longitudinal changes in the structure of white matter after stroke remain largely unexplored. We aimed to characterize white matter micro- and macrostructure over 3 years after stroke and study associations with white matter metrics and cognitive functions. METHODS: Patients with first-ever or recurrent ischemic stroke of any etiology in any vascular territory were compared with stroke-free age- and sex-matched controls. Those diagnosed with hemorrhagic stroke, TIA, venous infarction, or significant medical comorbidities, psychiatric and neurodegenerative disorders, substance abuse, or history of dementia were excluded. Diffusion-weighted MRI data at 3, 12, and 36 months were analyzed using a longitudinal fixel-based analysis, sensitive to fiber tract-specific differences within a voxel. It was used to examine whole-brain white matter degeneration in stroke compared with control participants. We studied microstructural differences in fiber density and macrostructural changes in fiber-bundle cross-section, in relation to cognitive performance. Analyses were performed controlling for age, intracranial volume, and education (family-wise error-corrected p < 0.05, nonparametric testing over 5,000 permutations). RESULTS: We included 71 participants with stroke (age 66 ± 12 years, 22 women) and 36 controls (age 69 ± 5 years, 13 women). We observed extensive white matter structural degeneration across the whole brain, particularly affecting the thalamic, cerebellar, striatal, and superior longitudinal tracts and corpus callosum. Importantly, follow-up regression analyses in 72 predefined tracts showed that the decline in fiber density and cross-section from 3 months to 3 years was associated with worse cognitive performance at 3 years after stroke, especially affecting visuospatial processing, processing speed, language, and recognition memory. DISCUSSION: We conclude that white matter neurodegeneration in ipsi- and contralesional thalamic, striatal, and cerebellar tracts continues to be greater in stroke survivors compared with stroke-free controls. White matter degeneration persists even years after stroke and is associated with poststroke cognitive impairment. TRIAL REGISTRATION INFORMATION: ClinicalTrails.gov NCT02205424.

White matter microstructure and verbal fluency.

Poor performance on verbal fluency tasks is associated with an increased risk of post-stroke cognitive impairment. Grey matter regions supporting verbal fluency have been identified via lesion-symptom mapping, but the links between verbal fluency and white matter structure remain less well described. We examined white matter correlates of semantic (Category Fluency Animals) and phonemic or lexical fluency (COWAT FAS) after stroke, accounting for stroke severity measured with the National Institutes of health Stroke Scale (NIHSS), age, sex, and level of education. White matter fibre density and cross-section measures were automatically extracted from 72 tracts, using MRtrix and TractSeg software in 72 ischaemic stroke survivors assessed 3 months after their event. We conducted regression analyses separately for phonemic and semantic fluency for each tract. Worse semantic fluency was associated with lower fibre density in several tracts, including the arcuate fasciculus, superior longitudinal fasciculus, inferior occipito-frontal fasciculus, inferior longitudinal fasciculus, optic radiation, striato-occipital, thalamo-occipital tracts, and inferior cerebellar peduncle. Our stroke sample was heterogenous with largely non-overlapping and predominantly right-lateralised lesions (lesion distribution: left N = 27, right N = 43, bilateral N = 2), dissimilar to previous studies of verbal fluency. Yet, the tracts we identified as correlates of semantic fluency were all left-lateralised. No associations between phonemic fluency performance and fibre density metrics in any of the white matter tracts we extracted survived correction for multiple comparisons, possibly due to the limitations in the selection of tracts and sample characteristics. We conclude that when accounting for the effects of stroke severity, sex, age, and education, semantic fluency is associated with white matter microstructure in the left arcuate fasciculus, superior longitudinal fasciculus, and several occipital tracts, possibly reflecting the disconnection in the sagittal stratum. Our results obtained with fixel-based analysis, complement previous findings obtained with lesions-symptom mapping and neurodegenerative approaches.

Cortical thinning 3 years after ischaemic stroke is associated with cognitive impairment and APOE ε4.

