bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429377; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Improved alpha-beta power reduction via combined Electrical and Ultrasonic stimulation in a Parkinsonian Cortex-Basal Ganglia-Thalamus Computational Model Thomas Tarnaud, Wout Joseph, Ruben Schoeters, Luc Martens, Emmeric Tanghe Abstract—Objective: To investigate computationally the in- I. INTRODUCTION teraction of combined electrical and ultrasonic modulation of isolated neurons and of the Parkinsonian cortex-basal ganglia- N the last decade, neuromodulation by ultrasound (UN- thalamus loop. Methods: Continuous-wave or pulsed electrical MOD) has become more popular, due to its high spatial res- and ultrasonic neuromodulation is applied to isolated Otsuka I plateau-potential generating subthalamic nucleus (STN) and olution (millimeter resolution in the transversal direction with Pospischil regular, fast and low-threshold spiking cortical cells a single transducer), non-invasiveness, reversibility and safety in a temporally-alternating or simultaneous manner. Similar [1]–[6]. Furthermore, phased-arrays of ultrasound transducers combinations of electrical/ultrasonic waveforms are applied to a have been used for the non-invasive ablation of brain tumours Parkinsonian biophysical cortex-basal ganglia-thalamus neuronal or for subthalamotomy (high intensity focused ultrasound) network. Ultrasound-neuron interaction is modelled respectively for isolated neurons and the neuronal network with the NICE [7]–[10]. Consequently, similar technology could in theory be and SONIC implementations of the bilayer sonophore underlying used with Low Intensity Low Frequency Ultrasound (LILFU) mechanism. Reduction in α−β spectral energy is used as a proxy in order to target deep brain structures non-invasively for to express improvement in Parkinson’s disease by insonication neuromodulation [4], [11]–[13]. and electrostimulation. Results: Simultaneous electro-acoustic stimulation achieves a given level of neuronal activity at lower For the treatment of Parkinson’s disease, the subthalamic intensities compared to the separate stimulation modalities. Con- nucleus (STN) is an important target, also used in conventional versely, temporally alternating stimulation with 50 Hz electrical (electrical) deep brain stimulation (DBS). In electrical DBS, and ultrasound pulses is capable of eliciting 100 Hz STN firing an electrode lead is surgically implanted in the brain and rates. Furthermore, combination of ultrasound with hyperpo- connected with an implanted pulse generator via wires that larizing currents can alter cortical cell relative spiking regimes. In the Parkinsonian neuronal network, high-frequency pulsed run subcutaneously. Electrical pulses will then modulate the separated electrical and ultrasonic deep brain stimulation (DBS) activity of the neuronal tissue surrounding the implanted lead. reduce pathological α − β power by entraining STN-neurons. Conventional DBS has proven effective for the improvement In contrast, continuous-wave ultrasound reduces pathological of Parkinsonian symptoms and motor scores. However, the oscillations by silencing the STN. Compared to the separated surgery carries a risk of complications such as infection or stimulation modalities, temporally simultaneous or alternating electro-acoustic stimulation can achieve higher reductions in haemmorhage [14]–[17]. Here, the potential application of α − β power for the same contraints on electrical/ultrasonic transcranial LILFU for non-invasive deep brain stimulation intensity. Conclusion: Continuous-wave and pulsed ultrasound has been considered before [4], [11]–[13], [18]. Furthermore, reduce pathological oscillations by different mechanisms. Electro- recent in vivo studies in MPTP (1-methyl-4-fenyl-1,2,3,6- acoustic stimulation further improves α−β power for given safety tetrahydropyridine) lesioned Parkinsonian mice have demon- limits and is capable of altering cortical relative spiking regimes. Significance: focused ultrasound has the potential of becoming a strated ultrasound-induced striatal dopamine normalization non-invasive alternative of conventional DBS for the treatment [19], [20], restored locomotion activity (open field test, pole of Parkinson’s disease. Here, we elaborate on proposed benefits test) [19]–[22], and an increase in striatal total superoxide dis- of combined electro-acoustic stimulation in terms of improved mutase (T-SOD) and glutathione peroxidase (GSH-PX) (neu- dynamic range, efficiency, resolution, and