Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies

Blood oxygenation level dependent (BOLD) contrast fMRI is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breathhold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue, and the peri-infarct tissue, both sub-acutely (~two weeks) and chronically (~four months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared to the controls may be confounded by a reduced CVR, longitudinal grouplevel BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity

Proinflammatory Cytokine Gene Polymorphisms in Bullous Pemphigoid

Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression

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; β=0.16) but not contralesional (P=0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; β=−0.26) and contralesional (P=0.006; β=−0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; β=−0.21) and extent of sensorimotor damage (P=0.003; β=−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.S.-L.L. is supported by NIH K01 HD091283; NIH R01 NS115845. A.B. and M.S.K. are supported by National Health and Medical Research Council (NHMRC) GNT1020526, GNT1045617 (A.B.), GNT1094974, and Heart Foundation Future Leader Fellowship 100784 (A.B.). P.M.T. is supported by NIH U54 EB020403. L.A.B. is supported by the Canadian Institutes of Health Research (CIHR). C.M.B. is supported by NIH R21 HD067906. W.D.B. is supported by the Heath Research Council of New Zealand. J.M.C. is supported by NIH R00HD091375. A.B.C. is supported by NIH R01NS076348-01, Hospital Israelita Albert Einstein 2250-14, CNPq/305568/2016-7. A.N.D. is supported by funding provided by the Texas Legislature to the Lone Star Stroke Clinical Trial Network. Its contents are solely the responsibility of the authors and do not necessarily represent the of ficial views of the Government of the United States or the State of Texas. N.E.-B. is supported by Australian Research Council NIH DE180100893. W.F. is sup ported by NIH P20 GM109040. F.G. is supported by Wellcome Trust (093957). B.H. is funded by and NHMRC fellowship (1125054). S.A.K is supported by NIH P20 HD109040. F.B. is supported by Italian Ministry of Health, RC 20, 21. N.S. is supported by NIH R21NS120274. N.J.S. is supported by NIH/National Institute of General Medical Sciences (NIGMS) 2P20GM109040-06, U54-GM104941. S.R.S. is supported by European Research Council (ERC) (NGBMI, 759370). G.S. is supported by Italian Ministry of Health RC 18-19-20-21A. M.T. is sup ported by National Institute of Neurological Disorders and Stroke (NINDS) R01 NS110696. G.T.T. is supported by Temple University sub-award of NIH R24 –NHLBI (Dr Mickey Selzer) Center for Experimental Neurorehabilitation Training. N.J.S. is funded by NIH/National Institute of Child Health and Human Development (NICHD) 1R01HD094731-01A1

A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research

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 (β = 0.21; 95% CI 0.04-0.38, 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

Using fMRI to investigate speech production in healthy adults and patients with post-stroke aphasia

This thesis presents an investigation of brain networks mediating both language-specific and domain-general control of propositional speech production in health and following left hemisphere stroke. The research used univariate and multivariate analyses of functional magnetic resonance imaging data as participants produced sentential speech in response to stimuli (Speech). The activity of specific brain networks during Speech was compared against different baseline conditions. Two studies on healthy participants confirmed a language-specific role for a left fronto-temporo-parietal (LFTP) network. Propositional speech was accompanied by a relative suppression of activity in domain-general networks including a right fronto-temporo-parietal (RFTP) network, default mode network (DMN), and cingulo-opercular (CingOper) network. A separate study investigated alterations in the activity of these networks following a chronic left hemisphere stroke. The network measures in patients were related to those from the healthy participants. There was an up-regulation of the CingOper network during Speech, a task the patients found difficult. Although the activity within individual networks was not predictive of speech production in patients, the relative activity between networks was a predictor of both within-scanner and out-of-scanner performance, over and above that predicted from lesion volume and various demographic factors. Specifically, the robust functional imaging predictors were the differential activity between the DMN and both the left and right fronto-temporo-parietal networks. The patients also demonstrated an altered speech-related between-networks functional connectivity. A further study of cerebrovascular reactivity measurements suggested that signal changes in the healthy tissue remote from the infarct were unlikely to be confounded by cerebrovascular reactivity changes following stroke. The results of the thesis indicate that recovery of speech production after stroke, is not adequately captured by notions of brain regions ‘taking over’ lost domain-specific functions. Rather it is best considered as the interaction between what remains of domain-specific networks and the domain-general systems that regulate behaviour.Open Acces

Task-induced brain activity in aphasic stroke patients: what is driving recovery?

