Definition and Overview
The central autonomic network (CAN) is a set of interconnected neural structures distributed in the cerebral cortex, limbic system, hypothalamus, and brainstem. It is a regulatory system within the brain that maintains body homeostasis by regulating autonomic output and integrating visceral sensory information. In 1993, the concept of CAN was established when Benarroch, a neurologist at the Mayo Clinic in the United States, systematized brain regions related to the autonomic nervous system, which had been studied scattered, into one functional network.
Traditionally, the autonomic nervous system has been understood to be centered around the peripheral structures, the sympathetic and parasympathetic ganglia. However, with the introduction of the CAN model, it became clear that autonomic nervous control is not a simple peripheral reflex but a hierarchical processing process at multiple levels of the brain. CAN integrates sensory information (interoception) coming from the internal organs and adjusts the output ratio of the sympathetic and parasympathetic nerves in real time according to environmental changes and emotional states.
In the activation likelihood estimation meta-analysis published by Beissner et al. in 2013, the core components of CAN were empirically identified by synthesizing 128 functional neuroimaging studies. According to this analysis, the pre-insula, anterior cingulate cortex, and amygdala are the regions most consistently activated in autonomic tasks.
construction structure
CAN consists of several neural structures arranged hierarchically from the cerebral cortex level to the brainstem level.
insula
The insular cortex is a key hub of CAN and is the primary cortical receptive area for viscerosensory information. Sensory information coming from all internal organs, such as the heart, stomach, lungs, and bladder, passes through the posterior medial ventral nucleus (VMpo) of the thalamus, reaches the posterior insula, and is sequentially processed anteriorly. The entire insula is responsible for conscious awareness of interoception and forms subjective feelings about the state of one's body.
Oppenheimer et al. (1992) induced changes in heart rate and blood pressure by directly stimulating the insula during epilepsy surgery. Bradycardia and a decrease in blood pressure were observed when stimulating the left insula, and tachycardia and an increase in blood pressure were observed when stimulating the right insula, confirming the left-right asymmetric cardiovascular regulatory function of the insula. This discovery provided a clue to understanding the mechanism by which cardiac complications occur after insular stroke.
anterior cingulate cortex
The anterior cingulate cortex (ACC), along with the insula, is a cortical-level hub for autonomic nervous system control. It serves to connect cognitive evaluation and emotional arousal information to autonomic output. The pregenual area of the ACC shows a positive correlation with parasympathetic nerve activity, and the subgenual area shows a positive correlation with sympathetic nerve activity.
amygdala
The amygdala is a central structure in the processing of threat-related emotions such as fear and anxiety, and mediates autonomic responses to emotional stimuli. It projects directly from the central nucleus of the amygdala to the hypothalamus and brainstem, causing defensive responses such as sympathetic nerve activation, increased heart rate, increased blood pressure, and increased respiratory rate. In patients with anxiety disorders, hyperactivation of the amygdala is directly related to chronic sympathetic hyperactivity.
hypothalamus
The hypothalamus is the integrative center of CAN, which synthesizes information from the upper cerebral cortex and limbic system and transmits it to the lower brainstem autonomic nuclei. The paraventricular nucleus (PVN) is a key structure in autonomic regulation within the hypothalamus and simultaneously regulates sympathetic nerve activation and stress hormone (cortisol) secretion. The lateral hypothalamus controls arousal and energy metabolism, and the anterior hypothalamus (preoptic area) controls body temperature regulation and the sleep-wake cycle.
brainstem autonomic nucleus
The final common pathway for autonomic output is located in the brainstem.
- Nucleus tractus solitarius (NTS): This is the site where visceral afferent fibers first synapse and is the primary relay station for all visceral sensory information. It is the starting point for key autonomic reflexes, such as baroreceptor reflexes and chemoreceptor reflexes.
- Dorsal motor nucleus of vagus (DMNV): The main nucleus of origin of parasympathetic output, which transmits parasympathetic signals to the gastrointestinal tract, heart, etc.
- Nucleus ambiguus (NA): The nucleus of origin of the cardiac vagus nerve, which produces respiratory sinus arrhythmia and is directly reflected in the high-frequency component (HF-HRV) of heart rate variability.
- Ventrolateral medulla (VLM): Located in the vasomotor center that maintains sympathetic tone, it is the final effective pathway for blood pressure regulation.
function
Visceral sensory integration
CAN's primary function is to collect and integrate sensory information from internal organs. Sensory signals originating from baroreceptors in the heart, chemoreceptors in the aortic arch and carotid sinus, mechanoreceptors in the gastrointestinal tract, and stretch receptors in the lungs reach the nucleus tractus solitarius via the vagus nerve and glossopharyngeal nerve. This information is transmitted to the insula and anterior cingulate cortex via the posterior medial ventral nucleus and parabasal nucleus of the thalamus, forming conscious interoception.
In healthy adults, interoceptive accuracy is reported to be about 65-70% on average in heart rate detection tasks, and the higher this figure, the better the heart rate variability and emotion control ability.
Autonomic output control
CAN maintains homeostasis of cardiovascular, respiratory, digestive, and body temperature conditions by adjusting the output ratio of the sympathetic and parasympathetic nerves in real time. Higher structures (prefrontal cortex, anterior cingulate cortex) exert tonic inhibition on lower structures (hypothalamus, brainstem nuclei), and when this inhibition is properly maintained, flexible fluctuations in autonomic output are possible. Thayer and Lane According to the neurovisceral integration model proposed by (2009), the more functionally the prefrontal cortex inhibits the amygdala pathway, the higher the vagal tone, which is manifested as an increase in heart rate variability.