Cortical thinning has been described in many neurodegenerative diseases and used for both diagnosis and disease monitoring. The imaging signatures of post-stroke vascular cognitive impairment have not been well described. We investigated the trajectory of cortical thickness over 3 years following ischaemic stroke compared to healthy stroke-free age- and sex-matched controls. We also compared cortical thickness between cognitively normal and impaired stroke survivors, and between APOE ɛ4 carriers and non-carriers. T1-weighted MRI and cognitive data for 90 stroke survivors and 36 controls from the Cognition And Neocortical Volume After Stroke (CANVAS) study were used. Cortical thickness was estimated using FreeSurfer volumetric reconstruction according to the Desikan-Killiany parcellation atlas. Segmentation inaccuracies were manually corrected and infarcted ipsilesional vertices in cortical thickness maps were identified and excluded using stroke lesion masks traced a-priori. Mixed-effects regression was used to compare cortical thickness cross-sectionally between groups and longitudinally between timepoints. Healthy control and stroke groups did not differ on demographics and most clinical characteristics, though controls were less likely to have atrial fibrillation. Age was negatively associated with global mean cortical thickness independent of sex or group, with women in both groups having significantly thicker cortex. Three months post-stroke, cortical thinning was limited and focal. From 3 months to 3 years, the rate of cortical thinning in stroke was faster compared to that in healthy controls. However, this difference in cortical thinning rate could not survive family-wise correction for multiple comparisons. Yet, cortical thinning at 3 years was found more spread especially in ipsilesional hemispheres in regions implicated in motor, sensory, and memory processing and recovery. The cognitively impaired stroke survivors showed greater cortical thinning, compared to controls, than those who were cognitively normal at 3 years. Also, carriers of the APOE ɛ4 allele in stroke exhibited greater cortical thinning independent of cognitive status. The temporal changes of cortical thickness in both healthy and stroke cohorts followed previously reported patterns of cortical thickness asymmetry loss across the human adult life. However, this loss of thickness asymmetry was amplified in stroke. The post-stroke trajectories of cortical thickness reported in this study may contribute to our understanding of imaging signatures of vascular cognitive impairment.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

Neural correlates of co-occurring pain and depression: an activation-likelihood estimation (ALE) meta-analysis and systematic review.

The relationship between pain and depression is thought to be bidirectional and the underlying neurobiology 'shared' between the two conditions. However, these claims are often based on qualitative comparisons of brain regions implicated in pain or depression, while focused quantitative studies of the neurobiology of pain-depression comorbidity are lacking. Particularly, the direction of comorbidity, i.e., pain with depression vs. depression with pain, is rarely addressed. In this systematic review (PROSPERO registration CRD42020219876), we aimed to delineate brain correlates associated with primary pain with concomitant depression, primary depression with concurrent pain, and equal pain and depression comorbidity, using activation likelihood estimation (ALE) meta-analysis. Neuroimaging studies published in English until the 28th of September 2021 were evaluated using PRISMA guidelines. A total of 70 studies were included, of which 26 reported stereotactic coordinates and were analysed with ALE. All studies were assessed for quality by two authors, using the National Institute of Health Quality Assessment Tool. Our results revealed paucity of studies that directly investigated the neurobiology of pain-depression comorbidity. The ALE analysis indicated that pain with concomitant depression was associated with the right amygdala, while depression with concomitant pain was related primarily to the left dorsolateral prefrontal cortex (DLPFC). We provide evidence that pain and depression have a cumulative negative effect on a specific set of brain regions, distinct for primary diagnosis of depression vs. pain.

Grey and white matter atrophy 1 year after stroke aphasia.

Dynamic whole-brain changes occur following stroke, and not just in association with recovery. We tested the hypothesis that the presence of a specific behavioural deficit after stroke would be associated with structural decline (atrophy) in the brain regions supporting the affected function, by examining language deficits post-stroke. We quantified whole-brain structural volume changes longitudinally (3-12 months) in stroke participants with (N = 32) and without aphasia (N = 59) as assessed by the Token Test at 3 months post-stroke, compared with a healthy control group (N = 29). While no significant difference in language decline rates (change in Token Test scores from 3 to 12 months) was observed between groups and some participants in the aphasic group improved their scores, stroke participants with aphasia symptoms at 3 months showed significant atrophy (>2%, P = 0.0001) of the left inferior frontal gyrus not observed in either healthy control or non-aphasic groups over the 3-12 months period. We found significant group differences in the inferior frontal gyrus volume, accounting for age, sex, stroke severity at baseline, education and total intracranial volume (Bonferroni-corrected P = 0.0003). In a subset of participants (aphasic N = 14, non-aphasic N = 36, and healthy control N = 25) with available diffusion-weighted imaging data, we found significant atrophy in the corpus callosum and the left superior longitudinal fasciculus in the aphasic compared with the healthy control group. Language deficits at 3 months post-stroke are associated with accelerated structural decline specific to the left inferior frontal gyrus, highlighting that known functional brain reorganization underlying behavioural improvement may occur in parallel with atrophy of brain regions supporting the language function.

Atrophy of Ipsilesional Hippocampal Subfields Vary Over First Year After Ischemic Stroke.

