Activity in the brain can be decomposed at a high level into two interacting domains: the chemical domain, and the electrical signaling domain. These domains are not separate – electrical signaling is implemented by neurochemical transmission at the synapse – yet we can fruitfully characterize separately the two worlds of neuromodulatory chemical action and of electrical activation. The world of electrical activation constitutes the fast communication system and the “what” of perceptual experience, while the world of chemical action constitutes the “how” of signal transmission and the basic operating of the nervous system. 

The chemical domain has a concentrated center of control in the lateral hypothalamus (LH), as the lateral hypothalamus contains orexinergic neurons. Orexin serves as a master neuromodulator of the major neuromodulators dopamine, serotonin, norepinephrine, and histamine. Orexin thus modulates at a fundamental level arousal and wakefulness, motivation for rewarding stimuli, energy metabolism, stress response, cognitive function, and autonomic function. This gives the lateral hypothalamus wide-ranging control of neuromodulatory state.

The electrical signaling domain has a concentrated center of control in the thalamic reticular nucleus (TRN). The fibers of the TRN innervate the entirety of the thalamus, allowing for inhibition of stimuli throughout the cortico-thalamic system. This is why Francis Crick believed the TRN to be the implementer of the “spotlight of attention” that defines conscious awareness. 

Each of these subcortical command centers is innervated by a region of the prefrontal cortex (PFC): the lateral hypothalamus is innervated by the ventromedial prefrontal cortex (vmPFC), and the thalamic reticular nucleus is innervated by the dorsolateral prefrontal cortex (dlPFC). Key roles of the vmPFC and dlPFC, which are often viewed as cortical command centers, are captured by their innervations of these subcortical command centers. The dlPFC is a command center for attention control and cognitive control, which it likely executes as inhibitory control of thalamic electrical signaling via its innervation of the TRN. This, of course, controls the data that reaches the dlPFC. The vmPFC is a command center for emotion and autonomic regulation, which it likely executes (in part) as control of orexinergic (meta-)modulation of other neuromodulators. These changes in neuromodulatory state change how the vmPFC responds and to what it responds. The subcortical command centers thus exert control over the prefrontal command centers by way of their low-level control mechanisms. Together, these form two parallel command circuits for the electrical and chemical domains.