The estimated prevalence of aphasia in the UK and the USA is 250 000 and 1 000 000, respectively. The commonest aetiology is stroke. The impairment may improve with behavioural therapy, and trials using cortical stimulation or pharmacotherapy are undergoing proof-of-principle investigation, but with mixed results. Aphasia is a heterogeneous syndrome, and the simple classifications according to the Broca-Wernicke-Lichtheim model inadequately describe the diverse communication difficulties with which patients may present. Greater knowledge of how intact neural networks promote recovery after aphasic stroke, either spontaneously or in response to interventions, will result in clearer hypotheses about how to improve the treatment of aphasia. Twenty-five years ago, a pioneering study on healthy participants heralded the introduction of functional neuroimaging to the study of mechanisms of recovery from aphasia. Over the ensuing decades, such studies have been interpreted as supporting one of three hypotheses, which are not mutually exclusive. The first two predate the introduction of functional neuroimaging: that recovery is the consequence of the reconstitution of domain-specific language systems in tissue around the lesion (the ‘perilesional’ hypothesis), or by homotopic cortex in the contralateral hemisphere (the ‘laterality-shift’ hypothesis). The third is that loss of transcallosal inhibition to contralateral homotopic cortex hinders recovery (the ‘disinhibition’ hypothesis). These different hypotheses at times give conflicting views about rehabilitative intervention; for example, should one attempt to activate or inhibit a contralateral homotopic region with cortical stimulation techniques to promote recovery? This review proposes that although the functional imaging data are statistically valid in most cases, their interpretation has often favoured one explanation while ignoring plausible alternatives. In our view, this is particularly evident when recovery is attributed to activity in ‘language networks’ occupying sites not observed in healthy participants. In this review we will argue that much of the distribution of what has often been interpreted as language-specific activity, particularly in midline and contralateral cortical regions, is an upregulation of activity in intact domain-general systems for cognitive control and attention, responding in a task-dependent manner to the increased ‘effort’ when damaged downstream domain-specific language networks are impaired. We further propose that it is an inability fully to activate these systems that may result in sub optimal recovery in some patients. Interpretation of the data in terms of activity in domain-general networks affords insights into novel approaches to rehabilitation

The multidimensional nature of aphasia recovery post-stroke.

Language is not a single function, but instead results from interactions between neural representations and computations that can be damaged independently of each other. Although there is now clear evidence that the language profile in post-stroke aphasia reflects graded variations along multiple underlying dimensions ('components'), it is still entirely unknown if these distinct language components have different recovery trajectories and rely on the same, or different, neural regions during aphasia recovery. Accordingly, this study examined whether language components in the subacute stage: (i) mirror those observed in the chronic stage; (ii) recover together in a homogeneous manner; and (iii) have recovery trajectories that relate to changing activation in distinct or overlapping underlying brain regions. We analysed longitudinal data from 26 individuals with mild-moderate aphasia following left hemispheric infarct who underwent functional MRI and behavioural testing at ∼2 weeks and ∼4 months post-stroke. The language profiles in early post-stroke aphasia reflected three orthogonal principal components consisting of fluency, semantic/executive function and phonology. These components did not recover in a singular, homogeneous manner; rather, their longitudinal trajectories were uncorrelated, suggesting that aphasia recovery is heterogeneous and multidimensional. Mean regional brain activation during overt speech production in unlesioned areas was compared with patient scores on the three principal components of language at both the early and late time points. In addition, the change in brain activation over time was compared with the change on each of the principal component scores, both before and after controlling for baseline scores. We found that different language components were associated with changing activation in multiple, non-overlapping bilateral brain regions during aphasia recovery. Specifically, fluency recovery was associated with increasing activation in bilateral middle frontal gyri and right temporo-occipital middle temporal gyrus; semantic/executive recovery was associated with reducing activation in bilateral anterior temporal lobes; while phonology recovery was associated with reducing activation in bilateral precentral gyri, dorso-medial frontal poles and the precuneus. Overlapping clusters in the ventromedial prefrontal cortex were positively associated with fluency recovery but negatively associated with semantic/executive and phonology recovery. This combination of detailed behavioural and functional MRI data provides novel insights into the neural basis of aphasia recovery. Because different aspects of language seem to rely on different neural regions for recovery, treatment strategies that target the same neural region in all stroke survivors with aphasia might be entirely ineffective or even impair recovery, depending on the specific language profile of each individual patient

A Bayesian optimization approach for rapidly mapping residual network function in stroke.

