Back in medical school, my first opportunity to hold a brain proved to be markedly disappointing. Shortly after removal from autopsy, the brain is markedly slippery and gelatinous in consistency. It is somewhat uncanny to realize that the cradle of our personality, dreams and desires isn’t made of a robust substance. Years later, within a Medical Examiner’s setting, I found that brains that had been exposed to prolonged lack of oxygen used to slip past my fingers. If I needed to handle any of them, I would first microwave them. I hoped that cooking them this way would coagulate any remaining proteins, much like turning the runny chicken egg yolk into a solid. Once at the dissection table, cuts of the brain reveal it is not a solid, but has fluid filled cavities. These cavities, called ventricles, provide an aqueduct system for fluid to fill and then surround the brain. The liquid in the ventricles is very much like plasma with the exception that its protein content is very low. This clear liquid is derived from blood in tufts of capillaries that protrude from the ventricles and from there go on to bath the entire central nervous system.
Figure: Lateral view of the brain.
Plasma is used in culture media as it provides many of the nutrients required to support cell life, to promote cell proliferation, and to transform the immature cellular elements into their mature state. It seems logical to consider that surrounding this bag of plasma, or ventricles, we have the rapidly dividing cells from which most of the brain is derived. This follows the principle of economy within the brain where things that are supposed to work together are usually found apposing each other.
In the brain, the fluid in the ventricles helps sustain the rapid division of surrounding cells. In effect, early in gestation the tissue surrounding the ventricles is probably the most active proliferating zone of the whole body. This requirement for energy makes the periventricular tissue quite vulnerable to a variety of insults that ultimately may express themselves as mental disorders.
This rapid zone of diving cells surrounding the ventricles is sometimes called the periventricular germinal zone or matrix. This name is misplaced as germ cells are traditionally thought to give rise to gametes (in females an egg or in males a sperm). Under the microscope, examining tissue stained with hematoxylin and eosin, the periventricular matrix looks like a sea of blue cells. Hematoxylin is a blue dark blue or violet stain used to stain substances like DNA or RNA which are acidic. The blue staining of the perventricular matrix is a result of the large concentration of nuclei in this region. At higher magnification, these cells are small and have little cytoplasm to characterize them. The nuclei provide an idea as to how to gage the activity of a cell while the cytoplasm allows us to characterize its specialization. The microscopic picture of the periventricular zone is one of highly active but poorly differentiated cells suggesting that their main role is cell division. The tissue bears resemblance to some types of aggressive small cell tumors. However, contrary to a tumor, the cells of the periventricular matrix are fairly consistent in shape and size, don’t bear abnormal divisions, and there is no hemorrhage nor areas of dead tissue.
Periventricular germinal cells stack up in columns 5-12 cells deep depending on gestational age. The tissue is highly vascular, populated by small thin vessels that facilitate the transfer of oxygen and nutrients from the blood to cells in the brain. A cursory examination of the periventricular matrix readily suggests its fragility. The lack of supporting connective tissue, the plethora of thin walled vessels, and the high energy requirements establishes a dangerous environment in the periventricular matrix precariously positioning the same between health and disease.
In prematurity, usually babies less than 30 weeks gestation or under 1,500 gms, vessels in the germinal matrix may break open producing hemorrhages. These hemorrhages may be confined to the periventricular zone or dissect their way into the ventricles. The attendant hemorrhage may put pressure on brain tissue causing, in some cases, severe damage. These babies are at a higher risk for developing autism. The introduction of technological advancements (e.g., mechanical ventilation, exogenous surfactant) has increased survival rates, making prematurity an important cause for autism and related comorbidities.
Figure: Germinal matrix hemmorhage.
In other areas of the body connective tissue is abundant and lends support to organs, giving them their shape, helping protect, insulate and even store energy. This fibrous connective tissue is absent within the brain and only seen at its periphery in a protective cover called meninges. Fibrous connective tissue makes its appearance in the brain with penetrating injuries and some abscesses. The lack of connective tissue (e.g. fatty or adipose) makes it difficult for the brain to store energy nutrients. In the brain, connective tissue is replaced by supportive cells called glia. These cells support and insulate neurons from each other, help in the exchange of nutrients, and sometimes provide networks for signal processing.
Vessels in the brain tend to have important differences from those in other parts of the body. Veins, for example, lack valves, are thinner and have no muscle tissue in their wall. Valves tend to control the flow of blood in one direction only. In the legs, valves keep the flow of blood moving towards the heart. In varicose vein, the valves do not close properly as the vessel is distended. The end result is that blood backs up, distends the vessel and compounds the circulation problem in a vicious circle. The blood in the varicose thus tends to stagnate and, in some cases, reverse its normal pattern of blood flow. The lack of valves in veins of the brain means that blood can flow backwards and increase intracranial pressure. I remember in doing my lumbar punctures on patients that often we were asked to probe the patency of this system. With a needle in the lumbar cistern and attached to a manometer you could observe small variations in the pressure of the cerebrospinal fluid with respiration. A slight compression of the neck collapsing the jugular vein, leads to a larger increase in cerebrospinal fluid pressure (Queckenstedt’s maneuver). The latter test is sometimes used when examining for blockage of the fluid as it circulates through the nervous system. I remember examining many brains where I could presume the cause of death just by looking at the venous engorgement in the tissue covering the brain. A person whose preagonal state included cardiac failure would have blood stasis and backup pressure leading to the brain. In these cases, blood is not efficiently moved out of the heart and creates pressure retrogradely. Venous vessels in the brain were distended, including some of its smaller branches, and exhibited splotchy hemorrhages.
It is interesting to note that regardless of the many changes that give clues to pathology in the brain, none of them seem to be present in the brains of autistic individuals. Structural changes, when present, are prone to be seen in secondary autism and usually imply both a more severe end of the spectrum and the probable presence of comorbidities. This suggests that changes in idiopathic cases may escape the level of resolution of a gross examination of the brain.
Many years ago, when I was pondering on the lack of gross neuropathological changes in autism I realized that we faced a similar state of ignorance in other neuropsychiatric conditions. At that point I remembered having read about “paradigm shifts” as a way to advance science. Basically, major advancements in science are made by looking at old problems from a novel perspective. In this case, I decided to look for pathology in the brains of autistic individuals from the standpoint of circuitry rather than single cells. The results of such investigations led me to describe cortical abnormalities
It is truly exciting because I can see light at the end of the tunnel. Our findings in autism makes us believe that many clinical symptoms are concatenated, one explaining the other. We were able to describe abnormalities in the microprocessors of the cerebral cortex (minicolumns), a bias in the excitatory/inhibitory balance of the cortex, predicted changes in connectivity in the white matter, abnormal regulation of the autonomic nervous system, and a putative intervention based on transcranial magnetic stimulation. Those interested in more information can read some of our previous blogs: