The human brain is capable of shaping the excitability and interaction in neuronal assemblies as an adaptation to changing external influences. Such plasticity of different cortical regions, e.g. motor networks, represents a fundamental requirement of human brain functions. Plasticity is altered in Parkinsons disease (PD) predominantly because of neurodegeneration of dopaminergic cells. Due to the defined cellular loss and neurotransmitter deficits in PD, this disease can serve as a model disease of how dopamine deficiency, initially predominantly in the basal ganglia and later expanding to other brain regions, produces disease-related changes in cortical motor networks, but also how the motor system adapts to these alterations. Cortical plasticity in PD was first tested by pairing sensory stimulation of the median nerve with transcranial magnetic stimulus (TMS) over the primary motor cortex (M1). Recent innovative paired associative stimulation (PAS) protocols modified this approach in healthy subjects by repeatedly pairing TMS pulses given over M1 with those applied to secondary motor areas to analyze the modifiability of cortico-cortical motor networks. Applying these protocols in PD patients is of special interest due to the fact that previous functional magnetic resonance imaging (fMRI) studies have repeatedly shown altered cortical connectivity patterns in PD. These patterns are characterized by a loss of activity within basal ganglia-fronto-mesial cortical loops and probably compensatory hyperactive basal ganglia-dorsal PM (PMd) connections after a dopaminergic drug withdrawal (OFF state) and normalisation after L-Dopa administration (On state). These findings were corroborated by neurophysiological studies, e.g. TMS studies showing altered PMd-M1 interactions that were reversed by L-dopa administration and repetitive TMS of the PMd. Deep brain stimulation (DBS) of the subthalamic nucleus has become an established treatment option in PD in addition to oral dopaminergic replacement therapy and can complement PAS protocols. Against this background, we now propose to explore alterations in basal ganglia-PMd-M1 plasticity in PD using a novel PAS protocol where STN-DBS is coupled with PMd-M1-TMS applied in DBS stimulated PD patients in the OFF and On state. Demonstrating these cortical-subcortical associative plasticity circuits in PD can help understanding the underlying mechanisms of cortical plasticity, as well as motor network alterations in PD and may deepen our understanding of the therapeutic effects of DBS in these patients. Such information are essential for further developing strategies to foster plasticity functions in these patients and other neurodegenerative disorders.
Background: In patients with Parkinson’s disease the dorsal premotor cortex appears to be abnormally active which also affects connections to the primary motor cortex with a shift towards increased facilitation. Dopaminergic therapy can normalise such pathologically facilitated interaction and strengthen intracortical inhibitory circuits. Deep brain stimulation is an effective treatment option that has shown to increase primary motor cortex inhibition in Parkinson’s disease in various transcranial magnetic stimulation studies. However, the clear mechanism of action of DBS, as well as its influences on premotor-motor interaction is still a matter of debate. Methods: In this project, we investigated eight Parkinson’s disease patients in whom we time-locked single deep brain stimulation pulses of the subthalamic nucleus to MR-neuronavigated transcranial magnetic dual-coil, paired-pulse stimulation of the dorsal premotor area and the primary motor cortex. These experiments were complemented by transcranial magnetic stimulation measurements of the premotor-motor interaction when the deep brain stimulation was switched off and compared to 11 healthy age and sex-matched control subjects. Results: Parkinson’s disease patients showed facilitated premotor-motor interaction with deep brain stimulation being switched off and compared to healthy controls. This increased premotor-motor excitation was reduced when deep brain stimulation was switched on and further resulted in premotor-motor inhibition when subthalamic nucleus stimulation preceded premotor pulses by 25 ms. Conclusions: Dorsal premotor cortex influences on the primary motor cortex are abnormally facilitated in Parkinson’s disease patients. Subthalamic nucleus deep brain stimulation is able to reverse this pathologic premotor excitation at a medium interstimulus interval, which most likely represent an othodromic indirect subthalamicpallidal-thalamic-premotor-motor cortex circuits in our study design. Future plans: The applicant will continue her research work at the University of Lübeck and will further investigate the possibility of inducing primary motor cortex plasticity through paired associative stimulation at the identified ISI of subthalamic nucleus deep brain stimulation and dorsal premotor cortex transcranial magnetic stimulation. Her research scholarship at the University of Toronto helped her to establish a novel neurophysiological paradigm relevant for the understanding of deep brain stimulation in Parkinson's disease, increase her scientific knowledge and proficiency and lay the foundation for receiving additional funding from the University of Lübeck to continue her research work and further explore basal ganglia-premotor-motor cortex connectivity.
|Effective start/end date
|01.01.16 → 31.12.17
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):