Definition and Overview
The central autonomic network (CAN) is a collection of interconnected neural structures distributed across the cerebral cortex, limbic system, hypothalamus, and brainstem that regulates autonomic output and integrates visceral sensory information to maintain bodily homeostasis [1]. The concept of CAN was established in 1993 when Benarroch, a neurologist at the Mayo Clinic, systematized previously scattered research on autonomic-related brain regions into a single functional network [1].
Traditionally, the autonomic nervous system was understood primarily through peripheral structures such as sympathetic and parasympathetic ganglia. However, the introduction of the CAN model clarified that autonomic regulation is not simply a peripheral reflex but a hierarchical processing operation spanning multiple levels of the brain [2]. The CAN integrates visceral sensory information (interoception) and adjusts the sympathetic-parasympathetic output ratio in real time according to environmental changes and emotional states.
In a 2013 activation likelihood estimation meta-analysis published by Beissner et al., 128 functional neuroimaging studies were synthesized to empirically identify the core components of the CAN. According to this analysis, the anterior insula, anterior cingulate cortex, and amygdala are the regions most consistently activated during autonomic tasks [3].
Component Structures
The CAN is composed of multiple neural structures arranged hierarchically from the cerebral cortex to the brainstem [1][5].
Insular Cortex
The insular cortex is a central hub of the CAN and the primary cortical receiving area for visceral sensory information. Sensory information from all visceral organs -- heart, gastrointestinal tract, lungs, bladder -- reaches the posterior insula via the posterior ventromedial nucleus (VMpo) of the thalamus and is sequentially processed anteriorly [5]. The anterior insula is responsible for conscious awareness of interoception, forming subjective feelings about one's own bodily state.
Oppenheimer et al. (1992) directly electrically stimulated the insular cortex during epilepsy surgery, inducing changes in heart rate and blood pressure. Left insular stimulation produced bradycardia and hypotension, while right insular stimulation produced tachycardia and hypertension, confirming the lateralized cardiovascular regulatory function of the insular cortex [6]. This finding provided a clue to understanding the mechanism of cardiac complications following insular strokes.
Anterior Cingulate Cortex
The anterior cingulate cortex (ACC), together with the insular cortex, serves as a cortical-level hub for autonomic regulation. It connects cognitive appraisal and emotional arousal information to autonomic output [3]. The pregenual region of the ACC shows a positive correlation with parasympathetic activity, while the subgenual region is associated with sympathetic activity [4].
Amygdala
The amygdala is the central structure for processing threat-related emotions such as fear and anxiety, and mediates autonomic responses to emotional stimuli [1]. The central nucleus of the amygdala projects directly to the hypothalamus and brainstem, triggering defensive responses including sympathetic activation, increased heart rate, elevated blood pressure, and increased respiratory rate. In patients with anxiety disorders, amygdala hyperactivation is directly linked to chronic sympathetic overactivation [4].
Hypothalamus
The hypothalamus serves as the integrative center of the CAN, synthesizing information descending from the cerebral cortex and limbic system and relaying it to brainstem autonomic nuclei [5]. The paraventricular nucleus (PVN) is the key structure for autonomic regulation within the hypothalamus, simultaneously controlling sympathetic activation and stress hormone (cortisol) secretion. The lateral hypothalamus governs arousal and energy metabolism, while the anterior hypothalamus (preoptic area) regulates thermoregulation and the sleep-wake cycle [1].
Brainstem Autonomic Nuclei
The brainstem contains the final common pathways for autonomic output [1][5].
- Nucleus tractus solitarius (NTS): The initial synaptic site for visceral afferent fibers and the primary relay station for all visceral sensory information. It serves as the starting point for key autonomic reflexes including the baroreceptor reflex and chemoreceptor reflex.
- Dorsal motor nucleus of the vagus (DMNV): A major origin nucleus for parasympathetic output, transmitting parasympathetic signals to the gastrointestinal tract, heart, and other organs.
