targeting-neuronal-fiber-tracts-for-deep-brain-stimulation-therapy

Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for ...

University of Utah

In a companion paper we showed that random channel and synaptic noise improve the ability of a biologically realistic, GENESIS-based computational model of the Hermissenda eye to encode light intensity. In this paper we explore mechanisms for noise-induced improvement by examining contextual spike-timing relationships among neurons in the photoreceptor network. In other systems, synaptically connected pairs of spiking cells can develop phase-locked spike-timing relationships at particular, well-defined frequencies. Consequently, domains of stability (DOS) emerge in which an increase in the frequency of inhibitory postsynaptic potentials can paradoxically increase, rather than decrease, the firing rate of the postsynaptic cell. We have extended this analysis to examine DOS as a function of noise amplitude in the exclusively inhibitory Hermissenda photoreceptor network. In noise-free simulations, DOS emerge at particular firing frequencies of type B and type A photoreceptors, thus producing a nonmonotonic relationship between their firing rates and light intensity. By contrast, in the noise-added conditions, an increase in noise amplitude leads to an increase in the variance of the interspike interval distribution for a given cell; in turn, this blocks the emergence of phase locking and DOS. These noise-induced changes enable the eye to better perform one of its basic tasks: encoding light intensity. This effect is independent of stochastic resonance, which is often used to describe perithreshold stimuli. The constructive role of noise in biological signal processing has implications both for understanding the dynamics of the nervous system and for the design of neural interface devices.

Mechanisms of noise-induced improvement in light-intensity encoding in Hermissenda photoreceptor network.

Neurons are notoriously noisy devices. Although the traditional view posits that noise degrades system performance, recent evidence suggests that noise may instead enhance neural information processing under certain conditions. Here we report that random channel and synaptic noise improve the ability of a biologically realistic computational model of the Hermissenda eye to encode light intensity. The model was created in GENESIS and is based on a previous model used to examine effects of changes in type B photoreceptor excitability, synaptic strength, and network architecture. The network consists of two type A and three type B multicompartmental photoreceptors. Each compartment contains a population of Hodgkin-Huxley-type ion channels and each cell is stimulated via artificial light currents. We found that the addition of random channel and synaptic noise yielded a significant improvement in the accuracy of the network's encoding of light intensity across eight light levels spanning 3.5 log units (P<0.001, modified Levene test). The benefits of noise remained after controlling for several consequences of randomness in the model. Additionally, improvements were not confined to perithreshold stimulus intensities. Finally, the effects of noise are not present in individual neurons, but rather are an emergent property of the synaptically connected network that is independent of stochastic resonance. These results suggest that noise plays a constructive role in neural information processing, a concept that could have important implications for understanding neural information processing or designing neural interface devices.

Random noise paradoxically improves light-intensity encoding in Hermissenda photoreceptor network.

Many centers are now using high-density microelectrodes during traditional intracranial electroencephalography (iEEG) both for research and clinical purposes. These microelectrodes are FDA-approved and integrate into clinical EEG acquisition systems. However, the electrical characteristics of these electrodes are poorly described and clinical systems were not designed to use them; thus, it is possible that this shift into clinical practice could have unintended consequences. In this study, we characterized the impedance of over 100 commercial macro- and microelectrodes using electrochemical impedance spectroscopy (EIS) to determine how electrode properties could affect signal acquisition and interpretation. The EIS data were combined with the published specifications of several commercial EEG systems to design digital filters that mimic the behavior of the electrodes and amplifiers. These filters were used to analyze simulated brain signals that contain a mixture of characteristic features commonly observed in iEEG. Each output was then processed with several common quantitative EEG measurements. Our results show that traditional macroelectrodes had low impedances and produced negligible distortion of the original signal. Brain tissue and electrical wiring also had negligible filtering effects. However, microelectrode impedances were much higher and more variable than the macroelectrodes. When connected to clinical amplifiers, higher impedance electrodes produced considerable distortion of the signal at low frequencies (<60 Hz), which caused significant changes in amplitude, phase, variance and spectral band power. In contrast, there were only minimal changes to the signal content for frequencies above 100 Hz. In order to minimize distortion with microelectrodes, we determined that an acquisition system should have an input impedance of at least 1 GΩ, which is much higher than most clinical systems. These results show that it is critical to account for variations in impedance when analyzing EEG from different-sized electrodes. Data from microelectrodes may yield misleading results unless recorded with high-impedance amplifiers.