BACKGROUND: The structural integrity of hippocampal subfields has been investigated in many neurological disorders and was shown to be better associated with cognitive performance than whole hippocampus. In stroke, hippocampal atrophy is linked to cognitive impairment, but it is unknown whether the hippocampal subfields atrophy differently. PURPOSE: To evaluate longitudinal hippocampal subfield atrophy in first year poststroke, in comparison with atrophy in healthy individuals. STUDY TYPE: Cohort. SUBJECTS: A total of 92 ischemic stroke (age: 67 ± 12 years, 63 men) and 39 healthy participants (age: 69 ± 7 years, 24 men). FIELD STRENGTH/SEQUENCE: A3 T/T1-MPRAGE, T2-SPACE, and T2-FLAIR. ASSESSMENT: FreeSurfer (6.0) was used to delineate 12 hippocampal subfields. Whole hippocampal volume was computed as sum of subfield volumes excluding hippocampal fissure volume. Separate assessments were completed for contralesional and ipsilesional hippocampi. STATISTICAL TESTS: A mixed-effect regression model was used to compare subfield volumes cross-sectionally between healthy and stroke groups and longitudinally between 3-month and 12-month timepoints. False discovery rate at 0.05 significance level was used to correct for multiple comparisons. Also, a receiver operating characteristic (ROC) curve analysis was performed to assess differentiation between healthy and stroke participants based on subfield volumes. RESULTS: There were no volume differences between groups at 3 months, but there was a significant difference (P = 0.027) in whole hippocampal volume reduction over time between control and stroke ipsilesionally. Thus, the ipsilesional whole hippocampal volume in stroke became significantly smaller (P = 0.035) at 12 months. The hippocampal tail was the highest single-region contributor (22.7%) to ipsilesional hippocampal atrophy (1.19%) over 9 months. The cornu ammonis areas (CA1) subfield volume reduction was minimal in controls and stroke contralesionally but significant ipsilesionally (P = 0.007). CA1 volume significantly outperformed whole hippocampal volume (P < 0.01) in discriminating between stroke participants and healthy controls in ROC curve analysis. DATA CONCLUSION: Greater stroke-induced effects were observed in the ipsilesional hippocampus anteriorly in CA1 and posteriorly in the hippocampal tail. Atrophy of CA1 and hippocampal tail may provide a better link to cognitive impairment than whole hippocampal atrophy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Post-stroke fatigue is associated with resting state posterior hypoactivity and prefrontal hyperactivity.

BACKGROUND: Fatigue is associated with poor functional outcomes and increased mortality following stroke. Survivors identify fatigue as one of their key unmet needs. Despite the growing body of research into post-stroke fatigue, the specific neural mechanisms remain largely unknown. AIM: This observational study aimed to identify resting state brain activity markers of post-stroke fatigue. METHOD: Sixty-three stroke survivors (22 women; age 30-89 years; mean 67.5 ± 13.4 years) from the Cognition And Neocortical Volume After Stroke study, a cohort study examining cognition, mood, and brain volume in stroke survivors following ischemic stroke, underwent brain imaging three months post-stroke, including a 7-minute resting state functional magnetic resonance imaging. We calculated the fractional amplitude of low-frequency fluctuations, which is measured at the whole-brain level and can detect altered spontaneous neural activity of specific regions. RESULTS: Forty-five participants reported experiencing post-stroke fatigue as measured by an item on the Patient Health Questionnaire-9. Fatigued compared to non-fatigued participants demonstrated significantly lower resting-state activity in the calcarine cortex (p < 0.001, cluster-corrected pFDR = 0.009, k = 63) and lingual gyrus (p < 0.001, cluster-corrected pFDR = 0.025, k = 42) and significantly higher activity in the medial prefrontal cortex (p < 0.001, cluster-corrected pFDR = 0.03, k = 45). CONCLUSIONS: Post-stroke fatigue is associated with posterior hypoactivity and prefrontal hyperactivity reflecting dysfunction within large-scale brain systems such as fronto-striatal-thalamic and frontal-occipital networks. These systems in turn might reflect a relationship between post-stroke fatigue and abnormalities in executive and visual functioning. This whole-brain resting-state study provides new targets for further investigation of post-stroke fatigue beyond the lesion approach.

Hippocampal subfield volumes are associated with verbal memory after first-ever ischemic stroke.

INTRODUCTION: Hippocampal subfield volumes are more closely associated with cognitive impairment than whole hippocampal volume in many diseases. Both memory and whole hippocampal volume decline after stroke. Understanding the subfields' temporal evolution could reveal valuable information about post-stroke memory. METHODS: We sampled 120 participants (38 control, 82 stroke), with cognitive testing and 3T-MRI available at 3 months and 3 years, from the Cognition and Neocortical Volume after Stroke (CANVAS) study. Verbal memory was assessed using the Hopkins Verbal Learning Test-Revised. Subfields were delineated using FreeSurfer. We used partial Pearson's correlation to assess the associations between subfield volumes and verbal memory scores, adjusting for years of education, sex, and stroke side. RESULTS: The left cornu ammonis areas 2/3 and hippocampal tail volumes were significantly associated with verbal memory 3-month post-stroke. At 3 years, the associations became stronger and involved more subfields. DISCUSSION: Hippocampal subfield volumes may be a useful biomarker for post-stroke cognitive impairment.