Modelling neurocardiac physiology and diseases using human pluripotent stem cells: current progress and future prospects.

Throughout our lifetime the heart executes cycles of contraction and relaxation to meet the body's ever-changing metabolic needs. This vital function is continuously regulated by the autonomic nervous system. Cardiovascular dysfunction and autonomic dysregulation are also closely associated; however, the degrees of cause and effect are not always readily discernible. Thus, to better understand cardiovascular disorders, it is crucial to develop model systems that can be used to study the neurocardiac interaction in healthy and diseased states. Human pluripotent stem cell (hiPSC) technology offers a unique human-based modelling system that allows for studies of disease effects on the cells of the heart and autonomic neurons as well as of their interaction. In this review, we summarize current understanding of the embryonic development of the autonomic, cardiac and neurocardiac systems, their regulation, as well as recent progress of in vitro modelling systems based on hiPSCs. We further discuss the advantages and limitations of hiPSC-based models in neurocardiac research.

Baroreflex Function in Cardiovascular Disease.

The baroreflex system is involved in modulating several physiological functions of the cardiovascular system and can modulate cardiac output, blood pressure, and cardiac electrophysiology directly and indirectly. In addition, it is involved in regulating neurohormonal pathways involved in the cardiovascular function, such as the renin-angiotensin-aldosterone system and vasopressin release. Baroreflex dysfunction is characterized by sympathetic overactivation and parasympathetic withdrawal and is associated with several cardiovascular diseases, such as hypertension, heart failure, and coronary artery disease. Targeting the baroreflex system via invasive (eg, baroreflex activation therapy and endovascular baroreceptor amplification) and noninvasive approaches (eg, slow breathing exercises and exercise training) has emerged as a novel pathway to manage cardiovascular diseases. Studies examining the long-term safety and efficacy of such interventions in various cardiovascular diseases are needed.

Impact of Concurrent Ischaemic Stroke on Unfavourable Outcomes in Men and Women with Dilated Cardiomyopathy.

Background: Growing evidence suggests that concurrent ischaemic stroke (IS) exacerbates the prognosis of patients with dilated cardiomyopathy (DCM) and that this effect may be further influenced by sex. However, the exact effect of sex remains unclear. This study aimed to explore the effects of the relevant risk factors on the prognosis of patients with DCM and concurrent IS. Considering the sex differences in DCM, this study further investigated the impact of concurrent IS on the prognosis of men and women with DCM. Methods: A total of 632 patients with DCM enrolled between 2016 and 2021 were included in this study. Clinical data were obtained from medical records, and all participants were followed up in the outpatient clinic or by telephone for at least 1 year. A Cox proportional hazards model and Kaplan-Meier curves were used to evaluate the effects of concurrent IS on the prognosis of patients with DCM. Results: Patients with DCM complicated with IS (DCM-IS) had significantly lower cumulative survival rates than patients with DCM without IS (non-IS) (74.6% vs. 84.2%, χ 2 = 6.85, p = 0.009). Additionally, IS was associated with greater risks of death and heart transplantation (HTx) in men (75.8% vs. 85.1%, χ 2 = 5.02, p = 0.025), but not in women (71.0% vs. 81.5%, χ 2 = 1.91, p = 0.167). Conclusions: This large-scale multicentre prospective cohort study demonstrated a poorer prognosis in patients with concurrent DCM and IS, particularly among men. Patients with DCM should not be overlooked in IS screening, emphasis should be placed on the occurrence of IS in patients with DCM. Early and proactive secondary prevention of cerebrovascular diseases might improve the prognosis of DCM patients. More intervention studies focusing on men with DCM complicated with IS should be prioritised.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83-0.96, effect size d = 1.9-5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation.NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Biological computation: hearts and flytraps.

The original computers were people using algorithms to get mathematical results such as rocket trajectories. After the invention of the digital computer, brains have been widely understood through analogies with computers and now artificial neural networks, which have strengths and drawbacks. We define and examine a new kind of computation better adapted to biological systems, called biological computation, a natural adaptation of mechanistic physical computation. Nervous systems are of course biological computers, and we focus on some edge cases of biological computing, hearts and flytraps. The heart has about the computing power of a slug, and much of its computing happens outside of its forty thousand neurons. The flytrap has about the computing power of a lobster ganglion. This account advances fundamental debates in neuroscience by illustrating ways that classical computability theory can miss complexities of biology. By this reframing of computation, we make way for resolving the disconnect between human and machine learning.

Cholinergic stimulation improves electrophysiological rate adaptation during pressure overload-induced heart failure in rats.

