We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3-4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3-4 weeks: median of 16 s; SCS 5 weeks: median of 7 s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata. •Spinal cord stimulation (SCS) suppresses neurally induced atrial fibrillation (AF).•Effectiveness of SCS in AF suppression increases with time.•SCS minimally impacts active and passive properties of individual intrinsic cardiac neurons.•SCS modifies synaptic efficacy of the IC network.•SCS differentially impacts the neurotransmission to the accommodating sub-population of IC neurons.

To evaluate whether cervical spinal neurons can influence cardiac indices and myocyte viability in the acutely ischemic heart, the hearts of anesthetized rabbits subjected to 30. min of LAD coronary arterial occlusion (CAO) were studied 3. h after reperfusion. Control animals were compared to those exposed to pre-emptive high cervical cord stimulation (SCS; the dorsal aspect of the C1-C2 spinal cord was stimulated electrically at 50. Hz; 0.2. ms; 90% of motor threshold, starting 15. min prior to and continuing throughout CAO). Four groups of animals were so tested: 1) neuroaxis intact; 2) prior cervical vagotomy; 3) prior transection of the dorsal spinal columns at C6; and 4) following pharmacological treatment [muscarinic (atropine) or adrenergic (atenolol, prazosin or yohimbine) receptor blockade]. Infarct size (IS) was measured by tetrazolium, expressed as percentage of risk zone. C1-C2 SCS reduced acute ischemia induced IS by 43%, without changing the incidence of sudden cardiac death (SCD). While SCS-induced reduction in IS was unaffected by vagotomy, it was no longer evident following transection of C6 dorsal columns or atropinization. Beta-adrenoceptor blockade eliminated ischemia induced SCD, while alpha-receptor blockade doubled its incidence. During SCS, myocardial ischemia induced SCD was eliminated following vagotomy while remaining unaffected by atropinization. These data indicate that, in contrast to thoracic spinal neurons, i) cranial cervical spinal neurons affect both adrenergic and cholinergic motor outflows to the heart such that ii) their activation modifies ventricular infarct size and lethal arrhythmogenesis.

Neuropeptide signaling play critical roles in maintaining distinct behavioral states and orchestrating transitions between them. However, elucidating the mechanisms underlying neuropeptide modulation of neural circuits in vivo remains a major challenge. The nematode Caenorhabditis elegans serves as an excellent model organism to study neuropeptide signaling mechanisms encoded in relatively simple neural circuits. We have used the C. elegans egg-laying circuit as a model to understand how neuropeptide signaling modifies circuit activity to generate opposing behavioral outcomes. C. elegans egg-laying behavior is composed of alternating cycles of two states – short bursts of egg deposition (active phases) and prolonged periods of quiescence (inactive phases). We have identified two neuropeptides (NLP-7 and FLP-11) that are locally released from a group of neurosecretory cells (uv1) and coordinate the temporal organization of egglaying by prolonging the duration of inactive phases. These neuropeptides regulate activity within the core circuit by inhibiting serotonergic transmission between its individual components (HSN motorneurons and Vm2 vulval muscles). This inhibition is achieved at least in part, by reducing synaptic vesicle abundance in the HSN synaptic regions. To identify potential downstream signaling components that mediate the actions of these neuropeptides, we have performed a forward genetic screen and have identified a strong candidate. In addition, we are trying to identify the receptor(s) of these neuropeptides by using a candidate gene approach. Together, we demonstrate that local neuropeptide signaling maintains the periodicity of distinct behavioral states by regulating serotonergic transmission in the core neural circuit.

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No description available.

The cardiac nervous system consists of nested reflex feedback loops that interact to regulate regional heart function. Cardiac disease affects multiple components of the cardiac nervous system and the myocytes themselves. This study aims to determine: 1) how select components of the cardiac nervous system respond to acute cardiac stress, including myocardial ischemia (MI) and induced neural imbalance leading to cardiac electrical instability, and 2) how neuromodulation can affect neural-myocyte interactions to induce cardioprotection. Thoracic spinal cord stimulation (SCS) is recognized for its anti-anginal effects and ability to reduce apoptosis in response to acute MI, primarily via modulation of adrenergic efferent systems. The data presented here suggest that cervical SCS exerts similar cardioprotective effects in response to MI, but in contradistinction to thoracic SCS, uses both adrenergic and cholinergic efferent mechanisms to stabilize cardiomyocytes and the arrhythmogenic potential. SCS potentially can use efferent and/or anti-dromically activated cardiac afferents to mediate its cardioprotection. Thoracic SCS mitigates the MI-induced activation of both nodose and dorsal root ganglia cardiac-related afferents, doing so without antidromic activation of the primary cardiac afferents. Instead, thoracic SCS acts through altering the cardiac milieu thereby secondarily affecting the primary afferent sensory transduction. In response to cardiac stressors, reflex activation of efferent activity modifies mechanical and electrical functions of the heart. Excessive activation of neuronal input to the cardiac nervous system can induce arrhythmias. Stimulation of intrathoracic mediastinal nerves directly activates subpopulations of intrinsic cardiac neurons, thereby inducing atrial arrhythmias. Neuromodulation, either thoracic SCS or hexamethonium, suppressed mediastinal nerve stimulation (MSNS)-induced activation of intrinsic cardiac neurons and correspondingly reduced the arrhythmogenic potential. SCS exerted its stabilizing effects on neural processing and subsequent effects on atrial electrical function by selectively targeting local circuit neurons within the intrinsic cardiac nervous system. Together these data indicate that neuromodulation therapy, using SCS, can mitigate the imbalances in cardiac reflex control arising from acute cardiac stress and thereby has the potential to slow the progression of chronic heart disease.

