Melissa Trotman-Lucas, PhD

Wen TC, Sindhurakar A, Contreras Ramirez V, Park H, Gupta D, Carmel JB. Targeted Infarction of the Internal Capsule in the Rat Using Microstimulation Guidance. Stroke. 2019;50:2531-2538.

Lacunar stroke occurs when a penetrating arteriole becomes blocked, leading to ischemic damage to deep brain structures such as subcortical white matter or deep grey matter. Lacunes are small areas of cell damage that can cause significant disability to the sufferer. This type of cerebral ischemic occurrence accounts for a fifth of all strokes, resulting in varied clinical presentations. Lacunar stroke of the internal capsule, or IC, is associated with lasting motor deficits and poor recovery. It is critical to develop a reliable preclinical model, focusing on corticospinal tract (CST) damage located within the IC, as this damage is a reliable predictor of stroke severity and clinical outcome.

In this article commentary, the recent publication by Tong-Chun Wen and colleagues reporting lacunar infarction induction using microstimulation guidance is discussed. Microstimulation was used by the group as a guide as the IC is a small subcortical structure, within already limited rat white matter, with an elongated irregular shape that can vary with age, sex and strain. Wen et al. set out to develop a reliable preclinical IC stroke model that could produce tightly focused lesions to improve upon the various preclinical methods currently used, including chemical, physical and photo induced models. Chemical induction can result in off target injuries due to unpredictable diffusion of the inducting solution and physical induction, although closely imitating the mechanism of human lacunar stroke induction, requires significant surgical expertise. The group utilized photothrombolysis, where a photosensitive dye is first injected into the blood stream and then target vessels are illuminated by a laser light source inducing thrombus formation. The group enhanced this method with the addition of micro-electrical stimulation to guide placement of the illuminating optical fibre. This was achieved through the use of an optrode, a combined electrode and optical-fibre probe.

Wen et al. aimed to test whether microstimulation guidance could elicit accurate and reproducible fore limb axon lesions in the rat IC, and to further establish if this would infer lasting deficits on fore limb function. Initially, the researchers used microstimulation mapping and tracing to determine the fore and hind limb portions of the CST within the IC, the combined location of the limb tracts causing selective lesioning to be a significant challenge within the field. The obtained data was used to create motor maps allowing the group to determine that most hind limb responses were evoked from dorsolateral regions of the IC with fore limb responses largely evoked from medioventral regions of the IC. This topography was confirmed using adeno-associated viral tracers at the fore and hind limb sections of the motor cortex, allowing centroid coordinates for these tracts to be determined within the IC. Following the establishment of topography, the group used microstimulation guided photothrombolysis to lesion the IC. The use of stimulation guided photothrombolysis resulted in well-defined, on target, tissue injury that was consistent between rats. The lesions were not only consistent, they also produced a persistent and substantial reduction in manipulation ability of the affected forepaw. Furthermore, lesions were ~66% smaller than previously published reports of photothrombotic IC lesions undertaken without microstimulation guidance.

The reported model is relevant for the investigation of injury and white matter adaptation following damage and would also have use in preclinical therapy development. Reorganization of the CST and sensorimotor network occur following internal capsule stroke; this model may be useful to help better understand the processes involved in this reorganization. Additionally, the limited nature of white matter in the rat makes the study of white matter injury technically difficult; this model may allow accurate investigation of white matter damage without the involvement of grey matter damage as seen with less specific preclinical infarction models. However, there are limitations to this model, as with other photothrombotic models, in that the model does not mimic the exact pathology of lacunar stroke, which in the clinic is likely to be the result of a blockage to a penetrating arteriole. Furthermore, the IC contains both sensory and motor neuron tracts, the post-lesion outcomes could be further assessed for both sensory and motor effects utilizing a wider panel of sensorimotor tasks. The accuracy and replicability of the lacunar infarcts derived by this technique may prove useful in knockout strains to better understand cellular and signaling dysfunction resulting from lacunar infarctions. Furthermore, long-term cognitive decline is a significant outcome in clinical lacunar stroke; therefore, undertaking longer-term studies to assess the effects of potential therapies is essential and could easily be achieved with this model. With the high prevalence of lacunar infarcts, it is key to continue research to enable the field to move towards improvements in post stroke outcome and establish effective and viable treatments.