Most popular science-savvy folks would argue it’s your frontal lobe, because that’s “what makes us human.” After all, it is much larger in us than in our close cousins, the chimps and apes, and many language functions are believed to have some key residence there. Others might say it’s the limbic system which is supposedly responsible for our emotions (many of which are actually quite primitive such as hunger and physical attraction), and perhaps the occasionally less region-committed scholarly sort of person might argue that it’s not one region but a series of regions and the connections between them that make us human, like our mirror-neuron system which may allow us to get the gist of social situations and act accordingly.

Drawn in 1911 by Ramon y Cajal.

Many researchers will simply tell you that the region they’ve studied the most is – of course – the most important. So, if you asked me – based on my experiences and observations in neuroscience – I would say that it seems to be the hippocampus. I would venture that funding from the NIH for this tiny region – barely the size of a walnut on either side – outstrips the rest by far. So the question is, why?

As you can see, the Hippocampus is the most widely-published region of the brain! Therefore, it simply must be the most important.

But tautological academic reasoning aside, there are many reasons why I consider the hippocampus to be the “most important.”

1) The hippocampus is central in the pathology of Alzheimer’s disease and many other dementias which are garnering attention as life expectancy increases and our population ages. In Alzheimer’s (the most common form of age-associated dementia) the hippocampus is the first to go, in frontotemporal dementias the hippocampus is primarily involved along with the frontal lobes.

The classic clinical case of H.M. showed how removing the hippocampus from both sides (a bilateral hemispherectomy – which sounds like you’re removing an entire brain but can just refer to removing the hippocampi) could lead to an inability to form any new episodic memories (memories of contextual events in ones life). To be a little more precise, H.M. only had two-thirds of his hippocampi removed along with his parahippocampal gyri and amygdala on both sides, and he had anterograde amnesia (inability to form new memories) along with some retrograde amnesia (problems with accessing old memories). He could however, still form new procedural memories.

2) The hippocampus is also infamous in epilepsy. The goal for H.M.’s hippocampal resection surgery was to control his seizures. Many surgically curable epilepsies involve the medial temporal lobe, the region of the brain which comprises the hippocampus, amygdala, entorhinal cortex, and various other structures involved in wiring together the senses and the memories that form from them. Epilepsy patients often have memory deficits during their seizures, and many of them have trouble finding the proper medication because the side-effects of epilepsy drugs perturb how memories are managed. In particular, it’s these short-term memories, or rather the formation of new memories, or perhaps even more specifically the transition from short-term to long-term memories that’s adversely affected.

3) Hippocampal memory formation has been shown to require the formation of new neurons. For a long time the human brain was believed to be incapable of forming new neurons, it was thought that all neurons were terminally differentiated and that there were no neural stem cells. However, in the 1980s it was shown that the dentate gyrus region of the hippocampus was indeed capable of creating new neurons and contained a resident stem cell population. Since then the subventricular zone of the brain has also been found to have neural stem cells. More recently, the dentate gyrus stem cell theory was further substantiated by studies that demonstrated impaired memory formation in rats with the inhibition of neurogenesis (new neuron growth) in the hippocampus.

4) The hippocampus is also implicated in other cognitive functions. It is essential for spatial navigation. In fact, observations in both mice and humans have shown that the entorhinal cortex – a region that shares membership with the hippocampus in the medial temporal lobe – directly feeds a spatial “grid” into the hippocampus. The hippocampus then uses these “grids” to form a more specific maps of places. These “grid cells” and “place cells” are fascinating because you can watch them form from one experiment to the next! It’s like an ever changing internal GPS.

5) This overnight memory formation has implicated the hippocampus in dream formation. It has been shown that as rats travel through a maze, they form grid cells and place cells, and these cells fire in a specific sequence depending on what route the rats take through the maze. This sequence can be seen again at night – only at a slightly faster pace – in the sleeping rats. It’s as if they are fast-forwarding through the memory of the maze throughout that day – perhaps to facilitate learning – perhaps to store long-term memories – or perhaps as part of some biological phenomenon we don’t quite yet understand!

6+) But wait! There’s more! Not only does this wonderful area of your brain serve as your address book, your photo collection, your map of the world, your supplier of stem cells, and your dream-machine, it also performs many other tasks and has been doing so in different capacities throughout our evolutionary history! I will post on that later, but for now, try to remember this post, go find your bed, and rest well so you can consolidate it into long-term memory as your fast-forward through it in your dreams so that you can fully enjoy the next one!

So… now what do you consider the most important part of the brain?

Some nice reviews if you have access to Nature Reviews Neuroscience:

The hippocampus and memory

The hippocampus and neurogenesis

Jamie Oliver, a British chef gone hands-on food activist has recently started a show on ABC entitled Food Revolution. The goal? Revamp America’s eating habits so that obesity, heart disease, and all those other deliciously disgusting metabolic ailments with modifiable risk factors are reduced. His first challenge? Huntington, West Virginia. The impetus? A report on CDC statistics interpreted by the AP which showed Huntington as the nation’s (and probably the world’s) unhealthiest city. In a nutshell:

This nascent revolution caught my attention for a very personal reason. Not only am I a physician in training encountering obesity and diabetes on a regular basis, but I grew up thirty minutes away from Huntington in Charleston, West Virginia and experienced first-hand what it’s like to have rampant obesity and poor eating standards as the norm.

