Computational aspects of parvalbumin-positive interneuron function

The activity of neurons is dependent on the manner in which they process synaptic inputs from other cells. In the event of clustered synaptic input, neurons can respond in a nonlinear manner through synaptic and dendritic mechanisms. Such mechanisms are well established in principal excitatory neurons throughout the brain, where they increase neuronal computational ability and information storage capacity. In contrast for parvalbumin-positive (PV+) interneurons, the most common cortical class of in- hibitory interneuron, synaptic integration is thought to be either linear or sub-linear in nature, facilitating their role as mediators of precise and fast inhibition. This thesis addresses situations in which PV+ interneurons integrate synaptic inputs in a nonlinear manner, and explores the functions of this synaptic processing. First, I describe a form of cooperative supralinear synaptic integration by local excitatory inputs onto PV+ interneurons, and I extend these results to show how this augments the computational capability of PV+ cells within spiking neuron networks. I also explore the importance of polyamine-modulation of synaptic receptors in mediating sublinear synaptic integration, and discuss how this expands the array of mechanisms known to perform similar functions in PV+ cells. Finally, I present work manipulating PV+ cells experimentally during epilepsy. I consider these findings together with recent scientific advances and suggest how they account for a number of open questions and previously contradictory theories of PV+ interneuron function

Optimal strategies for electrical stimulation with implantable neuromodulation devices

Electrical stimulation (ES) is a neuromodulation technique that uses electrical pulses to modulate the activity of excitable cells to provide a therapeutic effect. Many past and present ES applications use rectangular current waveforms that have been well studied and are easy to generate. However, an extensive body of scientific literature describes different stimulation waveforms and their potential benefits. A key measure of stimulation performance is the amplitude required to reach a certain percentual threshold of activation, as it directly influences important ES parameters such as energy consumption per pulse and charge density. The research summarized in this thesis was conducted to re-examine some of the most-commonly suggested ES waveform variations in a rodent in-vivo nerve-muscle preparation. A key feature of our experimental model is the ability to test stimulation with both principal electrode configurations, monopolar and bipolar, under computer control and in randomized order. Among the rectangular stimulation waveforms, we investigated the effect of interphase gaps (IPGs), asymmetric charge balanced pulses, and subthreshold conditioning pre-pulses. For all these rectangular waveforms, we surprisingly observed opposite effects in the monopolar compared to the bipolar stimulation electrode configuration. The rationale for this consistent observation was identified by analyzing electroneurograms (ENGs) of the stimulated nerve. In the monopolar configuration, biphasic pulses first evoked compound action potentials (eCAPs) as a response to the first field transition. In the bipolar electrode configuration, that is the mode in which many contemporary ES devices, including the envisioned miniaturized electroceuticals, operate, eCAPs were first elicited at the return electrode in response to the middle field transition of biphasic pulses. As all rectangular waveform variations achieve their effect by modulating the amplitude and timing of cathodic (excitatory) and anodic (inhibitory) field transitions, the inverted current profile at the bipolar return electrode explains these observed opposite effects. Further we investigated the claimed benefits of non-rectangular, Gaussian stimulation waveforms in our animal model. In our study only moderate energy savings of up to 17% were observed, a finding that is surprising in light of the predicted range of benefits of up to 60% energy savings with this novel waveform in question. Additionally, we identified a major disadvantage in terms of substantially increased maximum instantaneous power requirements with Gaussian compared to rectangular stimuli. We examined physiological changes in fast twitch muscle following motor nerve injury, and optimal stimulation strategies for activation of denervated muscle. While a high frequency doublet has previously been identified to enhance stimulation efficiency of healthy fast twitch muscle, an effect that has been termed “doublet effect”, we here show that this benefit is gradually lost in muscle during denervation. Lastly, the effect of long duration stimulation pulses, that are required to activate denervated muscle, on nerve is examined. We show that these long pulses can activate nerves up to three times when the three field transition within the biphasic pulses are separated by more than (i.e., when the phase width is above) the refractory period of that nerve. This observation challenges state-of-the-art computational models of extracellular nerve stimulation that do not seem to predict such multiple activations. Further, an undesired up to threefold co-activation of innervated structures nearby the denervated stimulation target warrants further research to study whether these co-activations can be lessened with alternative stimulation waveforms such as ramped sawtooth pulses

System Level Assessment of Motor Control through Patterned Microstimulation in the Superior Colliculus

We are immersed in an environment full of sensory information, and without much thought or effort we can produce orienting responses to appropriately react to different stimuli. This seemingly simple and reflexive behavior is accomplished by a very complicated set of neural operations, in which motor systems in the brain must control behavior based on populations of sensory information. The oculomotor or saccadic system is particularly well studied in this regard. Within a visual environment consisting of many potential stimuli, we control our gaze with rapid eye movements, or saccades, in order to foveate visual targets of interest. A key sub-cortical structure involved in this process is the superior colliculus (SC). The SC is a structure in the midbrain which receives visual input and in turn projects to lower-level areas in the brainstem that produce saccades. Interestingly, microstimulation of the SC produces eye movements that match the metrics and kinematics of naturally-evoked saccades. As a result, we explore the role of the SC in saccadic motor control by manually introducing distributions of activity through neural stimulation. Systematic manipulation of microstimulation patterns were used to characterize how ensemble activity in the SC is decoded to generate eye movements. Specifically, we focused on three different facets of saccadic motor control. In the first study, we examine the effective influence of microstimulation parameters on behavior to reveal characteristics of the neural mechanisms underlying saccade generation. In the second study, we experimentally verify the predictions of computational algorithms that are used to describe neural mechanisms for saccade generation. And in the third study, we assess where neural mechanisms for decoding occur within the oculomotor network in order to establish the order of operations necessary for saccade generation. The experiments assess different aspects of saccadic motor control, which collectively, reveal properties and mechanisms that contribute to the comprehensive understanding of signal processing in the oculomotor system

