Introduction

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Neurosurgical Perspective

The pineal gland is at a site to which all surgical approaches are treacherous and where mass lesions produce interesting clinical syndromes. It has an extensive histopathology disproportionate to its diminutive size. Until fairly recently, not much was known of the gland's significance, and there seemed to be little reason for neurosurgeons to trouble themselves with attempting to understand its physiology.
Zoologists and comparative anatomists had long postulated a photoreceptor function for the pineal by analogy to phylogenetically lower species. It was not until recent times, with the advent of radioimmunoassays that detect pineal products and staining techniques that define the complex interconnections between the organ and its near and distant neighbors, that the physiology and clinical importance of the pineal were understood.
The emerging picture confirms many of the pineal's postulated functions but also suggests a far broader influence than previously imagined. It seems that the pineal is indeed a photoreceptor organ, synchronizing many of the hormonal and neurobehavioral activities of the organism to circadian variations in environmental light; however, there is far more to pineal physiology. The known and probable influences of the gland continue to become more diverse. Pineal physiology provides insight not just into one small part of the brain, but into its integration with the entire nervous system.

Historical Perspective

So small and remote as to be easily overlooked in a rapid perusal of the cerebrum, the pineal gland has been a source of fascination for philosopher and physician alike since its discovery by HerophiIus in 300 H.C. Galen dubbed the gland konareion (conarium in Latin), meaning "shaped like a pinecone." Descartes believed that the pineal's central location uniquely qualified it to be the "seat of the soul." To those for whom the anatomic situation was too suggestive not to postulate a psychic link, the pineal was the "sphincter of the mind."

Evolution of Techniques to Study the Pineal

Science began to make inroads in pineal physiology with early anatomic studies of animals such as fish and amphibians, which also possess pineal glands but in more superficial locations adjacent or in close proximity to visual structures. The human pineal is buried deep within the brain, far from the surface where it might interact directly with sources of light. Therefore, its photoreceptor function was not appreciated until anatomists could trace pathways from the optic apparatus to the pineal and comparative anatomists determined that the organ monitoring environmental photic information was the same in lower animals and humans. Only then did awareness of the link between this gland and photoperiodic homeostasis begin to emerge.
The efferent arm of pineal function was elucidated later, more than 50 years ago, with the isolation and demonstration of melatonin, "the pineal factor that lightens melanocytes." The essential link between melatonin action and photoperiodicity was described shortly thereafter.

For 4 decades, isolation and assay techniques for a long list of biosynthetic precursors, intermediaries, neurotransmitters and peptide hormones have overwhelmed an entire scientific journal devoted to pineal research. Although the volume of data renders impossible, for the moment, the assemblage of a comprehensive summary of pineal physiology. it clearly establishes the gland's central role in coordinating vertebrate physiology.

The pineal is studied at the chemical level by analysis of its products and of interactions between these and others isolated from organs throughout the body. Individual pineal cells from a variety of species are subjected to chemical and physical manipulations. The isolated pineals of subhuman species have been examined and purified homogenates used in a variety of culture and tissue experiments. In vivo experiments are most frequently done in rats and lower animals but also in primates. Human in vivo studies are becoming increasingly feasible with improved techniques for chemical analysis and imaging of the nervous system.

Much of what is known about pineal physiology is learned from manipulations of exposure of an organism to light - the major influence on pineal physiology. Comparison of physiologic parameters before and after pinealectomy provides clues to the organ's function.

For a variety of reasons, frequently ethical ones, relatively few studies of pineal physiology have been done on human beings. Much of the available information about how the pineal operates and what its functions are is derived from animal studies, cell cultures, and tissue preparations. The precise significance of many experimental findings for humans is nebulous. Many of the functions ascribed to the human pineal are based on extrapolations from in vitro and nonhuman data.

Phylogenetic Clues to Pineal Function

Comparisons among species provide important clues to the pineal's role in humans. Phylogenetically, the gland has been primarily a photoreceptor organ. Throughout vertebrate species it is closely related to the optic apparatus. Some species have cortical and medullary portions of the pineal: the significance of this is unknown.

Pineal volume does appear to correlate with variations in hormonal activity. Species with larger pineals (relative to total organism size) tend to be homoeothermic (vs. heterothermic) and to have diurnal physiologic cycles (vs. nocturnal). Tropical animals tend to have smaller pineals than those adapted to living in temperate climates, where seasonal variations in temperature and daily duration of sunlight make reproductive timing more critical.

The pineal is present in all vertebrates. In lower species its location is often more superficial and its association with photoreceptor function is more obvious. Through evolution. the pineal changed from a photoreceptor organ to one associated with an organism's interactions with the light-dark cycle.

Analogies between mammalian and amphibian photoreceptors (anatomic, chemical or functional) are not identities. Interesting and exciting theories about human pineal function are frequently extrapolated from animal research or even from in vitro tissue or cell culture preparations. Cautious appraisal of pineal data from nonhuman studies is warranted to avoid over- or underestimation of the gland's importance in humans.

The pineal arises as an evagination of the neuroepithelial roof of the third ventricle, between the habenula and the posterior commissure in the second month of gestation. Neuroepithelial cells become pinealocytes, whereas mesenchymal cells become the connective tissue strands, fibroblasts and vessels of the gland. The pineal develops from two lobes that fuse. The gland's orientation changes from vertical to horizontal. Innervation of the gland is completed in the prenatal period.

At birth there are two types of pinealocyte which are distinguishable to approximation 3 years of age. Type I pinealocytes are S-100-positive and neuron-specific enolase-negative; type II pinealocytes are enolase-positive. S-100-negative, and melatonin negative. At birth. type I cells predominate. but by 1 year of age, they are outnumbered by type II cells.

Secretory activity, specifically of the primary pineal product melatonin, varies throughout the course of development. Serum melatonin levels increase from the third postnatal month to preschool age. They then decline steadily from preschool age until sexual maturity. This pattern raises the interesting possibility that, contrary to previous beliefs, the gland's effects on development are not necessarily related to sexual maturation. The pineal reaches its adult size by age 4 years and undergoes no significant histologic changes from childhood to adulthood.

Regional Gross Anatomy

The anatomic location of the pineal with respect to nearby neural and vascular structures accounts for the difficulty in surgical access as well as for the neurological symptoms that may accompany mass lesions arising in the gland. From the physiologic perspective, the pineal is well situated to serve as the hub of a system of input, mri and regulation among numerous diverse brain regions.

Also called the epithalamus, the pineal is located in the posterior most portion of the epithelial roof of the third ventricle. The posterior commissure is found posteroinferiorly. Anteriorly the gland is in continuity with the habenular trigone and the striae medullaris thalami. The posterior portion of the corpus callosum, the splenium overlies the pineal.

Although the gland is suspended in the pineal recess, a CSFfilled cistern contiguous with the quadrigeminal cistern, the gland itself is not bathed in spinal fluid but rather is surrounded by a pial layer. Because the organ is solid, the substances it produces are probably not primarily released directly into the third ventricle but rather into the vascular system.

Major vascular structures lying in proximity to the pineal or passing by it are the medial posterior choroidal arteries (the major feeders to the gland) and numerous perforators. Ample venous outflow seems to facilitate the distribution of synthesized substances. Drainage is into the vein of Galen via the internal cerebral veins: the veins of Rosenthal are situated just lateral and superior to the pineal. Behind the gland is the precentral vein of the cerebellum.

Microscopic Anatomy

Microscopically the pineal appears as clusters of parenchymal cells enclosed by bands of connective tissue of variable thickness that consist of fibrous astrocytes and other cell types. The pineal is surrounded by a capsule and is composed of lobules with separating connective tissue septae. Astrocytes are shown to be abundant by glial fibrillary acidic protein (GFAP) staining and form a barrier between vessels and pinealocytes.

There are many different cell types in the gland. In addition to supporting, neuronal, and endothelial cells, the stroma is made up of pinealocytes, which themselves may be subdivided by histologic and electron microscopic, and increasingly by biochemical and functional, criteria.

