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The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periacqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells.

The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.