BACKGROUND: Left ventricular (LV) electrical maladaptation to increased heart rate in failing myocardium contributes to morbidity and mortality. Recently, cardiac cholinergic neuron activation reduced loss of contractile function resulting from chronic trans-aortic constriction (TAC) in rats. We hypothesized that chronic activation of cardiac cholinergic neurons would also reduce TAC-induced derangement of cardiac electrical activity. METHODS: We investigated electrophysiological rate adaptation in TAC rat hearts with and without daily chemogenetic activation of hypothalamic oxytocin neurons for downstream cardiac cholinergic neuron stimulation. Sprague Dawley rat hearts were excised, perfused, and optically mapped under dynamic pacing after 16 weeks of TAC with or without 12 weeks of daily chemogenetic treatment. Action potential duration (APD60) and conduction velocity (CV) maps were analyzed for regional rate adaptation to dynamic pacing. RESULTS: At lower pacing rates, untreated TAC induced elevated LV epicardial APD60. Fitted APD60 steady state (APDss) was reduced in treated TAC hearts. At higher pacing rates, treatment heterogeneously reduced APD60 compared to untreated TAC hearts. Variance of conduction loss was reduced in treated hearts compared to untreated hearts during fast pacing. However, CV was markedly reduced in both treated and untreated TAC hearts throughout dynamic pacing. At 150msec pacing cycle length, APD60 v. diastolic interval (DI) dispersion was reduced in treated hearts compared to untreated hearts. CONCLUSIONS: Chronic activation of cardiac cholinergic neurons improved electrophysiological adaptation to increases in pacing rate during development of TAC-induced heart failure. This provides insight into the electrophysiological benefits of cholinergic stimulation as a treatment for heart failure patients.

RNAs in Brain and Heart Diseases.

In the era of single-cell analysis, one always has to keep in mind the systemic nature of various diseases and how these diseases could be optimally studied. Comorbidities of the heart in neurological diseases as well as of the brain in cardiovascular diseases are prevalent, but how interactions in the brain-heart axis affect disease development and progression has been poorly addressed. Several brain and heart diseases share common risk factors. A better understanding of the brain-heart interactions will provide better insights for future treatment and personalization of healthcare, for heart failure patients' benefit notably. We review here emerging evidence that studying noncoding RNAs in the brain-heart axis could be pivotal in understanding these interactions. We also introduce the Special Issue of the International Journal of Molecular Sciences RNAs in Brain and Heart Diseases-EU-CardioRNA COST Action.

Cardiac Dysfunction in Neurocritical Care: An Autonomic Perspective.

A number of neurologic disorders can cause cardiac dysfunction by involving the conductive system and contractile apparatus of the heart. This is especially prominent in the neurocritical care setting where the spectrum of cardiac dysfunction due to acute neurologic injury ranges from trivial and isolated electrocardiographic changes to malignant arrhythmias and sudden death (Table 1). The mechanism of these cardiac complications is complex and not fully understood. An understanding of the neuroanatomical structures and pathways is of immense importance to comprehend the underlying pathophysiology that culminates as cardiac damage and dysregulation. Once the process is initiated, it can complicate and adversely affect the outcome of primary neurologic conditions commonly seen in the neurocritical care setting. Not only are these cardiac disorders under-recognized, there is a paucity of data to formulate evidence-based guidelines regarding early detection, acute management, and preventive strategies. However, certain details of clinical features and their course combined with location of primary neurologic lesion on neuroimaging and data obtained from laboratory investigations can be of great value to develop a strategy to appropriately manage these patients and to prevent adverse outcome from these cardiac complications. In this review, we highlight the mechanisms of cardiac dysfunction due to catastrophic neurologic conditions or due to stress of critical illness. We also address various clinical syndromes of cardiac dysfunction that occur as a result of the neurologic illness and in turn may complicate the course of the primary neurologic condition.

Head Rules Over the Heart: Cardiac Manifestations of Cerebral Disorders.

