Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

Abstract

Background: Stroke patients with mild-moderate upper extremity motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals.

Objective: To determine whether stroke lesions in an upper extremity rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research.

Methods: Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery.

Results: Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1% had lesions resembling proximal middle cerebral artery or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model.

Conclusions: ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared with lesions in general stroke populations and widely studied animal models of recovery, ICARE participants had smaller, more subcortically based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models.

Keywords: anterior choroidal artery infarction; corticospinal tract; magnetic resonance imaging; middle cerebral artery occlusion; rehabilitation; upper extremity paresis.

Figure 1

Template analysis using the ICARE Neuroimaging Viewer. After identifying the group of templates corresponding to the angle at which the head was scanned, the template that best matched the axial slice was chosen and overlaid on top of the diffusion weighted image (DWI) image. The template was rotated clockwise and enlarged to match the outer border of the brain. This process was repeated for each axial slice to be sure the predominant area captured the template subdivision in the 3 dimensional center of the lesion. In this example the predominant area was scored as anterior choroidal (ACH). AC0/AC3 – anterior cerebral artery subdivisions, MC1/MC2/MC3/MC5 – middle cerebral artery subdivisions, PCA – posterior cerebral artery, IB – insular branches, LS – lenticulostriates, THP – thalamoperforating.

Figure 2

Map displaying the incidence of stroke lesions centered in each template subdivision (predominant area) for (A) Ischemic stroke participants and (B) ICH participants. The incidence was normalized to the template subdivision with the highest incidence, which was the anterior choroidal (ACH) for both ischemic stroke and ICH. To better delineate lesion involvement in the posterior circulation, the vascular territory data from the template analysis was replaced by the predominant area analysis for the brainstem / cerebellum. Note that the ACH vascular distribution extends into the anteromedial region of the temporal horns, but the vast majority of ACH involvement was confined to the internal capsule / basal ganglia. AC0/AC1/AC2/AC3 – anterior cerebral artery subdivisions, MC1/MC2/MC3/MC4/MC5 – middle cerebral artery subdivisions, PCA – posterior cerebral artery, HA – Heubner’s artery, IB – insular branches, LS – lenticulostriates, THP – thalamoperforating, BA – basilar artery, VA – vertebral artery.

Figure 3

Stroke lesion planimetric volumes for ICARE participants (n = 297). The y-axis on the right denotes the approximate volume of the MCA territory in humans.