Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, 6500 HB Nijmegen, The Netherlands.
Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Centre of Expertise for Parkinson and Movement Disorders, 6500 HB Nijmegen, The Netherlands.
Brain. 2020 May 1;143(5):1498-1511. doi: 10.1093/brain/awaa083.
Parkinson's tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson's disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson's patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson's tremor.
帕金森震颤与基底神经节和小脑-丘脑-皮质回路中的大脑活动有关。一个常见的临床观察是，震颤在认知负荷（如心算）期间明显增加，导致严重残疾。先前的研究表明，这种震颤放大与多巴胺能治疗效果降低有关。了解震颤放大的机制及其与儿茶酚胺的关系可能有助于通过靶向治疗更好地控制这种症状。我们推断，在认知负荷期间，震颤放大可能是由于对控制震颤幅度的小脑-丘脑-皮质回路的调制影响（自上而下）、觉醒系统（自下而上）、认知控制网络（自上而下）或它们的组合。我们通过测量 33 名震颤性帕金森病患者在停用药物期间交替休息和认知负荷（心算）期间的同时肌电图和功能磁共振成像来测试这些假设。同时记录心率和瞳孔直径以标记觉醒系统的活动（包括去甲肾上腺素传入）。正如预期的那样，震颤幅度与小脑-丘脑-皮质回路的活动相关；认知负荷增加了震颤幅度、瞳孔直径、心率和分布于额顶叶皮层、脑岛、丘脑和前扣带皮层的认知控制网络的大脑活动。通过网络分析获得的新发现表明，认知负荷通过两种不同的方式增加小脑-丘脑-皮质回路的活动来影响震颤：通过刺激丘脑活动，可能通过觉醒系统（因为这种调制与瞳孔直径的变化相关），并通过增强认知控制网络与小脑-丘脑-皮质回路之间的连接。我们得出结论，当帕金森病患者经历认知负荷时，自上而下的觉醒系统和自上而下的认知控制网络都会放大震颤。旨在减弱去甲肾上腺素能活动或认知需求的干预措施可能有助于减少帕金森震颤。