neuronal selectivity. roprotective antioxidant enzymes) [21]. Moreover, ultrasound Index Terms—Ultrasonic neuromodulation, deep brain stimu- focused at the STN or globus pallidus (GP) downregulates lation, basal ganglia, intramembrane cavitation, computational the Bax to Bcl-2 ratio (Bax and Bcl-2 are proapoptotic modeling and antiapoptotic, respectively), resulting in a reduction of cleaved-caspase 3 activity in the substantia nigra [22]. Also, in vitro, an increased dopamine release in PC12 cells upon low- intensity continuous insonication is observed in [19]. These first studies on ultrasonic neuromodulation for Parkinson’s disease, indicate that transcranial LILFU could be a promising T. Tarnaud, W. Joseph, R. Schoeters, L. Martens, and E. Tanghe are with alternative to conventional electrical DBS or L-DOPA (L-3,4- the Department of Information Technology (INTEC-WAVES/IMEC), Ghent University/IMEC, Technologypark 126, 9052 Zwijnaarde, Belgium. E-mail: di-hydroxy-phenylalanine) therapy. Here, UNMOD could be [email protected] applied for patient selection or to optimize the choice of the bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429377; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 2 deep brain target for conventional DBS. nially, resulting in maximal modulation depth by temporal However, the underlying mechanism of ultrasonic neuro- interference at the targeted deep brain region, allowing non- modulation is not well understood. Several tentative mecha- invasive deep stimulation in mice. However, computational nisms have been proposed, e.g., bilayer sonophores [23]–[25], studies have predicted that results of TI-DBS in humans acoustic-radiation pressure [26]–[28], mechanosensitivity of might be less favourable [50], [51]. Besides improving the protein channels [29], [30], flexoelectricity [31], extracellular placement, waveforms, and number of the TI-DBS anode- cavitation [32], and thermodynamically-based models [33]. cathode pairs, another option could be to combine the benefits Here, computational models will help in order to compare of TI-DBS and UNMOD by application in tandem. Here, to the predictions of a proposed mechanism with experimen- our best knowledge for the first time, we study the response to tal observations. Similarly, computational models have been combined ultrasonic and electrical neuromodulation in isolated used to improve understanding of deep brain stimulation neuron models. Then, we investigate the benefits of their and Parkinson’s disease, i.a., DBS-induced normalization of combined application in the neuronal CTX-BG-TH network. thalamic relay [34], [35], beta-oscillatory power [36], [37] and GPi-bursting [38], importance of antidromic activation of the hyperdirect pathway [39], [40], short-term synaptic depression II. METHODS and axonal failure [41], mechanisms of the generation and interaction of Parkinsonian beta-oscillations [37], [42], and A. Cortex-Basal Ganglia-Thalamus Neuronal Network effects on learning and impulsivity [43], [44]. Consequently, in this study, our goal is to achieve the A computational neuronal network model of the cortex- following two novelties. First, to investigate the capability basal ganglia-thalamus loop was realised in the DynaSim ® and efficiency of ultrasonic neuromodulation to reduce beta- MATLAB -toolbox for neural modeling and simulation [52] oscillatory power, as a proxy for Parkinsonian bradykine- (Euler discretisation, time step ∆t = 10 µs for the Parkinso- sia, in a computational model of the cortex-basal ganglia- nian network, electrical DBS and continuous-wave ultrasound, thalamus neuronal (CTX-BG-TH) network. Here, we imple- ∆t = 5 µs for ultrasonic DBS, and ∆t = 2:5 µs for mented a fully biophysical Hodgkin-Huxley based network of combined ultrasound and electrostimulation: a lower temporal the cortex-basal ganglia-thalamus, based on earlier models of discretization step is used for ultrasonic or combined electroa- the basal ganglia [34]–[36] and of the cortex [25], [45]–[47]. In coustic stimulation, due to higher computational stiffness). All particular, a computational spiking-neuron model (as opposed simulations are run for 11 s, where initialisation-dependent to firing rate based models) of the CTX-BG-TH has been network transient effects during the first second are removed. proposed in [36], with integrate-and-fire representations for A schematic overview of the network topology is given in the cortical cells. We included biophysical cortical Pospischil- Fig. 1(a). The cortical network (CTX) is