Figure 1. Differentiated Intrinsic Photosensitive Retinal Ganglion Cells (ipRGCs).

Output of the ipRGCs to the olivary pretectal nuclei in the midbrain and the suprachiasmatic nucleus (SCN) in the hypothalamus in 2 pathways. In the first pathway, the blue lines represent those retinal projections that target midbrain circuitry involved in the production of the pupillary light reflexes. In the second pathway, the green path represents the projection from the retina to the SCN in the hypothalamus. On retinal activation, the SCN tonically inhibits the paraventricular nucleus (PVN) of the hypothalamus. Without the SCN-mediated inhibitory inputs to the PVN, the tonic activation pathway would result in the synthesis and release of pineal melatonin. ipRGCs send inputs into the midbrain pretectal nuclei, followed by innervation of the parasympathetic circuits within the Edinger-Westphal complex of the nuclear apparatus of cranial nerve III. From here, long preganglionic pupillary light reflex–mediating fibers travel superficially in the oculomotor nerve in a dorsomedial distribution until innervating the ciliary ganglion. Final projections are then transmitted as the short ciliary nerves to the sphincter muscle of the iris, thereby producing miosis of the pupils. In the second path in healthy participants, the ipRGCs send inputs to the SCN followed by inhibitory projections from the SCN to the PVN; in this way, light suppresses melatonin secretion. This complex circuitry illustrates the effects of light vs dark phases of the wake-sleep cycle transitions, which are coordinated by retinohypothalamic network physiology. Generally, the descending pathway (and then ascending following the exit of the postganglionic fibers from the lateral spinal cord into the superior cervical ganglion) from the PVN to the pineal gland results in the tonic response characteristics that promote melatonin release. However, during sunlight hours and in healthy individuals, the activation of the retinohypothalamic tract results in activation of the SCN, which then acts to inhibit the PVN and the end product of its stimulation pathway: melatonin. Alternately, and following its withdrawal of inhibitory innervation from the SCN, the PVN cell clusters are now disinhibited, and engage this highly discrete and crucially important neuroendocrine axis—the pineal-derived melatonin release apparatus—one that figures prominently in the delicate balance between sleep and waking. In multiple sclerosis (MS), over the span of the disease course, nearly 100% of the patients (if we combine both evident as well as occult mechanisms of tissue injury) will have sustained damage to the retinal architecture with corresponding ramifications on visual system processes, such as light and object formation in the central nervous system, the coordination of the pupillary light reflexes and the important mechanisms where light processed in the retina can influence a constellation of the body’s homeostatic milieu (eg, sleep-wake, neuroendocrine, energy and mood states, thermoregulation, eating and satiety, maintenance of glycemic control, and sexual behavior).