Functional Lesion Network Mapping of Sensory Deficits After Ischemic Stroke
Abstract
BACKGROUND:
Sensory deficits are common after stroke, leading to disability and poor quality of life. Although lesion locations and patterns of structural brain network disruption have been associated with sensory disturbances, the relation with functional lesion connectivity has not yet been established.
METHODS:
Retrospective analysis of a prospective cohort study of patients with acute ischemic stroke. Indirect functional lesion network mapping to identify brain regions remote from the primary lesion associated with deficits on the Rivermead Assessment of Somatosensory Performance test. Associations between Rivermead Assessment of Somatosensory Performance scores and functional connectivity of the lesion site with prespecified components of the somatosensory system.
RESULTS:
One hundred one patients (mean age, 62 years; 32% women) from the TOPOS study (Topological and Clinical Prospective Study About Somatosensation in Stroke). Lesion network mapping identified a bilateral fronto-parietal network associated with sensory deficits in the acute phase after stroke. There were graded associations between deficits and functional lesion connectivity to sensory cortices, but not the thalamus.
CONCLUSIONS:
Infarcts in brain regions remote from, but functionally connected, to the somatosensory network are associated with somatosensory deficits measured by the Rivermead Assessment of Somatosensory Performance test, reflecting the hierarchical functional anatomy of sensory processing. Further research is needed to translate these findings into improved prognosis and personalized rehabilitation strategies.
Graphical Abstract
Sensory symptoms are common after ischemic stroke.1 They aggravate motor deficits and are a contributor to disability and poor quality of life.2 Based on lesion studies and experimental evidence, the somatosensory system is known to comprise hierarchically organized components that process receptor inputs into perception and behavior.3 Ischemic lesions directly affecting gray matter areas, such as the primary and secondary cortex, the insula, or thalamus can cause sensory deficits.4 Moreover, structural disconnection of these areas by damage to underlying white matter may lead to similar clinical phenotypes.5
Complementary to the anatomic network structure of the brain, there is a growing appreciation for the spatio-temporal organization of brain activity, reflecting distributed neuronal processing as a correlate of neurological function. Investigations of lesion-induced changes in functional connectivity patterns have helped identify prognostic imaging biomarkers to guide rehabilitation of motor and cognitive function for patients with stroke.6
However, the association between sensory deficits and the functional anatomy of ischemic lesions in patients with stroke has not been established.
We performed indirect lesion network mapping of somatosensory deficits in a cohort of patients with acute stroke. The aim of the study was to characterize the common functional connectivity profile of ischemic lesions associated with sensory deficits and identify functional hubs of sensory processing. We also compared the functional eloquence of anatomically defined components of the somatosensory system.
METHODS
The data that support the findings of this study are available from the corresponding author on reasonable request.
Study Design and Participants
We retrospectively analyzed clinical and imaging data from the prospective observational cohort study TOPOS (Topological and Clinical Prospective Study About Somatosensation in Stroke) conducted at the University Medical Center Hamburg-Eppendorf. The study was approved by the local Ethics Committee and included consecutive adult patients with first-ever acute stroke with an imaging-confirmed ischemic lesion within 4 days after ictus. Exclusion criteria included severe aphasia preventing consent and relevant neurological and psychiatric comorbidities.4 Informed consent was given before participation in the study.
Clinical Characterization
Within 5 days after stroke, somatosensory function was examined using the Rivermead Assessment of Somatosensory Performance battery.7 Standardized testing provided, for each patient, a composite score between 0 (complete loss of sensation) and 193 (intact sensation) to reflect deficits in multiple sensory domains.
Imaging Acquisition and Preprocessing
Brain imaging was acquired between 3 and 7 days after stroke, including diffusion-weighted and fluid-attenuated inversion recovery magnetic resonance sequences. Ischemic lesions were segmented, binarized, and registered to the Montreal Neurological Institute reference space, as previously described.8,9
Lesion Network Mapping
We used Lead-DBS v2.6 to compute mean functional connectivity maps for each brain lesion.10 Reference resting-state data were obtained from an age-matched cohort of 89 stroke-free subjects. After averaging the blood oxygen level–dependent signal over voxels comprising a lesion, functional connectivity to every brain voxel was quantified by the Pearson correlation coefficient between lesion-averaged and voxel-specific blood oxygen level–dependent time series. Mean connectivity maps were obtained by averaging over the reference cohort.
In addition to lesion connectivity maps, we computed functional somatosensory networks by seed-based correlation from primary and secondary somatosensory cortices as well as the thalamus and its ventral posterior nucleus obtained from the Julich histological atlas.11 In sensitivity analyses we seeded lesion connectivity maps from gray matter only to exclude noisy blood oxygen level–dependent signals from white matter and mean-imputed lesion sites in functional connectivity maps to reduce autocorrelation.