The staple foods in my classmates’ diets were corn dogs, chicken nuggets, curly fries, pepperoni pizza, and steak. Now, there’s nothing categorically wrong with any of these foods – in fact if they’re made well they can be quite delicious and to an extent healthy. They can certainly be part of a balanced meal if other components match up. But, when those foods are all you have for breakfast, lunch, and perhaps even dinner, something is wrong. And when the government is funding and outright approving menus that drive this sort of eating, you have an epidemic in the making.

I was sheltered from this incubator for unhealthy eating habits due to a fortunate family situation. I grew up a vegetarian, my family rarely ate out, and most of my life (courtesy of a wonderful mother) I brought my own lunch to school. I found the smell of cafeteria food in my schools to be downright nauseating and I could never quite empathize with my friends’ excitement when corn dogs, pepperoni rolls, or even breakfast pizzas were served. Healthy eating was wiping the grease off your pizza with a paper napkin, and many would sneak back into line to get seconds!

In his show, Oliver deals with people and environments so familiar I feel as if I’m reliving the less pleasant part of my youth. The most horrifying aspect of it all now is to see how early the unhealthy eating habits begin! There are kids who cannot name vegetables, who cringe upon seeing them and spit them out before even having a taste. Kids, who when given the choice, elect processed food despite explicitly knowing it’s bad for them! After all, their palates consist of very few colors: processed meat, processed vegetables, and processed sugar. How can they even ask for different food if they have never had it? How are they even to conceive of it? They have to be exposed by their school or their family.

Schools are left impotent as they must fulfill rigid budget constraints and follow contorted guidelines based on an outdated food pyramid (which may as well be from Giza). Unmotivated administrators and underpaid staff have no desire to innovate around these challenges. Some families are in situations where preparing food is difficult, but most families are just without the knowledge or motivation to impel them to make better decisions. Oliver tries to tackle society from all these angles and more with thoughtful and impressive tactics, but encounters surprising resistance.

I would recommend checking the show out on ABC or on hulu, and I would love to hear what people think are the best solutions to this major problem.

Everything humans do can be explained as a combination of behaviors they exhibit. These behaviors in turn are caused by the interaction of various systems in the body such as the endocrine, nervous, and reproductive systems. These systems function due to the interaction of the cells which form them. Cellular physiology is determined by a set of biochemical pathways which respond to stimuli from the environment. These biochemical pathways have certain kinetics and thermodynamics which can be elucidated by chemistry. Chemistry is just applied physics.

THEREFORE, a set of physics equations, properly connected and implemented at the right scale, could predict human behavior. They would probably be able to do so probabilistically, however, if we could figure out all possible “hidden variables” we could give a definite answer to what any person would do in any given situation.

THEREFORE, human behavior is deterministic, and the human world is fatalistic.

THEREFORE, we have no free will.

Agree or disagree? I will deconstruct this one on another post, but it’s fun to think about. Physicists have trouble with the three-body problem, neuroscientists want to solve the brain with computers, and philosophers dispute whether free will truly exists. So… what do you think?

I especially find this to be the case when discussing neurological disease and cancer. Upon thinking some more about neurological disease and how it is often oversimplified and misunderstood, I thought it might be worthwhile to talk a little about how I think medicine has dealt with major challenges in the past, and how it will have to change to deal with future challenges. This is just a brisk overview with overlapping major points. I will skip over details and perhaps omit things others would consider significant, but it will convey the point that there are different challenges for which one approach alone is not necessarily appropriate.

I find that medicine can be divided into eras with the following major goals: tackling acute diseases and curing infections, managing chronic diseases and keeping degenerative processes at bay, and learning to delay the effects of aging and other (sometimes iatrogenic) byproducts  of our medical successes. Each of these challenges is further complicated for both detection and treatment must be made accessible to an ever increasing and changing populations that might be affected by a disease.

Figure 1: Change in causes of mortality throughout the 20th century.

Medicine as a science saw it’s first major reproducible successes in the era of infectious disease. The era prior to it was marked by a short average life span, a lower quality of life, and a certain inevitability that those who contract a serious illness could either get well on their own, be cured by limited means, or suffer and eventually die. Many medical treatments, especially surgeries, had very high mortality rates.  Scientific breakthroughs such as germ theory, sterilization, and public sanitization along with the discovery and application of antibiotics and vaccinations saved and lengthened innumerable lives. Medicine became established in this era,  when you were sick, you would call the doctor and he (at the time they were all he) would come to diagnose you and treat you. The diagnosis would usually consist of a physical examination where the physician searched for certain pathological signs that pointed to specific diseases. There was very little complexity in these cases, the patient had no autonomy, the physician had all the authority, and the disease was either cured or not. In a sense, very little has changed since then in the way we conceptualize (or rather, idealize) the role of the doctor in medicine.