The Brain-Heart interaction is becoming increasingly important as the underlying pathophysiological mechanisms become better understood. "Neurocardiology" is a new field which explores the pathophysiological interplay of the brain and cardiovascular systems. Brain-heart cross-talk presents as a result of direct stimulation of some areas of the brain, leading to a sympathetic or parasympathetic response or it may present as a result of a neuroendocrine response attributing to a clinical picture of a sympathetic storm. It manifests as cardiac rhythm disturbances, hemodynamic perturbations and in the worst scenarios as cardiac failure and death. Brain-Heart interaction (BHI) is most commonly encountered in traumatic brain injury and subarachnoid hemorrhage presenting as dramatic electrocardiographic changes, neurogenic stunned myocardium or even as ventricular fibrillation. A well-known example of BHI is the panic disorders and emotional stress resulting in Tako-tsubo syndrome giving rise to supraventricular and ventricular tachycardias and transient left ventricular dysfunction. In this review article, we will discuss cardiovascular changes caused due to the disorders of specific brain regions such as the insular cortex, brainstem, prefrontal cortex, hippocampus and the hypothalamus; neuro-cardiac reflexes namely the Cushing's reflex, the Trigemino-cardiac reflex and the Vagal reflex; and other pathological states such as neurogenic stunned myocardium /Takotsubo cardiomyopathy. There is a growing interest among intensivists and anesthesiologists in brain heart interactions as there are an increasing number of cases being reported and there is a need to address unanswered questions, such as the incidence of these interactions, the multifactorial pathogenesis, individual susceptibility, the role of medications, and optimal management. KEY MESSAGES: BHI contribute in a significant way to the morbidity and mortality of neurological conditions such as traumatic brain injury, subarachnoid hemorrhage, cerebral infarction and status epilepticus. Constant vigilance and a high index of suspicion have to be exercised by clinicians to avoid misdiagnosis or delayed recognition. The entire clinical team involved in patient care should be aware of brain heart interaction to recognize these potentially life-threatening scenarios. HOW TO CITE THIS ARTICLE: Hrishi AP, Lionel KR, Prathapadas U. Head Rules Over the Heart: Cardiac Manifestations of Cerebral Disorders. Indian J Crit Care Med 2019;23(7):329-335.

Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

KEY POINTS: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. ABSTRACT: Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n = 8, 'cardiac' configuration) or with electrode positions reversed (n = 8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20 Hz), intensity (0-3.5 mA) and pulse widths (130-750 µs) over 14 months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR ≈ 0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells.

The cardiovascular and nervous systems are deeply connected during development, health, and disease. Both systems affect and regulate the development of each other during embryogenesis and the early postnatal period. Specialized neural crest cells contribute to cardiac structures, and a number of growth factors released from the cardiac tissue (e.g., glial cell line-derived neurotrophic factor, neurturin, nerve growth factor, Neurotrophin-3) ensure proper maturation of the incoming parasympathetic and sympathetic neurons. Physiologically, the cardiovascular and nervous systems operate in harmony to adapt to various physical and emotional conditions to maintain homeostasis through sympathetic and parasympathetic nervous systems. Moreover, neurocardiac regulation involves a neuroaxis consisting of cortex, amygdala, and other subcortical structures, which have the ability to modify lower-level neurons in the hierarchy. Given the interconnectivity of cardiac and neural systems, when one undergoes pathological changes, the other is affected to a certain extent. In addition, there are specific neurocardiac diseases that affect both systems simultaneously, such as Huntington disease, Lewy body diseases, Friedreich ataxia, congenital heart diseases, Danon disease, and Timothy syndrome. Over the last decade, in vitro modeling of neurocardiac diseases using induced pluripotent stem cells (iPSCs) has provided an invaluable opportunity to elevate our knowledge about the brain-heart connection, since previously primary cardiomyocytes and neurons had been extremely difficult to maintain long-term in vitro. Ultimately, the ability of iPSC technology to model abnormal functional phenotypes of human neurocardiac disorders, combined with the ease of therapeutic screening using this approach, will transform patient care through personalized medicine in the future. © 2016 Wiley Periodicals, Inc.

Heart failure and Alzheimer's disease.

It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.

Historical Perspective of the Cardiac Autonomic Nervous System.

The contemporary history of the cardiac autonomic nervous system includes early descriptions of neuroanatomy in the 19th century, followed by an understanding of the physiologic determinants of neurocardiology in the 20th century. Neurology and cardiology preceded the arrival of clinical cardiac electrophysiology, a specialized field in medicine devoted to the diagnosis and treatment of cardiac arrhythmias. The rapid growth in pharmacology, ablation, pacing and defibrillation, associated with significant technological breakthroughs, have resulted in new opportunities for neuromodulation in the 21st century. Small changes in autonomic tone can potentially provide important therapeutic benefits for patients with cardiac and arrhythmia disorders.

Cardiac Neuroanatomy and Fundamentals of Neurocardiology.

Cardiac control is mediated via nested-feedback reflex control networks involving the intrinsic cardiac ganglia, intra-thoracic extra-cardiac ganglia, spinal cord, brainstem, and higher centers. This control system is optimized to respond to normal physiologic stressors; however, it can be catastrophically disrupted by pathologic events such as myocardial ischemia. In fact, it is now recognized that cardiac disease progression reflects the dynamic interplay between adverse remodeling of the cardiac substrate coupled with autonomic dysregulation. With advances in understanding of this network dynamic in normal and pathologic states, neuroscience-based neuromodulation therapies can be devised for the management of acute and chronic cardiac pathologies.