Adaptive Closed-Loop Neuromorphic Controller for Use in Respiratory Pacing

Respiratory pacing can treat ventilatory insufficiency through electrical stimulation of the respiratory muscles, or the respective innervating nerves, to induce ventilation. It avoids some of the adverse effects associated with mechanical ventilation such as risk of diaphragm atrophy and lung damage. However, current respiratory pacing systems provide stimulation in an open-loop manner. This often requires users to undergo frequent tuning sessions with trained clinicians if the specified stimulation parameters are unable to induce sufficient ventilation in the presence of time-varying changes in muscle properties, chest biomechanics, and metabolic demand. Lack of adaptation to these changes may lead to complications arising from hyperventilation or hypoventilation. A novel adaptive closed-loop neuromorphic controller for respiratory pacing has been developed to address the need for closed-loop control respiratory pacing capable of responding to changes in metabolic production of CO2, diaphragm muscle health, and biomechanics. A 3-stage processes was utilized to develop the controller. First, an adaptive controller that could follow a preset within-breath volume profile was developed in silico and evaluated in vivo in anesthetized rats with an intact spinal cord or with diaphragm hemiparesis induced by spinal cord hemisection. Second, a neuromorphic computational model was developed to generate a desired trajectory that reflects changes in breath volume and respiratory rate in response to arterial CO2 levels. An enhanced controller capable of generating and matching this model-based desired trajectory was evaluated in silico and in vivo on rats with depressed ventilation and diaphragm hemiparesis. Finally, the enhanced adaptive controller was modified for human-related biomechanics and CO2 dynamics and evaluated in silico under changes of metabolic demand, presence of muscle fatigue, and after randomization of model parameters to reproduce expected between-subject differences. Results showed that the adaptive controller could adapt and modulate stimulation parameters and respiratory rate to follow a desired model-generated breath volume trajectory in response to dynamic arterial CO2 levels. In silico studies aimed at assessing potential for clinical translation showed that an enhanced controller modified for human use could successfully control ventilation to achieve and maintain normocapnic arterial CO2 levels. Overall, these results suggest that use of an adaptive closed-loop controller could lead to improved ventilatory outcomes and quality of life for users of adaptive respiratory pacing

Properties of maximum length sequence and nonlinear volterra slice otoacoustic emissions

Evoked otoacoustic emissions (EOAEs) are produced by the cochlea and provide anobjective and non-invasive measure of cochlear function. A new technique, based onMaximum Length Sequences (MLSs) enables stimulus rates of up to 5000 clicks/s to beused, and gives increased speed and sensitivity of testing. Volterra slice otoacousticemissions (VSOAEs) can be extracted from the response using this technique. Theserepresent nonlinear temporal interaction components and are more sensitive to changes incochlear pathology than the conventional response. Conventional EOAE amplitude differsbetween ears and sexes; female subjects having responses of greater amplitude than malesubjects and right ears larger responses than left ears. As a pre-requisite to clinical use it isnecessary to establish if these differences occur with the Maximum length sequenceotoacoustic (MLSOAE) technique and with VSOAEs and whether they change with stimulusrate, order or slice. The relationship between VSOAEs, Spontaneous otoacoustic emissions(SOAEs), Distortion product otoacoustic emissions (DPOAEs) and the input/output function(I/O) for click-evoked OAEs (CEOAEs) recorded at the conventional rate (40 clicks/s) wasalso investigated to assess if these measures of cochlear nonlinearity were related to oneanother.In the first set of experiments 80 ears of normally hearing adults were tested. MLSOAEswere recorded at eight stimulus rates and two stimulus levels. For the second and thirdexperiments 45 ears of normally hearing adults were tested. SOAEs, DPOAEs, theinput/output function (I/O) for CEOAEs at the conventional rate (40 clicks/s) and at fourstimulus levels, and VSOAEs at three stimulus rates were recorded.Female subjects were found to have statistically significantly larger MLSOAEs than malesubjects and gave larger amplitude responses in their right ears. This sex difference wasobserved with VSOAEs. A rate effect was also demonstrated with the amplitude of theMLSOAEs decreasing with an increase in rate. The VSOAE amplitude was greater for thesecond order compared with the third order response, and slice one had a greater amplitudethan slice two. VSOAEs of higher amplitude were obtained in SOAE-positive ears. There wasa significant relationship between the slope of the I/O function of the CEOAE and theVSOAEs.The study has provided normative data for MLSOAE testing and for VSOAEs. The dataobtained suggest that the amplitude (CEOAE I/O function) and temporal (VSOAEs)nonlinearities arise from the same generators, whereas the frequency domain nonlinearities(SOAEs & DPOAEs) have different generators. MLSOAEs and VSOAEs have great potentialfor clinical use

Applications of EMG in Clinical and Sports Medicine

This second of two volumes on EMG (Electromyography) covers a wide range of clinical applications, as a complement to the methods discussed in volume 1. Topics range from gait and vibration analysis, through posture and falls prevention, to biofeedback in the treatment of neurologic swallowing impairment. The volume includes sections on back care, sports and performance medicine, gynecology/urology and orofacial function. Authors describe the procedures for their experimental studies with detailed and clear illustrations and references to the literature. The limitations of SEMG measures and methods for careful analysis are discussed. This broad compilation of articles discussing the use of EMG in both clinical and research applications demonstrates the utility of the method as a tool in a wide variety of disciplines and clinical fields