Modulation of interhemispheric inhibition for the treatment of subcortical stroke

描述（由申请人提供）：皮质脊髓束保留皮质损伤是皮质下中风或多发性硬化症的可能结果，可导致严重偏瘫或偏瘫。当损伤完全时，康复预后极差。在这些病例中，受影响半球的皮层重组不太可能导致运动恢复，因为下行皮质纤维已经被破坏。虽然将运动表征转移到非受损半球可能是这类患者运动康复的最可行途径，但这种转移可能会受到受影响侧备用皮层对侧半球皮层持续的半球间抑制（IHI）的限制。在正常状态下，这些连接被认为抑制了同侧半身上每个半球的潜在运动表征。这条研究路线的目标是开发一种基于神经调节的治疗方法来破坏这种抑制作用，导致对侧半球对受影响半身的运动控制的潜在抑制解除，并增强运动恢复。实验将在两个具体目标下进行。我们的方法包括使用胼胝体的慢性电刺激来调节半球间通讯，并在功能上破坏正在进行的IHI。在具体目标1中，目标是确定慢性刺激胼胝体对完全皮质脊髓/内囊损伤的灵长类动物模型运动恢复的影响。在放置胼胝体刺激电极和头侧记录室后，将单侧绘制内囊并通过记录室放置电极消融。损伤的完整性将通过经颅磁刺激产生的运动诱发电位来确认。在三个月的自然恢复后，将进行两个为期三个月的治疗，动物被分配在两个治疗组中接受治疗，在另一个治疗组接受假治疗。运动功能监测将使用改进的布林克曼板作为主要结果测量。在目标2中，我们将确定对胼胝体的慢性刺激是否与对侧运动皮层的运动表征变化有关。我们预计慢性胼胝体刺激将导致对侧半球获得运动表征和对身体受影响侧的控制。从拟议的实验中获得的初步数据将用于随后的临床前应用。

DESCRIPTION (provided by applicant): Cortex-sparing damage to the corticospinal tract, a possible outcome in cases of subcortical stroke or multiple sclerosis, can result in severe hemiparesis or hemiplegia. When the damage is complete, the prognosis for rehabilitation is extremely poor. In these cases, cortical reorganization of the affected hemisphere is unlikely to result in motor recovery given that the descending corticofugal fibers have been destroyed. And while transfer of motor representation to the non-affected hemisphere may be the most viable route to motor rehabilitation for such patients, such a transfer is likely to be limited by the persistence of interhemispheric inhibition (IHI) from the spared cortex of the affected side upon the contralesional hemispheric cortex. In the normal state, these connections are thought to suppress the latent motor representation of each hemisphere over the ipsilateral hemibody. The goal of this line of research is to develop a neuromodulation-based treatment approach to disrupt this suppressive effect, leading to disinhibition of the contralesional hemisphere's latent potential for motor control over the affected hemibody and enhance motor recovery. Experimentation will be carried out in two specific aims. Our approach involves the use of chronic, electrical stimulation of the corpus callosum to modulate interhemispheric communication and functionally disrupt on-going IHI. In specific aim 1, the goal is to determine the effect of chronic stimulation of the corpus callosum on motor recovery in a primate model of complete corticospinal/internal capsule lesion. Following placement of the corpus callosum stimulation electrode and a cephalic recording chamber, the internal capsule will be mapped unilaterally and ablated with electrodes placed through the chamber. The completeness of the lesion will be confirmed using motor evoked potentials derived from transcranial magnetic stimulation. Following three months of natural recovery, two three-month treatment blocks will take place with animals assigned to receive treatment during one of the two blocks and sham treatment in the other block. Motor function will be monitored using the modified Brinkman board as the primary outcome measure. In aim 2, we will determine whether chronic stimulation of the corpus callosum is associated with changes in motor representation of the contralesional motor cortex. We expect that chronic corpus callosum stimulation will lead the contralesional hemisphere to acquire motor representation and control over the affected side of the body. The preliminary data acquired from the proposed experimentation will be used for a subsequent pre-clinical application. PUBLIC HEALTH RELEVANCE: The goal of this study is to determine whether electrical stimulation of certain brain regions can be used to improve recovery in patients with motor deficits following stroke or other types of brain damage. In some cases of subcortical stroke, a type of stroke where the damage occurs deep in the brain, there is limited opportunity for recovery as the fibers that connect the brain to the body have been destroyed. There is evidence that the opposite side of the brain may have a latent ability to assume motor function over the side of the body that is impaired, however this ability is limited by on-going interactions that occur between the two sides of the brain by way of the corpus callosum. To address this, we propose to disrupt this communication between the two sides of the brain by electrically stimulating the corpus callosum in an animal model of stroke. The effect of stimulation on both motor recovery and the motor representation of the side of the body affected by the stroke will be monitored over time. New treatments that can further enhance recovery of function after strokes are necessary and, if proven efficacious, will have a dramatic impact given the combined high incidence and prevalence of neurological deficits and the high economic cost from stroke in the general population.