Signal distortion from microelectrodes in clinical EEG acquisition systems.

Recent studies in epilepsy, cognition, and brain machine interfaces have shown the utility of recording intracranial electroencephalography (iEEG) with greater spatial resolution. Many of these studies utilize microelectrodes connected to specialized amplifiers that are optimized for such recordings. We recently measured the impedances of several commercial microelectrodes and demonstrated that they will distort iEEG signals if connected to clinical EEG amplifiers commonly used in most centers. In this study we demonstrate the clinical implications of this effect and identify some of the potential difficulties in using microelectrodes.

Potential for unreliable interpretation of EEG recorded with microelectrodes.

Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response.

Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release.

The Use of Stimulation Field Models for Deep Brain Stimulation Programming.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.

Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies.

Deep brain stimulation (DBS) is a growing treatment option for movement and psychiatric disorders. As DBS technology moves toward directional leads with increased numbers of smaller electrode contacts, trial-and-error methods of manual DBS programming are becoming too time-consuming for clinical feasibility. We propose an algorithm to automate DBS programming in near real-time for a wide range of DBS lead designs.

Optimized programming algorithm for cylindrical and directional deep brain stimulation electrodes.

Traumatic brain injury (TBI) is a looming epidemic, growing most rapidly in the elderly population. Some of the most devastating sequelae of TBI are related to depressed levels of consciousness (e.g., coma, minimally conscious state) or deficits in executive function. To date, pharmacological and rehabilitative therapies to treat these sequelae are limited. Deep brain stimulation (DBS) has been used to treat a number of pathologies, including Parkinson disease, essential tremor, and epilepsy. Animal and clinical research shows that targets addressing depressed levels of consciousness include components of the ascending reticular activating system and areas of the thalamus. Targets for improving executive function are more varied and include areas that modulate attention and memory, such as the frontal and prefrontal cortex, fornix, nucleus accumbens, internal capsule, thalamus, and some brainstem nuclei. The authors review the literature addressing the use of DBS to treat higher-order cognitive dysfunction and disorders of consciousness in TBI patients, while also offering suggestions on directions for future research.

Article	Year
Mechanisms of noise-induced improvement in light-intensity encoding in Hermissenda photoreceptor network. Journal of neurophysiology\| PubMed ID: 18003872	2008
Random noise paradoxically improves light-intensity encoding in Hermissenda photoreceptor network. Journal of neurophysiology\| PubMed ID: 18003873	2008
Signal distortion from microelectrodes in clinical EEG acquisition systems. Journal of neural engineering\| PubMed ID: 22878608	2012
Potential for unreliable interpretation of EEG recorded with microelectrodes. Epilepsia\| PubMed ID: 23647099	2013
Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release. Brain stimulation\| PubMed ID: 25835354	2015
The Use of Stimulation Field Models for Deep Brain Stimulation Programming. Brain stimulation\| PubMed ID: 26358487	2015
Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates. Journal of neurophysiology\| PubMed ID: 27582298	2016
Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies. Frontiers in integrative neuroscience\| PubMed ID: 27920671	2016
Optimized programming algorithm for cylindrical and directional deep brain stimulation electrodes. Journal of neural engineering\| PubMed ID: 29235446	2018
Deep brain stimulation for the treatment of disorders of consciousness and cognition in traumatic brain injury patients: a review. Neurosurgical focus\| PubMed ID: 30064315	2018

Christopher R. Butson

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