Central Autonomic Network

Central autonomic network    A set of interconnected structures within the central nervous system responsible for generating appropriate changes in sympathetic and parasympathetic outflow. Experiments on animals have shown that the primary output nuclei reside in the medulla. o Relatively little is known about the roles of areas above the brainstem. Early studies in humans examined the effects of lesions or direct electrical stimulation. o Looking at lesions is not effective because it attempted to attribute function to a specific location without considering the operation of a network. o Interpretation of the effects of direct electrical stimulation of the cortex need to be taken with caution, as stimulation of the same site can produce positive (excitation) as well as negative (inhibition) behavioural responses. Functional MRI (fMRI)  Allows one to see the operation of the individual components of the network, rather than examining what happens when a certain component is lesioned or stimulated.  Have been used to investigate the operation of the central autonomic network during manoeuvres known to cause increases in muscle sympathetic nerve activity (MSNA). Key components  Certain areas of the brain are consistently activated during manoeuvres that increase MSNA or HR.  Insular cortex. o Inside the lateral sulcus. o Strongly implicated in cardiovascular control. o Patients with strokes limited to the insula have greater cardiovascular dysregulation. o Electrical stimulation of the right insular cortex in human subjects has been shown to increase BP. Opposite occurs stimulating the left insular cortex.  Anterior cingulate cortex. o The gyrus right over the corpus callosum. o Patients with lesions (rare) do not generate cardiovascular arousals (e.g. increased HR during stress) during cognitive tests. o Electrical stimulation in human subjects has been shown to increase BP. o Chronically depressed patients exhibit low activity within the perigenual division of the anterior cingulate cortex (periACC). Electrical stimulation in this region has shown to alleviate the depression.  Others: o Hypothalamus. o Medulla. o Prefrontal cortex. o Hippocampus. o Cerebellum. Control of sympathetic outflow to muscle  Recording MSNA at the same time as performing fMRI of the brain allows identification of areas of the central autonomic network involved in the generation of spontaneous bursts of MSNA.  Methodology. o MSNA amplitude was measured every 1s during the 4s interscan period. o BOLD fMRI signal intensity was measured 4s later during the 4s scanning period to account for neurovascular and conduction delays.  Different nuclei have shown to play a role in spontaneous MSNA: o Excitatory: RVLM. o Inhibitory: CVLM and NTS. Relationship between RVLM, CVLM and NTS  When bursts of muscle sympathetic nerve activity occurred, there were decreases in NTS and CVLM, and increases in RVLM activity. o Activity in RVLM was high when MSNA was high, and low when MSNA was low. o Activity in CVLM was high when MSNA was low, and low when MSNA was high. o This functionally defined reciprocal relationship fits with the known inhibitory connections between CVLM and RVLM.  RVLM is the primary output nucleus of muscle, splanchnic and renal vasoconstrictor drive, and also provides sympathetic drive to the heart and adrenal glands. o Bursts of muscle sympathetic nerve activity occur when BP is low and baroreceptor input to NTS is low, leading to a reduction in CVLM activity. o Low activity in CVLM means that there is less inhibition of RVLM and hence bursts of muscle sympathetic nerve activity are allowed to occur through withdrawal of this negative feedback.  The RVLM receives inputs not just from the CVLM (inhibitory), but from many sources, including direct excitatory inputs from NTS. o Metaboreceptors (group III and IV afferents in muscles) project to NTS, which sends direct excitatory projections to RVLM. o Peripheral chemoreceptors in the carotid body and aortic arch also project (via glossopharyngeal and vagus nerves) to NTS, which sends direct excitatory projections to RVLM. o So, while RVLM is inhibited by GABAergic inputs from CVLM, it is excited by direct glutamatergic projections from NTS; the interneurone in CVLM changes the sign of excitatory input from NTS into an inhibitory input to RVLM, changing the sign of the output from RVLM. o In addition to the NTS, the hypothalamus and periaqueductal grey matter contribute to the activity of the RVLM. Midbrain periaqueductal grey matter (PAG)  The PAG is important in setting the autonomic responses to superficial or deep pain. o Superficial: evokes escape behaviour, including increases in HR and BP, mediated by lateral columns of the midbrain PAG. o Deep: evokes a passive, coping strategy, including decreases in HR and BP, mediated by ventrolateral columns of the midbrain PAG.  