McPherson Jacob G, Ellis Michael D, Harden R Norman, Carmona Carolina, Drogos Justin M, Heckman Charles J, Dewald Julius P A
Department of Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Department of Biomedical Engineering, Florida International University, Miami, FL, United States.
Front Neurol. 2018 Jun 21;9:470. doi: 10.3389/fneur.2018.00470. eCollection 2018.
In chronic hemiparetic stroke, increased shoulder abductor activity causes involuntary increases in elbow, wrist, and finger flexor activation, an abnormal muscle coactivation pattern known as the flexion synergy. Recent evidence suggests that flexion synergy expression may reflect recruitment of contralesional cortico-reticulospinal motor pathways following damage to the ipsilesional corticospinal tract. However, because reticulospinal motor pathways produce relatively weak post-synaptic potentials in motoneurons, it is unknown how preferential use of these pathways could lead to robust muscle activation. Here, we hypothesize that the descending neuromodulatory component of the ponto-medullary reticular formation, which uses the monoaminergic neurotransmitters norepinephrine and serotonin, serves as a gain control mechanism to facilitate motoneuron responses to reticulospinal motor commands. Thus, inhibition of the neuromodulatory component would reduce flexion synergy expression by disfacilitating spinal motoneurons. To test this hypothesis, we conducted a pre-clinical study utilizing two targeted neuropharmacological probes and inert placebo in a cohort of 16 individuals with chronic hemiparetic stroke. Test compounds included Tizanidine (TIZ), a noradrenergic α agonist and imidazoline ligand selected for its ability to reduce descending noradrenergic drive, and Isradipine, a dihyropyridine calcium-channel antagonist selected for its ability to post-synaptically mitigate a portion of the excitatory effects of monoamines on motoneurons. We used a previously validated robotic measure to quantify flexion synergy expression. We found that Tizanidine significantly reduced expression of the flexion synergy. A predominantly spinal action for this effect is unlikely because Tizanidine is an agonist acting on a baseline of spinal noradrenergic drive that is likely to be pathologically enhanced post-stroke due to increased reliance on cortico-reticulospinal motor pathways. Although spinal actions of TIZ cannot be excluded, particularly from Group II pathways, our finding is consistent with a supraspinal action of Tizanidine to reduce descending noradrenergic drive and disfacilitate motoneurons. The effects of Isradipine were not different from placebo, likely related to poor central bioavailability. These results support the hypothesis that the descending monoaminergic component of the ponto-medullary reticular formation plays a key role in flexion synergy expression in chronic hemiparetic stroke. These results may provide the basis for new therapeutic strategies to complement physical rehabilitation.
在慢性偏瘫性卒中中，肩部外展肌活动增加会导致肘部、腕部和手指屈肌的非自主激活增加，这是一种异常的肌肉共同激活模式，称为屈曲协同运动。最近的证据表明，屈曲协同运动的表现可能反映了在患侧皮质脊髓束受损后对侧皮质-网状脊髓运动通路的募集。然而，由于网状脊髓运动通路在运动神经元中产生相对较弱的突触后电位，尚不清楚优先使用这些通路如何导致强大的肌肉激活。在此，我们假设脑桥-延髓网状结构的下行神经调节成分，其使用单胺能神经递质去甲肾上腺素和5-羟色胺，作为一种增益控制机制来促进运动神经元对网状脊髓运动指令的反应。因此，抑制神经调节成分将通过减弱脊髓运动神经元的活动来减少屈曲协同运动的表现。为了验证这一假设，我们进行了一项临床前研究，在16名慢性偏瘫性卒中患者队列中使用两种靶向神经药理学探针和惰性安慰剂。测试化合物包括替扎尼定（TIZ），一种去甲肾上腺素能α激动剂和咪唑啉配体，因其能够减少下行去甲肾上腺素能驱动而被选用，以及伊拉地平，一种二氢吡啶钙通道拮抗剂，因其能够在突触后减轻单胺对运动神经元的部分兴奋作用而被选用。我们使用先前验证的机器人测量方法来量化屈曲协同运动的表现。我们发现替扎尼定显著降低了屈曲协同运动的表现。这种作用主要通过脊髓起作用的可能性不大，因为替扎尼定是一种作用于脊髓去甲肾上腺素能驱动基线的激动剂，由于对皮质-网状脊髓运动通路的依赖增加，中风后这种驱动可能在病理上增强。虽然不能排除替扎尼定的脊髓作用，特别是来自II类通路的作用，但我们的发现与替扎尼定通过减少下行去甲肾上腺素能驱动和减弱运动神经元活动的脊髓上作用是一致的。伊拉地平的作用与安慰剂无差异，可能与较差的中枢生物利用度有关。这些结果支持了这样的假设，即脑桥-延髓网状结构的下行单胺能成分在慢性偏瘫性卒中的屈曲协同运动表现中起关键作用。这些结果可能为补充物理康复的新治疗策略提供基础。
