A Rat Model of Photothrombotic Capsular Infarct with a Marked Motor Deficit: A Behavioral, Histologic, and microPET Study

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Strokes attributable to subcortical infarcts have been increasing recently in elderly patients. To gain insight how this lesion influences the motor outcome and responds to rehabilitative training, we used circumscribed photothrombotic capsular infarct models on 36 Sprague-Dawley rats (24 experimental and 12 sham-operated). We used 2-deoxy-2-[(18)F]-fluoro-D-glucose-micro positron emission tomography (FDG-microPET) to assess longitudinal changes in resting-state brain activity (rs-BA) and daily single-pellet reaching task (SPRT) trainings to evaluate motor recovery. Longitudinal FDG-microPET results showed that capsular infarct resulted in a persistent decrease in rs-BA in bilateral sensory and auditory cortices, and ipsilesional motor cortex, thalamus, and inferior colliculus (P<0.0025, false discovery rate (FDR) q<0.05). The decreased rs-BA is compatible with diaschisis and contributes to manifest the malfunctions of lesion-specific functional connectivity. In contrast, capsular infarct resulted in increase of rs-BA in the ipsilesional internal capsule, and contralesional red nucleus and ventral hippocampus in recovery group (P<0.0025, FDR q<0.05), implying that remaining subcortical structures have an important role in conducting the recovery process in capsular infarct. The SPRT training facilitated motor recovery only in rats with an incomplete destruction of the posterior limb of the internal capsule (PLIC) (Pearson's correlation, P<0.05). Alternative therapeutic interventions are required to enhance the potential for recovery in capsular infarct with complete destruction of PLIC.

Section: Introductionmentioning

confidence: 99%

Longitudinal Changes in Resting-State Brain Activity in a Capsular Infarct Model

Kim

et al. 2014

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“…Photothrombosis has recently been used to target the internal capsule causing motor deficits lasting at least 3 weeks. 27 However, sensory function was not examined in this study, and lesions also involved the entopeduncular nucleus (corresponding to the human globus pallidus internus) that may lead to motor deficits and were adjacent to the optic tract that may cause vision defects. Moreover, mechanisms of photothrombotic injury may involve more than just tissue ischemia.…”

Section: Discussionmentioning

confidence: 93%

“…Finally, the absence of injury in other motor areas of the brain (e.g., cortex, striatum, and substantia nigra), as well as areas that may confound behavioral tests (e.g., optic nerve and tract, hippocampus), is an advantage over other models that result in white-matter injury, such as chronic forebrain hypoperfusion, chronic hypertension, intracarotid sodium laurate injection, or capsular photothrombotic lesion. 9,27,[32][33][34][35][36] Of course, ET-1 model has limitations. The mechanism of ischemia does not mimic lacunar pathophysiology, multiple vessels constrict at the same time, the duration of ischemia cannot be precisely controlled, and ET-1 targets not only endothelial and smooth muscle cells but also neurons and glia as a possible confounder.…”

Section: Discussionmentioning

confidence: 99%

Lasting Pure-Motor Deficits after Focal Posterior Internal Capsule White-Matter Infarcts in Rats

Blasi

Whalen

Ayata

2015

Small white-matter infarcts of the internal capsule are clinically prevalent but underrepresented among currently available animal models of ischemic stroke. In particular, the assessment of long-term outcome, a primary end point in clinical practice, has been challenging due to mild deficits and the rapid and often complete recovery in most experimental models. We, therefore, sought to develop a focal white-matter infarction model that can mimic the lasting neurologic deficits commonly observed in stroke patients. The potent vasoconstrictor endothelin-1 (n = 24) or vehicle (n = 9) was stereotactically injected into the internal capsule at one of three antero-posterior levels (1, 2, or 3 mm posterior to bregma) in male Sprague-Dawley rats. Endothelin-injected animals showed highly focal (~1 mm 3 ) and reproducible ischemic infarcts, with severe axonal and myelin loss accompanied by cellular infiltration when examined 2 and 4 weeks after injection. Only those rats injected with endothelin-1 at the most posterior location developed robust and pure-motor deficits in adhesive removal, cylinder and foot-fault tests that persisted at 1 month, without detectable sensory impairments. In summary, we present an internal capsule stroke model optimized to produce lasting pure-motor deficits in rats that may be suitable to study neurologic recovery and rehabilitation after white-matter injury.

“…Previously, we demonstrated that circumscribed SCI induced the depression of resting-state brain activity in bilateral cortices and striatum, and this observation was compatible with 'functional diaschisis' likely related to the neurological deficits. 18,19 Given that motor recovery was much better in the WSG than in the SSG, it is plausible that the extent of stimulation influenced both the degree and the speed of diaschisis reversal, leading to the difference in motor recovery. The microPET images support this result by showing wider activation of sensorimotor cortex and subcortical structures in the WSG than in the SSG.…”

Section: Discussionmentioning

confidence: 99%

Sensory-parietal cortical stimulation improves motor recovery in severe capsular infarct

Kim

Cho

Ree

et al. 2016

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The prevalence of subcortical white matter strokes in elderly patients is on the rise, but these patients show mixed responses to conventional rehabilitative interventions. To examine whether cortical electrical stimulation can promote motor recovery after white matter stroke, we delivered stimulation to a small or wide region of sensory-parietal cortex for two weeks in a rodent model of circumscribed subcortical capsular infarct. The sham-operated group (SOG) showed persistent and severe motor impairments together with decreased activation in bilateral sensorimotor cortices and striatum. In contrast, sensory-parietal cortex stimulation significantly improved motor recovery: final recovery levels were 72.9% of prelesion levels in the wide stimulation group (WSG) and 37% of prelesion levels in the small stimulation group (SSG). The microPET imaging showed reversal of cortical diaschisis in both groups: in both hemispheres for the WSG, and in the hemisphere ipsilateral to stimulation in the SSG. In addition, we observed activation of the corpus callosum and subcortical corticostriatal structures after stimulation. The results from the c-Fos mapping study were grossly consistent with the microPET imaging. Sensory-parietal cortex stimulation may therefore be a useful strategy for overcoming the limits of rehabilitative training in patients with severe forms of subcortical capsular infarct.