There is a direct projection from the ventrolateral columns of the midbrain PAG to the RVLM. Cortical areas  Contribute to resting levels of muscle sympathetic nerve activity.  Spontaneous MSNA was found in several cortical and subcortical areas. Cerebellum  There is a positive relationship between MSNA burst amplitude and signal intensity in the deep cerebellar nuclei, including the fastigial nuclei.  Electrical stimulation to the deep cerebellar nuclei have demonstrated cardiovascular and respiratory control, as it elicits an increase in BP.  It is thought that the fastigial nucleus exerts its action on sympathetic vasoconstrictor drive via projections to the brainstem.  Increases in BP inhibit the fastigial nucleus, presumably via baroreceptors. Dorsomedial hypothalamus  Part of the classical hypothalamic defence area.  Produces defensive behaviours and increases in arterial pressure, HR and skeletal muscle blood flow.  May represent a higher order hypothalamic centre, responsible for integrating autonomic, endocrine and even behavioural responses to emotional stress. Ventromedial hypothalamus  Does not appear to project directly to the spinal cord, but projects to many forebrain and brainstem sites known to regulate MSNA (e.g. DMH, midbrain periaqueductal grey, parabrachial nucleus, NTS).   Strong relationship between VMH and MSNA, suggesting a regulatory role for VMH in setting resting MSNA in normotensive individuals. VMH is also associated with appetite control, and so may contribute to the increased MSNA seen in obesity-related hypertension. Precuneus  Posteromedial portion of the parietal lobe.  Has extensive connections to the prefrontal cortex.  Recognised as a key region that connects strongly with other nodes of the default (idling) mode network; its activity is positively related to level of consciousness.  Precuneus may provide a “wakefulness drive” to resting muscle vasoconstrictor drive. o Supported by observation that activity in precuneus declines during deep sleep, when MSNA and BP also decline.  Some of the underlying activity within the default mode network may represent ongoing physiological activity related to the control of BP. Anatomical relationships  Resting MSNA is related to grey matter volume in certain areas, such as RVLM, anterior insula and precuneus.  Thus, there is a possibility that an individual’s regional brain structure may be a gross indicator of the functioning of homeostatic mechanisms such as those that control resting MSNA.  If this is true, then if the anatomy of such region is affected by factors such as repeated hypoxic events or increased body weight, they may generate increased MSNA, leading to hypertension. Central command  The “will” to exercise engages motor planning and motor execution areas of the cerebral cortex and cerebellum.  The set of motor commands to the skeletal muscles is transmitted from the primary motor cortex to the spinal motoneurones via the corticospinal tracts.  A parallel route, a corollary discharge, also engages autonomic areas in the brainstem. This may involve the insular cortex. o Autonomic activation results in increases in HR, BP and RR.  Mental imagery, without actual muscle activation, can also bring about cardiovascular adjustments. o The cardiovascular changes associated with motor command can be observed in experimental paralysis. o No muscles are activated but increases in HR and BP still occur. o The greater the effort (motor effort) the greater the responses. Control of sympathetic outflow to skin     Skin sympathetic nerve activity (SSNA), along with fMRI of the brain, maps areas of the central autonomic network responsible for the generation of spontaneous SSNA. Spontaneous SSNA were simply a consequence of personal internal thought processes which were not influenced by any external stimuli o Attentional consciousness: introspective thoughts. o Non-attentional consciousness: day-dreaming. Spontaneous fluctuations of SSNA were coupled to the: o Left ventroposterior thalamus. o Left posterior and right anterior insula. o Right orbitofrontal cortex. o Right frontal cortex. o Bilaterally, in the mid-cingulate cortex and precuneus. It has been hypothesised that these brain regions also monitor the internal state of the body and may regulate emotional changes. o Internal state is monitored via ascending, small diameter fibre projections that synapse within the ventroposterior thalamic nucleus (VMpo)  posterior insula  anterior insula  cingulate and prefrontal cortices (higher order). Emotionally-evoked autonomic responses  Sympathetic innervation of the skin primarily subserves thermoregulation, but has also shown to be as a means of emotional expression.  