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1. Control of coupled neural oscillations using near-periodic inputs

   https://doi.org/10.1063/5.0076508  

   Toth, Kaitlyn ; Wilson, Dan ( March 2022 , Chaos: An Interdisciplinary Journal of Nonlinear Science)

   Deep brain stimulation (DBS) is a commonly used treatment for medication resistant Parkinson’s disease and is an emerging treatment for other neurological disorders. More recently, phase-specific adaptive DBS (aDBS), whereby the application of stimulation is locked to a particular phase of tremor, has been proposed as a strategy to improve therapeutic efficacy and decrease side effects. In this work, in the context of these phase-specific aDBS strategies, we investigate the dynamical behavior of large populations of coupled neurons in response to near-periodic stimulation, namely, stimulation that is periodic except for a slowly changing amplitude and phase offset that can be used to coordinate the timing of applied input with a specified phase of model oscillations. Using an adaptive phase-amplitude reduction strategy, we illustrate that for a large population of oscillatory neurons, the temporal evolution of the associated phase distribution in response to near-periodic forcing can be captured using a reduced order model with four state variables. Subsequently, we devise and validate a closed-loop control strategy to disrupt synchronization caused by coupling. Additionally, we identify strategies for implementing the proposed control strategy in situations where underlying model equations are unavailable by estimating the necessary terms of the reduced order equations in real-time from observables.

    

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2. Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses

   https://doi.org/10.1371/journal.pcbi.1009609  

   Zhang, Xu ; Hancock, Roeland ; Santaniello, Sabato ( December 2021 , PLOS Computational Biology)

   Blackwell, Kim T. (Ed.)

   Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia. 

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3. Development and Optimization of a Novel Centrifugal Bioreactor with a Real-Time Monitoring Sensor for T Cell Exhaustion with Applications in Cancer Immunotherapy

   Brenden Fraser-Hevlin, Kitana M. ( November 2021 , Annual meeting American Institute of Chemical Engineers)

   Cancer has been one of the most significant and critical challenges in the field of medicine. It is a leading cause of death both in the United States and worldwide. Common cancer treatments such as radiation and chemotherapy can be effective in destroying cancerous tissue but cause many detrimental side effects. Thus, recent years have seen new treatment methods that do not harm healthy tissue, including immunotherapy. Adoptive cell therapy (ACT) is one form of immunotherapy in which patients’ immune cells are modified to target cancer cells and then reintroduced into the body. ACT is promising, but most current treatments are inefficient and costly. Widespread implementation of ACT has been a difficult task due to the high treatment cost and inefficient methods currently used to expand the cells. Additionally, if the manufacturing process is not carefully controlled, it can result in the cells losing their cancer-killing ability after expansion. To address the need for an economically feasible culture process to expand immune cells for immunotherapy, our laboratory has designed a centrifugal bioreactor (CBR) expansion system. The CBR uses a balance of centrifugal forces and fluid forces, as shown in Figure 1, to quickly expand infected CD8+ T-cells from a bovine model up to high population densities. With other applications, the CBR has achieved cell densities as high as 1.8 x 108 cells/mL over 7 days in an 11.4-mL chamber. For this study, our goal is to begin validating the CBR by optimizing the growth of CEM (human lymphoblastic leukemia) cells, which are similar cell to cytotoxic T lymphocytes (CTLs). This can be accomplished by measuring kinetic growth parameters based on the concentrations of glucose and inhibitory metabolites in the culture. We hypothesize that by designing a kinetic model from static culture experiments, we can predict the parameters necessary to achieve peak CEM and eventually CTL growth in the CBR. We will report on kinetic growth studies in which different glucose concentrations are tested, and a maximum specific growth rate and Monod constant determined, as well as studies where varying levels of the inhibitory growth byproducts, lactate and ammonium, are added to the culture and critical inhibitor concentrations are determined. Another recent conceptual development for the design of the CBR is a real-time monitoring and feedback control system to regulate the cellular environment, based on levels of surface co-receptors and mRNA signaling within the culture. Prior studies have pinpointed T cell exhaustion as a significant issue in achieving successful immunotherapy, particularly in treatments for solid tumors; T cell exhaustion occurs during a period of chronic antigen stimulation when the cells lose their ability to target and kill cancer cells, currently theorized to be associated with particular inhibitory receptors and cytokines in the immune system. Designing a system with a fiber optic sensor that can monitor the cell state and use feedback control to regulate the pathways involved in producing these receptors will ensure the cells maintain cytotoxic properties during the expansion process within a Centrifugal Fluidized Expansion we call the CentriFLEX. In this presentation, we will also report on early results from development of this exhaustion monitoring system. In brief, achieving optimal kinetic models for the CBR system and methods to prevent T cell exhaustion has the potential to significantly enhance culture efficiency and availability of immunotherapy treatments. 

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4. Defining information-based functional objectives for neurostimulation and control

   https://doi.org/10.23919/ACC.2019.8814601  

   Ghazizadeh, Elham ; Yi, Peng ; Ching, Shinung ( July 2019 , 2019 American Control Conference (ACC))

   Neurostimulation - the practice of applying exogenous excitation, e.g., via electrical current, to the brain - has been used for decades in clinical applications such as the treatment of motor disorders and neuropsychiatric illnesses. Over the past several years, more emphasis has been placed on understanding and designing neurostimulation from a systems-theoretic perspective, so as to better optimize its use. Particular questions of interest have included designing stimulation waveforms that best induce certain patterns of brain activity while minimizing expenditure of stimulus power. The pursuit of these designs faces a fundamental conundrum, insofar as they presume that the desired pattern (e.g., desyn-chronization of a neural population) is known a priori. In this paper, we present an alternative paradigm wherein the goal of the stimulation is not to induce a prescribed pattern, but rather to simply improve the functionality of the stimulated circuit/system. Here, the notion of functionality is defined in terms of an information-theoretic objective. Specifically, we seek closed loop control designs that maximize the ability of a controlled circuit to encode an afferent `hidden input,' without prescription of dynamics or output. In this way, the control attempts only to make the system `effective' without knowing beforehand the dynamics that are needed to be induced. We devote most of our effort to defining this framework mathematically, providing algorithmic procedures that demonstrate its solution and interpreting the results of this procedure for simple, prototypical dynamical systems. Simulation results are provided for more complex models, including an example involving control of a canonical neural mass model. 

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5. Asymmetric charge balanced waveforms direct retinal ganglion cell axon growth

   https://doi.org/10.1038/s41598-023-40097-6  

   Peng, M. G. ; Iseri, E. ; Simonyan, A. ; Lam, P. ; Kim, T. ; Medvidovic, S. ; Paknahad, J. ; Machnoor, M. ; Lazzi, G. ; Gokoffski, K. K. ( December 2023 , Scientific Reports)

   Abstract Failure to direct axon regeneration to appropriate targets is a major barrier to restoring function after nerve injury. Development of strategies that can direct targeted regeneration of neurons such as retinal ganglion cells (RGCs) are needed to delay or reverse blindness in diseases like glaucoma. Here, we demonstrate that a new class of asymmetric, charge balanced (ACB) waveforms are effective at directing RGC axon growth, in vitro, without compromising cell viability. Unlike previously proposed direct current (DC) stimulation approaches, charge neutrality of ACB waveforms ensures the safety of stimulation while asymmetry ensures its efficacy. Furthermore, we demonstrate the relative influence of pulse amplitude and pulse width on the overall effectiveness of stimulation. This work can serve as a practical guideline for the potential deployment of electrical stimulation as a treatment strategy for nerve injury. 

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