Statistical Analysis
Associations between somatosensory deficit and lesion connectivity were quantified for each voxel using the t-statistic from multiple linear regression. The natural logarithm of lesion volume was included as a covariate. Clusters of statistically significant positive associations (α=0.05) were determined using the threshold-free cluster enhancement method implemented in FSL (Oxford Centre for Functional Magnetic Resonance Imaging of the Brain Software Library).
For each patient, lesion load in the 4 predefined functional networks was computed by summing signed connectivity values over the voxels contained in that patient’s lesion mask. Rivermead Assessment of Somatosensory Performance score complements being positive and integer-valued, associations between lesion load and clinical deficits were quantified using generalized linear regression analysis with a Poisson response distribution and logarithmic link function. Dispersion parameters were estimated from the data. Positive and negative network lesion loads were explored separately.
RESULTS
Demographic and clinical details of N=101 patients with stroke are reported in (Table). Ischemic lesions were distributed across the whole brain with a focus on subcortical white matter (Figure 1A), There were more right-sided than left-sided infarcts (65 versus 36, P=0.004). Lesion connectivity maps were computed for all patients and are shown in (Figure 1B). Functional network mapping identified clusters of voxels in which lesion connectivity was associated with sensory deficits as measured by the Rivermead Assessment of Somatosensory Performance (Figure 1C). The functional hotspot contained >75% of the secondary somatosensory cortex (S2), about half of the posterior insula, and <20% of primary somatosensory cortex (S1), with a clear separation from motor areas (Figure 1D). Similar results were obtained with gray matter seeds and mean-imputed connectivity maps (Supplemental Material).
| TOPOS patients (N=101) | |
|---|---|
| Age, y, median (interquartile range) | 62 (54–72) |
| Gender (male), n (%) | 69 (68.3) |
| Baseline NIHSS, median (IQR) | 2 (1–4) |
| NIHSS item 8 (sensory loss), median (IQR) | 1 (0–1) |
| 0, n (%) | 48 (47.5) |
| 1, n (%) | 39 (38.6) |
| 2, n (%) | 14 (13.9) |
| Infarct size, mL, median (IQR) | 6.0 (1.1–29.9) |
| RASP (0–193), median (IQR) | 188 (160–192) |
IQR indicates interquartile range; NIHSS, National Institutes of Health Stroke Scale; RASP, Rivermead Assessment of Somatosensory Performance; and TOPOS, Topological and Clinical Prospective Study About Somatosensation in Stroke.
Associations between lesion load in predefined sensory networks seeded from the primary and secondary cortices and the thalamus, and deficits in different sensory modalities are shown in (Figure 2). Rivermead Assessment of Somatosensory Performance deficit was positively associated with total lesion load in the secondary (P<0.0001), but not the primary somatosensory network (P=0.0547) or in brain areas functionally connected to the thalamus (whole, P=0.911; ventroposterior nucleus of the thalamus, P=0.633). Results for positive and negative lesion load are reported in Figure S6.
DISCUSSION
Our study yields 2 insights into the relation between infarct topography and sensory deficits after ischemic stroke. Firstly, specific functional lesion connectivity profiles were associated with the severity of clinical symptoms. Secondly, we observed a gradient between the main components of the somatosensory system: ischemic damage to higher-order networks was more strongly associated with deficits in sensation after stroke than infarcts in locations connected to primary processing areas.
These results extend and contrast with previous findings from voxel-based lesion-symptom mapping, where ischemic damage to S1 was identified as the dominant immediate correlate of poststroke sensory deficits.4
Our findings are consistent with a directed flow of information through the sensory system from the thalamus to the somatosensory cortices. Structurally, the robustness of the thalamus to remote intracranial lesions points toward a large proportion of outgoing projection fibers, whereas the vulnerability of the cortical areas reflects a higher proportion of terminating connections. Consequently, our data suggest that the thalamus, at least for sensory processing, acts more like a relay station than an integrative hub. The gradient between primary and secondary cortices was less pronounced, indicating a combination of serial and parallel processing pathways, as previously described.12
Limitations of the present study include a lesion distribution constrained by vascular territories with a small number of thalamic or brain stem infarcts. Also due to our indirect approach of combining lesion locations obtained from clinical imaging with reference resting-state data, we were unable to quantify changes in functional connectivity between different lesion-remote components of the somatosensory network or estimate measures of directed connectivity.
In summary, this study illustrates the hierarchical functional anatomy of disturbed somatosensory processing after acute stroke.
ARTICLE INFORMATION
Supplemental Material
Supplemental Methods
Supplemental Results
Figures S1–S6
Table S1
Supplemental Material
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© 2023 American Heart Association, Inc.
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History
Received: 14 June 2023
Revision received: 31 August 2023
Accepted: 5 September 2023
Published online: 5 October 2023
Published in print: November 2023
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Disclosures
Disclosures Dr Thomalla reported receiving personal fees from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Portola, and Stryker and grant support from the European Union (FP7 Health), all outside the submitted work. The other authors report no conflicts.
Sources of Funding
Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB 936—178316478—C2 (Drs Cheng and Thomalla).
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