Post-stroke cognitive and linguistic impairments are debilitating conditions, with limited therapeutic options. Domain-general brain networks play an important role in stroke recovery and characterizing their residual function with functional MRI has the potential to yield biomarkers capable of guiding patient-specific rehabilitation. However, this is challenging as such detailed characterization requires testing patients on multitudes of cognitive tasks in the scanner, rendering experimental sessions unfeasibly lengthy. Thus, the current status quo in clinical neuroimaging research involves testing patients on a very limited number of tasks, in the hope that it will reveal a useful neuroimaging biomarker for the whole cohort. Given the great heterogeneity among stroke patients and the volume of possible tasks this approach is unsustainable. Advancing task-based functional MRI biomarker discovery requires a paradigm shift in order to be able to swiftly characterize residual network activity in individual patients using a diverse range of cognitive tasks. Here, we overcome this problem by leveraging neuroadaptive Bayesian optimization, an approach combining real-time functional MRI with machine-learning, by intelligently searching across many tasks, this approach rapidly maps out patient-specific profiles of residual domain-general network function. We used this technique in a cross-sectional study with 11 left-hemispheric stroke patients with chronic aphasia (four female, age ± standard deviation: 59 ± 10.9 years) and 14 healthy, age-matched control subjects (eight female, age ± standard deviation: 55.6 ± 6.8 years). To assess intra-subject reliability of the functional profiles obtained, we conducted two independent runs per subject, for which the algorithm was entirely reinitialized. Our results demonstrate that this technique is both feasible and robust, yielding reliable patient-specific functional profiles. Moreover, we show that group-level results are not representative of patient-specific results. Whereas controls have highly similar profiles, patients show idiosyncratic profiles of network abnormalities that are associated with behavioural performance. In summary, our study highlights the importance of moving beyond traditional 'one-size-fits-all' approaches where patients are treated as one group and single tasks are used. Our approach can be extended to diverse brain networks and combined with brain stimulation or other therapeutics, thereby opening new avenues for precision medicine targeting a diverse range of neurological and psychiatric conditions

Cognitive control and its impact on recovery from aphasic stroke

Aphasic deficits are usually only interpreted in terms of domain-specific language processes. However, effective human communication and tests that probe this complex cognitive skill are also dependent on domain-general processes. In the clinical context, it is a pragmatic observation that impaired attention and executive functions interfere with the rehabilitation of aphasia. One system that is important in cognitive control is the salience network, which includes dorsal anterior cingulate cortex and adjacent cortex in the superior frontal gyrus (midline frontal cortex). This functional imaging study assessed domain-general activity in the midline frontal cortex, which was remote from the infarct, in relation to performance on a standard test of spoken language in 16 chronic aphasic patients both before and after a rehabilitation programme. During scanning, participants heard simple sentences, with each listening trial followed immediately by a trial in which they repeated back the previous sentence. Listening to sentences in the context of a listen–repeat task was expected to activate regions involved in both language-specific processes (speech perception and comprehension, verbal working memory and pre-articulatory rehearsal) and a number of task-specific processes (including attention to utterances and attempts to overcome pre-response conflict and decision uncertainty during impaired speech perception). To visualize the same system in healthy participants, sentences were presented to them as three-channel noise-vocoded speech, thereby impairing speech perception and assessing whether this evokes domain general cognitive systems. As expected, contrasting the more difficult task of perceiving and preparing to repeat noise-vocoded speech with the same task on clear speech demonstrated increased activity in the midline frontal cortex in the healthy participants. The same region was activated in the aphasic patients as they listened to standard (undistorted) sentences. Using a region of interest defined from the data on the healthy participants, data from the midline frontal cortex was obtained from the patients. Across the group and across different scanning sessions, activity correlated significantly with the patients’ communicative abilities. This correlation was not influenced by the sizes of the lesion or the patients’ chronological ages. This is the first study that has directly correlated activity in a domain general system, specifically the salience network, with residual language performance in post-stroke aphasia. It provides direct evidence in support of the clinical intuition that domain-general cognitive control is an essential factor contributing to the potential for recovery from aphasic stroke