Pinealocytes make up 90 percent of the parenchyma of the gland. In sub mammalian species, they are derived from photoreceptor cells. In vertebrates there are thought to be two types of pineal cells, light and dark, so named on the basis of their responsiveness or unresponsiveness to light input at the retina, The existence of these two types in humans remains controversial.

Parenchymal pineal cells are thought to belong to the system of amine precursor uptake and decarboxylation (APUD) cells. They stain positively for neuron-specific enolase.

Pinealocytes are characterized by their prominent nuclei and nucleoli. Each pinealocyte has several cytoplasmic processes, which terminate in club-shaped endings on perivascular spaces and which may provide a means for communication between pinealocytes.

Because it produces substances chemically related to neurotransmitters, contains synaptic vesicles, secretes its products in response to stimulation of receptors on its cell membrane and originates in the ectoderm, the pinealocyte can be considered a "paraneuronal" cell. Kappers considers the pineal "a true endocrine organ" because pinealocytes, although derived from neuroectoderm, are not neurons.

In lower animals, pinealocytes morphologically resemble retinal photoreceptor cells. Some of the pinealocytes in these species have processes that resemble axons and many of them immuno-stain positively for gamma-aminobutyric acid (GABA).

Glial cells, primarily fibrous astrocytes, appear to serve both supportive and metabolic roles in the pineal, as they do in all central nervous system tissue. Staining with S-100 suggests that microglial cells are also present.

The endothelial cells that make up the vascular supply to the pineal do not have the tight junctions characteristic of the bloodbrain barrier: the pineal is thus rightly considered to be a circumventricular organ. Although parasympathetic, commissural. and peptidergic fibers have been demonstrated in the pineal. the only fibers with known physiologic significance in the gland are general visceral afferent sympathetics originating in the superior cervical ganglion and reaching the pineal via the nervi conarii. These postganglionic sympathetic fibers receive descending input from hypothalamic nuclei, particularly the suprachiasmatic nucleus (SCN), which receives direct input from retinal ganglion cells. Unmyelinated fibers travel through connective tissue in discrete bundles. In some animals all the sympathetic input reaches the pineal as unmyelinated fibers traveling with venules and arterioles, which vascularize the gland. There is also questionable parasympathetic innervation, possibly arriving via the habenula and posterior commissure. Neurotransmitters reach pineal cells not across a synaptic cleft but by diffusion after release from varicosities some distance away. Other cell and tissue types found in the pineal include fibrous connective tissue, skeletal muscle and lymphocytes.

Acervuli, corpora arenacea, or pineal calcifications, the familiar and important pineal landmarks seen on skull roentgenography and computed tomography (CT) of the head are still incompletely understood. Calcium accumulates along plasmalemma and intracellularly in pinealocytes. This may be the basis of calcium deposition, which occurs in an organic matrix produced by pinealocytes. The calcareous concretions grow along growth zones and are composed of calcium, magnesium and ammonium ions as well as calcium carbonate. The growth process is thought to be age- and sex-independent and is probably related to the gland's secretory activity.

Although the etiology of these concretions is not known, two theories have been proposed. In the first a carrier protein is thought to be released into intracellular vacuoles. In the second there is decreased drainage of tissue fluid from the gland. Acervuli are seen in 3 percent of pineals by age 1 year, in 7.1 percent by age 10, and in 33 percent by age 18.

The functional significance of pineal calcifications is unknown. Recent CT studies of pineal calcifications have attempted to correlate their presence with diseases such as schizophrenia.

Another incompletely understood phenomenon is the formation of benign pineal cysts. These mass lesions, which can reach proportions sufficient to result in clinical symptoms and signs, are thought to result either from degeneration of foci of gliosis within the gland or from sequestration of CSF during pineal development. Why this happens remains unknown. In a recent radiologic review, Golzarian et al. reported a 2,4 percent incidence in 500 consecutive magnetic resonance imaging studies. Pineal cysts can be found in 25 to -40 percent of subjects studied at autopsy.