Modulation of interhemispheric inhibition for the treatment of subcortical stroke

描述(申请人提供)：保留皮质的皮质脊髓束损伤，这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，康复的预后非常差。在这些情况下，鉴于下行的皮质分离纤维已经被破坏，受影响大脑半球的皮质重组不太可能导致运动恢复。虽然将运动表征转移到非患侧大脑半球可能是此类患者最可行的运动康复途径，但这种转移可能会受到患侧备用皮质对对侧大脑半球皮质持续存在的半球间抑制(IHI)的限制。在正常状态下，这些连接被认为抑制了同侧半身体上每个半球的潜在运动表征。这一系列研究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效应，导致对侧大脑半球对患侧身体进行运动控制的潜在潜力解除抑制，并促进运动恢复。实验将在两个具体目标下进行。我们的方法包括使用慢性的、电刺激的穹隆体来调节大脑半球之间的交流，并从功能上扰乱正在进行的IHI。在特定的目标1中，目标是确定在灵长类动物完全性皮质脊髓/内囊损伤模型中，慢性刺激穹隆体对运动恢复的影响。在放置了胼胝体刺激电极和头部记录室后，将单侧标测内囊并用穿过该记录室的电极消融。损伤的完整性将通过使用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之后，将进行两个为期三个月的治疗区块，其中一个区块的动物被分配接受治疗，另一个区块的动物接受假治疗。运动功能监测将使用改良的Brinkman板作为主要结果衡量标准。在目标2中，我们将确定慢性刺激的胼胝体是否与对侧运动皮质的运动表征的变化有关。我们预计，慢性的胼胝体刺激将导致对侧大脑半球获得运动表征和对患侧身体的控制。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。 公共卫生相关性：这项研究的目标是确定某些大脑区域的电刺激是否可以用来促进中风或其他类型脑损伤后运动障碍患者的康复。皮质下中风是一种发生在大脑深处的中风，在某些情况下，由于连接大脑和身体的纤维被破坏，恢复的机会有限。有证据表明，大脑的另一侧可能具有潜在的能力，在身体受损的一侧承担运动功能，但这种能力受到大脑两侧通过胼胝体发生的持续相互作用的限制。为了解决这一问题，我们建议通过电刺激中风动物模型的胼胝体来干扰大脑两侧之间的这种交流。随着时间的推移，将监测刺激对受中风影响的一侧身体运动恢复和运动表现的影响。新的治疗方法可以进一步促进中风后功能的恢复是必要的，如果被证明有效，将产生巨大的影响，因为在普通人群中，神经缺陷的发病率和流行率很高，而且中风的经济成本很高。

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.