- Nucleus ambiguus (NA): The origin nucleus for cardiac vagal neurons, generating respiratory sinus arrhythmia and directly reflected in the high-frequency component of heart rate variability (HF-HRV).
- Ventrolateral medulla (VLM): Contains the vasomotor center that maintains sympathetic tone, serving as the final effector pathway for blood pressure regulation.
Function
Visceral Sensory Integration
The primary function of the CAN is to collect and integrate sensory information ascending from visceral organs [5]. Sensory signals originating from cardiac baroreceptors, chemoreceptors of the aortic arch and carotid sinus, gastrointestinal mechanoreceptors, and pulmonary stretch receptors reach the nucleus tractus solitarius via the vagus and glossopharyngeal nerves. This information is relayed through the posterior ventromedial nucleus and ventrobasal nucleus of the thalamus to the insular cortex and anterior cingulate cortex, forming conscious interoception [3].
In healthy adults, interoceptive accuracy is reported at an average of approximately 65-70% on heartbeat detection tasks, with higher accuracy tending to correlate with better heart rate variability and emotional regulation capacity [4].
Autonomic Output Regulation
The CAN adjusts the output ratio of sympathetic and parasympathetic nervous systems in real time to maintain cardiovascular, respiratory, digestive, and thermoregulatory homeostasis [1]. Higher structures (prefrontal cortex, anterior cingulate cortex) exert tonic inhibition on lower structures (hypothalamus, brainstem nuclei), and when this inhibition is appropriately maintained, flexible modulation of autonomic output is possible. According to the neurovisceral integration model proposed by Thayer and Lane (2009), the more functionally intact the prefrontal cortex's inhibitory pathway to the amygdala, the higher the vagal tone, which is reflected in increased heart rate variability [4].
A resting SDNN (a time-domain measure of heart rate variability) of 100 ms or greater indicates adequate autonomic regulatory capacity, while values below 50 ms are associated with significantly increased cardiovascular event risk [4].
Emotion-Autonomic Connection
Emotional experiences inherently involve autonomic responses. The rapid heartbeat during fear and the slowing of breathing during relief occur because the amygdala and anterior cingulate cortex directly modulate brainstem autonomic nuclei [1]. The CAN model emphasizes that this emotion-autonomic connection is bidirectional. In addition to top-down pathways (brain to viscera), bottom-up pathways also exist whereby visceral states influence emotional processing in the brain, which is considered the neurological basis of embodied cognition [4].
In patients with anxiety disorders, excessive amygdala-insular connectivity can cause normal visceral sensations to be interpreted as threat signals, potentially triggering panic attacks. Conversely, when prefrontal-amygdala connectivity is strengthened, autonomic reactivity becomes stabilized [4].
Clinical Significance
Post-Stroke Autonomic Dysfunction
Insular strokes cause acute disruption of cardiac autonomic regulation. In studies by Oppenheimer et al., approximately 25-30% of insular infarction patients exhibited ECG abnormalities (QT prolongation, ST changes, arrhythmias) during the acute phase [6]. Right insular infarction is associated with sympathetic overactivation, increasing the risk of ventricular tachycardia and sudden cardiac death, while left insular infarction can trigger parasympathetic overactivation and bradycardia [6].
In strokes involving hypothalamic or brainstem lesions, more widespread autonomic dysfunction occurs, including thermoregulatory disturbance, orthostatic hypotension, and sweating abnormalities [2]. These autonomic complications have been reported as independent risk factors that worsen stroke prognosis.
Epilepsy and the Autonomic Nervous System
Heart rate changes during epileptic seizures are extremely common, with ictal tachycardia observed in approximately 80% or more of temporal lobe seizures [2]. This occurs because seizure activity spreads to the insular cortex and amygdala, directly stimulating the CAN. CAN dysfunction has also attracted attention as a mechanism underlying sudden unexpected death in epilepsy (SUDEP), with post-ictal suppression of brainstem autonomic nuclei hypothesized to cause cardiopulmonary arrest [2].