If SDNN, a time-domain indicator of heart rate variability at rest, is 100 ms or more, autonomic control ability is evaluated as good, and if it falls below 50 ms, the risk of cardiovascular events significantly increases.
Emotional-autonomic connection
Emotional experiences are inherently accompanied by autonomic responses. The reason why the heart beats faster in a fearful situation and breathing becomes slower when relieved is because the amygdala and anterior cingulate cortex directly control the autonomic nuclei of the brainstem. The CAN model emphasizes that this emotional-autonomic connection is bidirectional. There is not only a pathway from the brain to the gut (downward), but also a pathway through which visceral states affect emotional processing in the brain (upward), and this is seen as the neurological basis of embodied cognition.
If amygdala-insula connectivity is excessively increased in anxiety disorder patients, even normal visceral sensations may be interpreted as threat signals, leading to panic attacks. Conversely, when the prefrontal-amygdala connection is strengthened, autonomic reactivity is stabilized.
Clinical significance
Autonomic dysfunction after stroke
Stroke in the insula region results in rapid disturbance of cardiac autonomic regulation. In a study by Oppenheimer et al., electrocardiogram abnormalities (QT prolongation, ST changes, arrhythmia) were observed in the acute phase in approximately 25-30% of patients with insular infarction. Right insular infarction is associated with sympathetic hyperactivation, increasing the risk of ventricular tachycardia or sudden cardiac death, while left insular infarction can cause parasympathetic hyperactivation and bradycardia.
Strokes accompanied by hypothalamic or brainstem lesions result in more extensive autonomic disorders, including impaired temperature regulation, orthostatic hypotension, and sweating abnormalities. These autonomic complications are reported to be independent risk factors that worsen stroke prognosis.
Epilepsy and autonomic nervous system
Heart rate changes during epileptic seizures are a very common phenomenon, and ictal tachycardia is observed in 80% of temporal lobe seizures. This is because seizure activity spreads to the insula and amygdala and directly stimulates CAN. CAN abnormalities are also receiving attention as a mechanism for sudden unexpected death in epilepsy (SUDEP), and it is presumed that inhibition of brainstem autonomic nuclei after seizures causes cardiopulmonary arrest.
Emotional disorders and autonomic imbalance
A significant decrease in heart rate variability in patients with depression was confirmed through meta-analysis, and SDNN was reported to be 13 to 18 ms lower on average compared to healthy controls. This is interpreted as a result of a decrease in the amygdala inhibitory function of the prefrontal cortex, weakening the down-regulation of CAN. Similar CAN dysfunction is observed in anxiety disorders and post-traumatic stress disorder (PTSD), and clinical evidence is accumulating that improvement in autonomic indicators goes hand in hand with improvement in emotional symptoms.
inspection
Functional magnetic resonance imaging (fMRI)
Functional magnetic resonance imaging (fMRI) is a research and diagnostic tool that can directly observe activation patterns in CAN component regions. Functional connectivity of the CAN is assessed by measuring the hemodynamic responses of the insula, anterior cingulate cortex, amygdala, and hypothalamus during performance of autonomic tasks (Valsalva maneuver, cold pressure test, viewing emotion-evoking video, etc.). Beissner et al. (2013)'s meta-analysis synthesized fMRI data from 128 studies and confirmed that the anterior insula and central cingulate cortex showed the most consistent activation during autonomic tasks.
Heart rate variability (HRV) analysis
Heart rate variability (HRV) analysis is the most practical clinical test to indirectly evaluate CAN output status. Sympathetic-parasympathetic balance is evaluated through time domain indicators (SDNN, RMSSD) and frequency domain indicators (LF, HF, LF/HF ratio). The HF (0.15-0.40 Hz) component reflects cardiac vagal activity originating in the nucleus ambiguus and is used as an indicator of parasympathetic output of CAN. Low resting HF power suggests weakened prefrontal descending inhibition.
Quantitative electroencephalography (QEEG)
Quantitative electroencephalography (QEEG) evaluates the activity patterns of CAN higher structures (frontal lobe, temporal lobe) by quantitatively analyzing brain waves recorded from the scalp. Frontal alpha asymmetry reflects differences in left and right activity of the anterior cingulate cortex and insula and is correlated with autonomic nervous system control and emotional regulation. By simultaneously measuring HRV and QEEG, the functional status of the brain-heart axis can be identified in a more three-dimensional manner.
therapeutic approach
Transcranial Magnetic Stimulation (TMS)
Transcranial magnetic stimulation (TMS) is a treatment that modulates CAN function by non-invasively 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, increases vagal tone and improves heart rate variability. High-frequency (10-20Hz) rTMS increases cortical excitability and strengthens downward inhibition of the prefrontal cortex, which can alleviate sympathetic nerve hyperactivity.
Transcranial Direct Current Stimulation (tDCS)
Transcranial direct current stimulation (tDCS) is a method of controlling cortical excitability by delivering a weak direct current (1 to 2 mA) through the scalp. When an anode is placed in the prefrontal cortex, the excitability of the area increases and down-regulation of CAN is strengthened, thereby improving the balance of the autonomic nervous system. tDCS is attracting attention for its potential as an outpatient-based autonomic nerve control treatment due to its simple equipment and low side effects.
Neurovisceral integration-based approach
Based on Thayer's neurovisceral integration model, a multi-layered treatment approach aimed at restoring CAN function is being attempted. HRV training through biofeedback is a behavioral intervention that directly strengthens the tone of the nucleus ambiguus-vagal pathway, and respiratory control training (6 resonant breaths per minute) optimizes baroreceptor reflexes to increase closed-circuit gain in CAN. This non-pharmacological approach can be expected to have a synergistic effect when combined with drug treatment and brain stimulation treatment.