Of course, at the time doctors were not held accountable by any real legal or professional standards (the Hippocratic Oath was perhaps the only “standard,” and it is awfully vague), thus the cultural environment treated the physician with reverence and without question, almost as if he were a deity. Eventually, the power of the physician was magnified as taking cultures of various bodily matter became common practice in cases where the physical exam was insufficient, and slowly the big picture came together and physicians along with public health professionals began to eradicate developed areas (and even the world) of certain diseases. It was during this time that medicine picked up much of its terminology, the idea of a “disease” having a “cure” came from this era, and a certain underlying assumption that there was usually only one thing wrong with each person, and that one thing could be fixed to bring them back to health also arose. This progress inevitably led to the longer lifespan and better quality of life we see today.

However, what physicians at that time could not have foreseen was the next wave of pathologies that their patients would face. I would say that we have only been in this, the era of multifactorial chronic disease, for about fifty years. A longer lifespan leads to wear and tear on the body. Lifestyle choices as well as complex genetics lead to diseases such as atherosclerosis, diabetes, and cancer. These diseases are heterogeneous, atherosclerosis can occur in multiple places and lead to heart attacks and strokes in multiple regions. Diabetes was initially thought of a Type I, insulin dependent, and Type II, insulin resistant, but even that distinction grew fuzzy and more and more people are now classified with a mix of the two and the many complications that arise from the pathology including vision loss and peripheral neuropathies are becoming better understood.

Figure 2: Improvements in cancer treatment leading to increased survival.

Cancer is perhaps the public figurehead and the greatest scientific challenge for this disease category. It can arise in almost any tissue (some cancers, such as cardiac tissue, are just very rare), and it can debilitate and eventually lead to death in many ways. Detection of the spectrum of cancers has necessitated greater scientific advances that have led to advanced imaging methods, genetic tests, enzymatic assays, and other molecular biology driven approaches for diagnoses. The treatment of these diseases is variable, as they are often not caught until they have progressed too far. Thus, a public health push has been made to diagnose earlier and treat earlier. When treatment can occur early on, these diseases can often be kept at bay, but there are no real “cures” for most varieties.

The physician faces ever greater challenges in this era with patient management. Legally, there are obligations to ensure that not only existing pathologies are treated, but reasonably predictable potential pathologies are avoided. There are complicated end-of-life issues that bring patient autonomy, religion, finances, and the allocation of scarce resources into play. The amount of information for a single physician to know has grown to the point that no single individual or series of textbooks can contain it, as hundreds of new articles are published everyday based off of new medical research. The lines between the previously concrete definitions of “disease” and “cure” are growing blurrier and blurrier.

Figure 3: Increase in prevalance of Alzheimer's with aging (from a European study).

The future holds an even greater challenge, as neurological and psychiatric diseases defy the rules that the multifactorial chronic diseases follow. It is no longer clear exactly when or where one even begins to have pathological changes, how they can be avoided, and what structures should even be targeted. Much of this is due to the general process of aging, some of it is due to environmental insults, and perhaps some of it is even due to iatrogenic insults. Thus, there is much work being done to understand how complex biological systems work and interact within themselves and with each other in order to produce the exponentially complicating phenotype of a human.

When we throw around the terms “disease” or “cure” (words which are inextricably linked to the first era of medical success), we simplify everything back to the idea of a pathogen and a drug. A doctor comes to visit you, gives you a treatment, and solves your problem. This is no longer the case in much of medicine, and until we acknowledge that as a culture, I think we will fail to properly convey what we are now actually doing for patients as physicians.

For the time I will omit developmental and genetic diseases which have their own problems and I’ll avoid world-wide health problems that could be fixed if everyone could just get along and agree to a baseline quality of life. In a sense we are facing all of the these challenges and those above simultaneously now, for none of the eras actually pass, they just compound upon each other. For instance, infections have been revived as a major problem due to resistant strains of bacteria and potentially dangerous strains of flu. Which of course brings to mind HIV/AIDS, and viruses in general. We still do not have the proper theoretical knowledge to effectively handle viral infections. Additionally the world of infectious disease has shown us that after we elucidate the scientific puzzle, we often have the daunting task of implementing solutions on a global level so that discoveries can actually be applied and save lives. The tone of this has been bleak so far, however, there has been LOTS of progress in the past couple of decades, and we are starting to see the years of medical and basic science research pay off. I will address the above complications more specifically and discuss the pending solutions as I learn more and time goes on. There will be lots and lots to post about. I will say for now that overall, I am cautiously optimistic that we will ultimately succeed in improving the quality of life for our patients.

(Click on figures for sources.)

Coverage of this sort would ideally be more common for diseases such as Alzheimer’s, for the media all too often portrays these diseases as having a cure just around the corner. The current sort of exposure unnecessarily romantizes the disease and the science behind it in unrealistic ways and eventually desensitizes the public as no real cure is found time and time again.

There is also a brief yet insightful TED talk on the upcoming neurological epidemic, which brings to light how neurodegenerative diseases will be the next “scientific frontier” in medicine. Ultimately the problems we are fighting are all linked to aging, but that shall be left for another post.