Characterization of cortico-subthalamic networks during deep brain stimulation surgery in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established symptomatic treatment for Parkinson’s diseases (PD). However, knowledge on local electrophysiological biomarkers within the STN and their cortical connectivity profile is still scarce. Such information would be necessary for optimal positioning of the DBS leads based on PD network pathophysiology. This thesis describes the introduction and exploration of a novel technique for electrophysiological measurements during DBS surgery. Combined electroencephalography (EEG) with stepwise local field potentials recordings during insertion of the DBS lead was performed intraoperatively, thereby, allowing to capture local STN and cortico-subthalamic physiology with high speactral and spatial specificity. Our results revealed that strong beta oscillatory activity in the STN was located more dorsally than the STN-ipsilateral motor network phase coupling; the respective frequency bands were in the low and high beta-band, respectively. Moreover, the spot within the STN, where this STN-cortical phase coupling occurred, correlated highly with the STN spot where the phase of beta oscillations modulated the amplitude of high-frequency oscillations. This STN location was furthermore, characterized by information flowed from the ipsilateral motor cortex to the STN in the high beta-band suggesting a pathologically synchronized network with a direct STN-motor cortex connection via the hyperdirect pathway. Interestingly, the very same STN spot showed a resonance like responses to electrical stimulation suggesting a decoupling of pathologically synchronized STN-motor cortex connectivity during therapeutic DBS. In conclusion, this PhD thesis provides first evidence that macroelectrode recordings with the chronic electrode concurrent with EEG recordings are a reliable method for STN localization during DBS surgery. Additionally, combining LFP and EEG recordings during mapping of STN offered a new way of DBS targeting on the basis of pathological local biomarkers and network activity

Phase-dependent modulation as a novel approach for therapeutic brain stimulation

Closed-loop paradigms provide us with the opportunity to optimize stimulation protocols for perturbation of pathological oscillatory activity in brain-related disorders. In this vein, spiking activity of motor cortex neurons and beta activity of local field potentials in the subthalamic nucleus have both been used independently of each other as neuronal signals to trigger deep brain stimulation for alleviating Parkinsonism. These approaches were superior to the standard continuous high-frequency stimulation protocols used in daily practice. However, they achieved their effects by bursts of stimulation that were applied at high-frequency as well, i.e. independent of the phase information in the stimulated region. In this context, we propose that, by timing stimulation pulses relative to the ongoing oscillation, an alternative approach, namely the targeted perturbation of pathological rhythms, could be obtained.In this modeling study, we first captured the underlying dynamics of neuronal oscillations in the human subthalamic nucleus by phased coupled neuronal oscillators. We then quantified the nature of the interaction between these coupled oscillators by obtaining a physiologically informed phase response curve from local field potentials. Reconstruction of the phase response curve predicted the sensitivity of the phase oscillator to external stimuli, revealing phase intervals that optimally maximized the degree of perturbation. We conclude that our specifically timed intervention based on the coupled oscillator concept will enable us to identify personalized ways of delivering stimulation pulses in closed-loop paradigms triggered by the phase of pathological oscillations. This will pave the way for novel physiological insights and substantial clinical benefits. In addition, this precisely phased modulation may be capable of modifying the effective interactions between oscillators in an entirely new manner