Emotional arousal increases SSNA, causing sweat release, cutaneous vasoconstriction and piloerection.  Using the same approach as above (SSNA + fMRI) allows the examination of how the brain generates autonomic responses associated with emotional processing. o Performed by showing subjects neutral and emotionallycharged images.  Activity is increased in multiple areas of the brain, irrespective of the event being stimulated by positively (e.g. porn) or negatively (e.g. mutilation) charged images.  Areas of the brain that had significant increases in total SSNA include: o Orbital, dorsolateral and ventromedial prefrontal cortices. o Amygdala. o Nucleus accumbens. o Anterior insula.    The orbitofrontal and medial prefrontal cortices may be responsible for the subjective experience of viewing emotionally charged images. The amygdala on the other hand, through projections to the dorsolateral pons, may mediate the associated increases in SSNA. Psychopaths do not show autonomic arousal responses to fearful faces and showed activation only of the right amygdala. Conclusions: control of sympathetic outflow to muscle  Relationship between RVLM, CVLM and NTS. o MSNA is generated in RVLM. o Bursts of muscle sympathetic nerve activity occur when BP is low and baroreceptor input to NTS is low, leading to a reduction in activity of CVLM. o Low activity in CVLM means that there is less inhibition of RVLM, and hence bursts of muscle sympathetic nerve activity are allowed to occur through withdrawal of this negative feedback. o Reverse occurs when BP is increased; RVLM is inhibited and MSNA is reduced.  NTS also receives other excitatory inputs. o From arterial chemoreceptors, various afferents in the viscera and metaboreceptos in skeletal muscle. o Excitatory projections from NTS synapse directly in RVLM, such that chemoreceptors and metaborepeptor inputs cause excitatory responses in RVLM (baroreceptors cause inhibition via the intervening inhibitory interneurone in CVLM).  The PAG also has projections to the RVLM. o There is a direct projection from the ventrolateral columns of the PAG to RVLM; o PAG is important in setting the autonomic responses to superficial or deep pain.  Different cortical areas have been shown to contribute to MSNA. o The insular cortex is strongly implicated in cardiovascular control and contains barosensitive neurones; patients with strokes limited to the insula have greater cardiovascular dysregulation. o Electrical stimulation of the anterior cingulate cortex has been shown to increase BP; patients with lesions involving the anterior cingulate cortex do not generate cardiovascular arousals during cognitive tests. o Mental imagery can cause increases in HR and BP in the absence of muscular contraction (and activation of metaboreceptors), indicating that premotor cortical areas can access autonomic circuitry.  There is functional connectivity between several cortical and subcortical sites and the RVLM and primary output nucleus for MSNA. o This suggests that activity within suprabulbar areas (e.g. insula, dorsolateral prefrontal cortex, precuneus and hypothalamus) may regulate resting MSNA via projections to the RVLM. o A relationship between grey matter volume in these regions and resting MSNA suggests that structural changes in the brain associated with pathophysiology would be expected to influence sympathetic outflow. Conclusions: control of sympathetic outflow to skin  Spontaneous fluctuations in SSNA are coupled to the left, the left posterior and right anterior insula, the right orbitofrontal cortex, right frontal cortex, and bilaterally in the mid-cingulate cortex and precuneus.  Functional connectivity analysis revealed a strong positive coupling between the right orbitofrontal cortex and the right anterior insula, and between the precuneus and the left anterior and posterior insula, cerebellum, cingulate cortex and thalamus.  When viewing emotionally-charged images, amygdala projections to the dorsolateral pons may mediate the associated increases in S.  Emotional stimuli or cognitive processes can engage autonomic circuitry, causing increases in HR and sympathetic outflow to the skin.  Both emotional and autonomic responses are blunted in people who do not exhibit empathy.