Association Between Stroke Lesion Size and Atrial Fibrillation Detected After Stroke: An Observational Cohort Study.

BACKGROUND: Atrial fibrillation detected after stroke (AFDAS) is considered to be a distinct entity influenced by cardiogenic and neurogenic factors. We hypothesized that patients with AFDAS have larger stroke lesions than patients without atrial fibrillation (AF) and with known AF (KAF). METHODS AND RESULTS: Consecutive patients with magnetic resonance imaging-confirmed acute ischemic stroke admitted to a university hospital between October 2020 and January 2023 were prospectively registered. We categorized patients as AFDAS, no AF or KAF upon hospital discharge. We manually segmented diffusion-weighted imaging lesions to determine lesion volume. We analyzed 1420 patients (median age, 78; 47.2% women, median National Institutes of Health Stroke Scale score, 3; median hospital stay, 5 days). Of these, 81 had AFDAS (5.7%), 329 had KAF (23.2%) and 1010 had no AF (71.1%). Lesion volume was larger in patients with AFDAS (median, 5.4 mL [interquartile range, 1.0-21.6]) compared with patients with no AF and KAF (median, 0.7 [interquartile range,0.2-4.4] and 2.0 [interquartile range,0.3-11.1] mL, respectively; both P<0.001). Lesion volume was independently associated with AFDAS compared with no AF (adjusted odds ratio, 1.37 [95% CI, 1.20-1.58] per log mL) and KAF (adjusted odds ratio, 1.22 [95% CI, 1.07-1.41] per log mL). Patients in the highest lesion volume quartile (>6.5 mL) were more likely to be diagnosed with AFDAS compared with the lowest quartile (<0.22 mL, 13.6% versus 2.1%; adjusted odds ratio, 5.88 [95% CI, 2.30-17.40]). These associations were more pronounced when excluding 151 patients with nonembolic lesion pattern and similar when excluding 199 patients with KAF on oral anticoagulation. CONCLUSIONS: Larger stroke lesions were independently associated with AFDAS diagnosis during index stroke hospitalization highlighting a potential neurogenic contribution to AFDAS pathogenesis.

Cardiac Findings Following Cerebrovascular Disease.

BACKGROUND: Accumulating evidence suggests that cardiac findings after stroke are an important, yet understudied, manifestation of brain-heart interactions. Our aim was to investigate and compare cardiac findings after different cerebrovascular events (acute ischemic stroke, transient ischemic attack, and hemorrhagic stroke). METHODS AND RESULTS: There were 7113 patients screened who were treated between December 2013 and December 2020 at the University Hospital Zurich for ischemic stroke, transient ischemic attack, and hemorrhagic stroke. Seven hundred twenty-one patients without evidence of previous cardiac disease or presumed cardioembolic origin of their cerebrovascular disease and with at least 1 cardiac checkup were included. Clinical reports from the year following disease onset were screened for new cardiac findings, which were categorized as arrhythmia/electrocardiographic changes, myocardial alterations, valvular abnormalities, and coronary perfusion insufficiency. Differences in proportions of findings among groups were analyzed using the Pearson χ2 test or Fisher exact test. ECG changes were observed in 81.7% (n=474) of patients with ischemic stroke, 71.4% (n=70) of patients with transient ischemic attack, and 55.8% (n=24) of patients with hemorrhagic stroke (P<0.001). Myocardial alterations occurred often in all 3 groups (60.9% ischemic stroke [n=353], 59.2% transient ischemic attack [n=58], 44.2% hemorrhagic stroke [n=19]; P=0.396). CONCLUSIONS: Cardiac findings are frequent in patients with cerebrovascular disease, even without prior cardiac problems or suspected cardiac cause. Similarities, especially between patients with ischemic stroke and transient ischemic attack, were observed. Our data suggest that all patients with acute cerebrovascular events should receive thorough workup searching for cardiac manifestations.

Pathophysiologic Mechanisms in Cardiac Autonomic Nervous System and Arrhythmias.

The autonomic nervous system, including the central nervous system and the cardiac plexus, maintains cardiac physiology. In diseased states, autonomic changes through neuronal remodeling generate electrical mechanisms of arrhythmia such as triggered activity or increased automaticity. This article will focus on the pathophysiological mechanisms of arrhythmia to highlight the role of the autonomic nervous system in disease and the related therapeutic interventions.

Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs.

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.