Motor intent and control rely on complex high-level and spinal networks. Untilnow, little is known about this system’s organization and mechanisms. Whilecognitive abilities play an essential role in planning movements, learning andmemorizing, their involvement during stereotyped tasks execution, aslocomotion, is still controversial. Recently, the relationship between cognitivefunctions and gait has received increasing attention.Here, a machine learning approach is used to investigate the engagement ofdi↵erent cortical areas during motor activity. In particular, data coming fromthree subjects with implanted electrodes have been analyzed in the frequencydomain to predict their tasks’ state. The choice of intracortical data hasallowed to elude motion artifacts’ presence and exploitation concern. Goodand satisfactory results have been achieved in the case of not highlystereotyped activity. During ambulation, an evidence of an engagement of thebrain has been shown even if with lower classification performances. Moreover,the cortical areas that have emerged in this analysis seem to be in line withthe relative functionality hypothesized in literature.

<p> The nervous system exists as our interface to the world, both integrating and interpreting sensory information and coordinating voluntary and involuntary movements. Given its importance, it has become a target for neuromodulatory therapies. The research to develop these therapies cannot be done purely on living tissues - animals, manpower, and equipment make that cost prohibitive and, given the cost of life required, it would be unethical to not search for alternatives. Computation modeling, the use of mathematics and modern computational power to simulate phenomena, has sought to provide such an alternative since the work of Hodgkin and Huxley in 1952. These models, though they cannot yet replace in-vivo and in-vitro experiments, can ease the burden on living tissues and provide details difficult or impossible to ascertain from them. This thesis iterates on previous frameworks for performing in-silico experiments for the purposes of mechanistic exploration and threshold prediction. To do so, an existing volume conductor model and validated nerve-fiber model were joined and a series of programs were developed around them to perform a set of in-silico experiments. The experiments are designed to predict changes in thresholds of behaviors elicited by bioelectric neuromodulation to parametric changes in experimental setup and to explore the mechanisms behind bioelectric neuromodulation, particularly surrounding the recently discovered Low Frequency Alternating Current (LFAC) waveform. This framework improved upon its predecessors through efficiency-oriented design and modularity, allowing for rapid simulation on consumer-grade computers. Results show a high degree of convergence with in-vivo experimental results, such as mechanistic alignment with LFAC and being within an order of magnitude of in-vivo pulse-stimulation threshold results for equivalent in-vivo and in-silico experimental designs. </p>

No description available.

Focused ultrasound (FUS) mediated neuromodulation has become a trending topic due to its promising attributes that enable precise and transcranial neuromodulation. Despite multiple reports of FUS effects on neurons, nervous systems, and the human brain, the mechanisms underlying such excitation or inhibition remain controversial. In our previous study, we showed that 2.1 MHz FUS induced membrane depolarizations on single crayfish motor axons in the presence of voltage-gated channel blockers, which led to a nanopore hypothesis: FUS triggered lipid molecule reconfiguration and form ion-permeable nanopores on the axonal membrane. Based on this hypothesis, stretching of the axonal membrane due to swelling in low osmolarity should increase the probability of nanopore formation under FUS. As predicted, exposure to 75% hypotonic saline induced significant increases in amplitude and frequency of occurrence of those FUS-induced depolarizations (FUSD) while the onset latency of the FUSD showed a significant decrease. Those results support the hypothesis that FUSD can be modulated by mechanically altering membrane properties. Since FUS inevitably perturbs cell membranes, we examined the role of mechanosensitive K2P channels at the crayfish opener neuromuscular junction. At ultrasound intensity lower than those used to evoke FUSD, FUS consistently induced membrane hyperpolarization (FUSH) in motor axons but not muscle fibers, which may lack K2P. Since K2P channels are also thermosensitive, we varied the temperature from 12 to 32 °C. However, there was no significant correlation between FUSH amplitudes and temperature. Furthermore, FUSH was not inhibited by the K2P channel blockers, although the presence of the channels was confirmed by K2P blockers which increased input resistance and depolarized axonal resting membrane potential. Thus, it is unlikely that K2P channels underlie FUSH. We also studied the impact of FUS on propagating action potentials (APs) in the crayfish motor axons. APs recorded during FUS took off from a hyperpolarized membrane potential and exhibited larger amplitudes and shorter duration. Three hypotheses were examined and eliminated. The US modulated AP shape changes cannot be due to: (1) alterations in microelectrode characteristics, (2) the increase in the fraction of sodium channels in the closed and not-inactivated state due to the hyperpolarization and (3) US activation of K2P channels which in turn altered AP shapes. One potential mechanism that requires further investigation is that FUS may accelerate the activation of sodium channel opening. Other factors that may indirectly modulate AP shapes are discussed. In summary, results presented in this thesis suggest that FUS-mediated membrane responses in a single cell could vary depending on the FUS intensity and the type of ion channel a given cell expresses. Furthermore, ultrasound not only evokes changes membrane potential but also modulates action potentials. Collectively, these results represent significant contribution to the understanding of mechanisms underlying ultrasound neuromodulation at the cellular level.