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Optical imaging of disrupted functional connectivity following ischemic stroke in mice.

ABSTRACT: Recent human neuroimaging studies indicate that spontaneous fluctuations in neural activity, as measured by functional connectivity magnetic resonance imaging (fcMRI), are significantly affected following stroke. Disrupted functional connectivity is associated with behavioral deficits and has been linked to long-term recovery potential. FcMRI studies of stroke in rats have generally produced similar findings, although subacute cortical reorganization following focal ischemia appears to be more rapid than in humans. Similar studies in mice have not been published, most likely because fMRI in the small mouse brain is technically challenging. Extending functional connectivity methods to mouse models of stroke could provide a valuable tool for understanding the link between molecular mechanisms of stroke repair and human fcMRI findings at the system level. We applied functional connectivity optical intrinsic signal imaging (fcOIS) to mice before and 72 h after transient middle cerebral artery occlusion (tMCAO) to examine how graded ischemic injury affects the relationship between functional connectivity and infarct volume, stimulus-induced response, and behavior. Regional changes in functional connectivity within the MCA territory were largely proportional to infarct volume. However, subcortical damage affected functional connectivity in the somatosensory cortex as much as larger infarcts of cortex and subcortex. The extent of injury correlated with cortical activations following electrical stimulation of the affected forelimb and with functional connectivity in the somatosensory cortex. Regional homotopic functional connectivity in motor cortex correlated with behavioral deficits measured using an adhesive patch removal test. Spontaneous hemodynamic activity within the infarct exhibited altered temporal and spectral features in comparison to intact tissue; failing to account for these regional differences significantly affected apparent post-stroke functional connectivity measures. Thus, several results were strongly dependent on how the resting-state data were processed. Specifically, global signal regression alone resulted in apparently distorted functional connectivity measures in the intact hemisphere. These distortions were corrected by regressing out multiple sources of variance, as performed in human fcMRI. We conclude that fcOIS provides a sensitive imaging modality in the murine stroke model; however, it is necessary to properly account for altered hemodynamics in injured brain to obtain accurate measures of functional connectivity.

SUBMITTER: Bauer AQ

PROVIDER: S-EPMC4332714 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Optical imaging of disrupted functional connectivity following ischemic stroke in mice.

Bauer Adam Q AQ Kraft Andrew W AW Wright Patrick W PW Snyder Abraham Z AZ Lee Jin-Moo JM Culver Joseph P JP

NeuroImage 20140524

Recent human neuroimaging studies indicate that spontaneous fluctuations in neural activity, as measured by functional connectivity magnetic resonance imaging (fcMRI), are significantly affected following stroke. Disrupted functional connectivity is associated with behavioral deficits and has been linked to long-term recovery potential. FcMRI studies of stroke in rats have generally produced similar findings, although subacute cortical reorganization following focal ischemia appears to be more r ...[more]

PMID: 24862071

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Project description:Background and Purpose- The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain's connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function. Methods- In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain's prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length (L) was calculated for each connectome. The number of rich club regions affected were manually determined using each patient's diffusion weighted image. We investigated differences in L with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2-5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and L in outcome models, using linear regression and assessing the explained variance (R2). Results- Of 41 patients (mean age [range]: 70 [45-89] years), 61% were male. Lower L was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R2 increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score. Conclusions- In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.

Project description:Background: Post-stroke aphasia (PSA) results from brain network disorders caused by focal stroke lesions. However, it still remains largely unclear whether the impairment is present in intra- and internetwork functional connectivity (FC) within each resting-state network (RSN) and between RSNs in the subacute stage of PSA. Objectives: This study aimed to investigate the resting-state FC within and between RSNs in patients with PSA and observe the relationships between FC alterations and Western Aphasia Battery (WAB) measures. Methods: A total of 20 individuals with subacute PSA and 20 healthy controls (HCs) were recruited for functional MRI (fMRI) scanning, and only patients with PSA underwent WAB assessment. Independent component analysis was carried out to identify RSNs. Two-sample t-tests were used to calculate intra- and internetwork FC differences between patients with PSA and HCs. The results were corrected for multiple comparisons using the false discovery rate (FDR correction, p < 0.05). Partial correlation analysis was performed to observe the relationship between FC and WAB scores with age, gender, mean framewise displacement, and lesion volume as covariates (p < 0.05). Results: Compared to HCs, patients with PSA showed a significant increase in intranetwork FC in the salience network (SN). For internetwork FC analysis, patients showed a significantly increased coupling between left frontoparietal network (lFPN) and SN and decreased coupling between lFPN and right frontoparietal network (rFPN) as well as between lFPN and posterior default mode network (pDMN) (FDR correction, p < 0.05). Finally, a significant positive correlation was found between the intergroup difference of FC (lFPN-rFPN) and auditory-verbal comprehension (p < 0.05). Conclusion: Altered FC was revealed within and between multiple RSNs in patients with PSA at the subacute stage. Reduced FC between lFPN and rFPN was the key element participating in language destruction. These findings proved that PSA is a brain network disorder caused by focal lesions; besides, it may improve our understanding of the pathophysiological mechanisms of patients with PSA at the subacute stage.

Project description:Apraxia of speech is a motor speech disorder thought to result from impaired planning or programming of articulatory movements. It can be the initial or only manifestation of a degenerative disease, termed primary progressive apraxia of speech (PPAOS). The aim of this study was to use task-free functional magnetic resonance imaging (fMRI) to assess large-scale brain network pathophysiology in PPAOS. Twenty-two PPAOS participants were identified from a prospective cohort of degenerative speech and language disorders patients. All participants had a comprehensive, standardized evaluation including an evaluation by a speech-language pathologist, examination by a behavioral neurologist and a multimodal imaging protocol which included a task-free fMRI sequence. PPAOS participants were age and sex matched to amyloid-negative, cognitively normal participants with a 1:2 ratio. We chose a set of hypothesis driven, predefined intrinsic connectivity networks (ICNs) from a large, out of sample independent component analysis and then used them to initialize a spatiotemporal dual regression to estimate participant level connectivity within these ICNs. Specifically, we evaluated connectivity within the speech and language, face and hand sensorimotor, left working memory, salience, superior parietal, supramarginal, insular and deep gray ICNs in a multivariate manner. The spatial maps for each ICN were then compared between PPAOS and control participants. We used clinical measures of apraxia of speech severity to assess for clinical-connectivity correlations for regions found to differ between PPAOS and control participants. Compared to controls, PPAOS participants had reduced connectivity of the right supplementary motor area and left posterior temporal gyrus to the rest of the speech and language ICN. The connectivity of the right supplementary motor area correlated negatively with an articulatory error score. PPAOS participants also had reduced connectivity of the left supplementary motor area to the face sensorimotor ICN, between the left lateral prefrontal cortex and the salience ICN and between the left temporal-occipital junction and the left working memory ICN. The latter connectivity correlated with the apraxia of speech severity rating scale, although the finding did not survive correction for multiple comparisons. Increased connectivity was noted in PPAOS participants between the dorsal posterior cingulate and the left working memory ICN. Our results support the importance of the supplementary motor area in the pathophysiology of PPAOS, which appears to be disconnected from speech and language regions. Supplementary motor area connectivity may serve as a biomarker of degenerative apraxia of speech severity.

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Optical imaging of disrupted functional connectivity following ischemic stroke in mice.

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Optical imaging of disrupted functional connectivity following ischemic stroke in mice.

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