Emotional Disorders and Autonomic Imbalance
Meta-analyses have confirmed a significant reduction in heart rate variability in patients with depression, with SDNN reported to be an average of 13-18 ms lower compared to healthy controls [4]. This is interpreted as a result of diminished prefrontal inhibition of the amygdala, leading to weakened top-down regulation by the CAN. Similar CAN dysfunction is observed in anxiety disorders and post-traumatic stress disorder (PTSD), and clinical evidence is accumulating that improvements in autonomic markers parallel improvements in emotional symptoms [4].
Diagnostic Assessment
Functional Magnetic Resonance Imaging (fMRI)
Functional magnetic resonance imaging (fMRI) is a research and diagnostic tool that allows direct observation of activation patterns in CAN component regions [3]. Hemodynamic responses in the insular cortex, anterior cingulate cortex, amygdala, and hypothalamus are measured during autonomic provocation tasks (Valsalva maneuver, cold pressor test, emotional stimulus viewing) to assess CAN functional connectivity. In the meta-analysis by Beissner et al. (2013), fMRI data from 128 studies were synthesized, confirming that the anterior insula and mid-cingulate cortex showed the most consistent activation during autonomic tasks [3].
Heart Rate Variability (HRV) Analysis
Heart rate variability (HRV) analysis is the most practical clinical test for indirectly assessing CAN output status [4]. Time-domain indices (SDNN, RMSSD) and frequency-domain indices (LF, HF, LF/HF ratio) are used to evaluate sympathetic-parasympathetic balance. The HF component (0.15-0.40 Hz) reflects cardiac vagal activity originating from the nucleus ambiguus and is used as a parasympathetic output indicator of the CAN. Low resting HF power suggests weakened top-down inhibition from the prefrontal cortex [4].
Quantitative Electroencephalography (QEEG)
Quantitative electroencephalography (QEEG) quantitatively analyzes scalp-recorded brain waves to assess activity patterns of CAN's higher structures (frontal and temporal lobes). Frontal alpha asymmetry reflects lateralized activation differences between the anterior cingulate cortex and insular cortex, correlating with autonomic regulatory capacity and emotional regulation. Simultaneous measurement of HRV and QEEG provides a more comprehensive assessment of brain-heart axis function.
Therapeutic Approaches
Transcranial Magnetic Stimulation (TMS)
Transcranial magnetic stimulation (TMS) is a non-invasive treatment that modulates CAN function by stimulating the cerebral cortex. Research has reported that applying repetitive TMS (rTMS) to the dorsolateral prefrontal cortex (DLPFC) or medial prefrontal cortex strengthens the prefrontal-amygdala pathway, increasing vagal tone and improving heart rate variability [4]. High-frequency (10-20 Hz) rTMS enhances cortical excitability, strengthening prefrontal top-down inhibition and thereby alleviating sympathetic overactivation.
Transcranial Direct Current Stimulation (tDCS)
Transcranial direct current stimulation (tDCS) modulates cortical excitability by delivering weak direct current (1-2 mA) through the scalp. Placing the anode over the prefrontal cortex increases excitability in that region, strengthening CAN top-down regulation and improving autonomic balance. tDCS has attracted attention as a potential outpatient-based autonomic modulation therapy due to its simple equipment and minimal side effects.
Neurovisceral Integration-Based Approaches
Based on Thayer's neurovisceral integration model, multi-layered therapeutic approaches aimed at restoring CAN function are being explored [4]. HRV biofeedback training is a behavioral intervention that directly strengthens the nucleus ambiguus-vagus nerve pathway, while respiratory training (resonance breathing at 6 breaths per minute) optimizes the baroreflex to enhance CAN closed-loop gain. These non-pharmacological approaches can be combined with pharmacotherapy and brain stimulation for synergistic effects.