your brain is a two-faced liar

I am writing a post about schizophrenia as I speak, but to entertain you for the moment, here is a cool illusion, relevant to both schizophrenia and the recurrent theme of top-down processing!

a framework for schizophrenia, pt i

...and by tomorrow I meant two Fridays later.

But perhaps it was worth the wait.  The latest article I read was an opinion piece by Lisman et al. called "Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia", which does a pretty good job of summarizing its intent.  Here's a quick summary of the article, along with a quick summary of my own thoughts.

The article calls for an integrative, systems level approach to the neural circuitry underlying schizophrenia to facilitate the multi-level interactions between neurochemistry, gene expression, and environmental factors.

They recall that GABA—the primary inhibitory neurotransmitter of the CNS—has been shown to exhibit some degree of hypofunction in schizophrenia.  Moreover, the hypofunction is specific to two types of neurons: basket and chandelier interneurons, which both express parvalbumin, a calcium binding protein, and both synapse onto pyramidal cells.  An important point to note is that parvalbumin and GAD expression has been observed to be reduced, based on post mortem studies of brain tissue.  A pivotal experiment showed that the NMDA receptors, which have been implicated as one of the main dysfunctional receptors in schizophrenia, contributed significantly to excitation of interneurons, with special emphasis on the aforementioned parvalbumin-containing interneurons.  Thus, the net consequence of a decrease in inhibitory action is an increase in pyramidal cell activity, which has been confirmed by electrophysiology and measurements of glutamate release.  In addition, high-resolution functional imaging has shown that increases in metabolic activity are especially evident in the hippocampus*.  

While this helps establish a link between NMDA and GABA, why a decreased expression of parvalbumin and GAD?  They note that a previous study showed that an in vivo treatment of NMDA-receptor (NMDAR) antagonists results in a reduction of parvalbumin and GAD mRNA, as seen in schizophrenia.  The reduction in GAD, the enzyme that metabolizes glutamate into GABA, would likely result in a reduction of GABA transmission, decreasing inhibition.  Thus, they hypothesize that the role of these fast-spiking interneurons is to maintain homeostatic regulation of pyramidal cell firing.  In other words, these interneurons use NMDARs to gauge the activity of pyramidal cells so they can, in turn, compensate for changes in their firing.  Thus, antagonism of these receptors produce a false signal that results in a gradual loss of their inhibitory output.  

(I will finish this entry about the second half of the article shortly!)

*Ding ding ding!  More on this later.

schizophrenia 101

Every few months, neurological wanderlust grips me and I find myself scouring for a new subject to study. This time, I have been led to and seduced by the siren song of schizophrenia, O final frontier of amateur psychology! Lurking behind its somewhat superficial appeal as the embodiment of cultural insanity, however, is a wraith of molecular neuroscience so elusive that we have only caught glimpses of its shadows, which we have used to deduce its anatomy. For now, I'm going to introduce a few basic biological characteristics of schizophrenia that will be necessary in future discussions on hypothetical genetic, molecular, and morphological mechanisms.

First and foremost, schizophrenia is not, despite its etymology, related to split-brain patients, in which the corpus callosum—the thick bundle of axons bridging the two hemispheres of your cerebrum—is severed. Rather, it describes a mental disorder characterized by distorted perception of reality that can be lumped into two categories: positive or negative symptoms, which are so named because they describe an addition to normal experience—e.g. hallucinations, delusions, disorganized thought—or a loss of normal abilities—e.g. blunted affect, poverty of speech, lack of motivation, or anhedonia. These terms will form the basis of our psychological evaluations of neural theories we will discuss later on, so bear them in mind.

Second, schizophrenia is a profoundly heritable disorder, with a 50% of developing given identical genomes between two individuals — if your identical twin has schizophrenia, you're a flip of the coin away from developing it yourself. Critically, however, is that there is no one gene that can account for all cases; instead, we have identified dozens of candidate genes that contribute to the probability of its development. Some researchers have argued that mutated genes interact to contribute synergistically to developing schizophrenia, which is one of the hot topics we're gonna jump on later.

Third, just as there is no single gene responsible for schizophrenia, there is no one pathology, either psychological or neural, that is ubiquitous in all cases. The two most common pathologies are psychosis and enlarged ventricles, but these are certainly not necessary for diagnosis. Another important morphological feature found frequently in schizophrenia are aberrantly located and aligned neuron clusters found in the entorhinal cortex and white matter of the neocortex, which strongly suggest a neurodevelopmental component.

Four. The primary means of pharmacologically treating schizophrenia is by blocking dopamine receptors (D2), which laid the groundwork for the dopamine hypothesis of schizophrenia for decades since its first discovery. This is especially interesting given more recent studies using ketamine and PCP to emulate the symptoms of schizophrenia. Because these act as potent antagonists of glutamate, this sparked a flurry of research on a second neurochemical model of schizophrenia, which posited that a decrease in cortical glutamate creates a shift in chemical balance to dopamine, explaining why dopamine blockage relieves psychosis for at least some of the patients. This is, as you may have guessed, the glutamate hypothesis of schizophrenia.

That should be enough for now to prepare you for more in-depth issues about schizophrenia, which we can get into tomorrow! See you then!

wrap up: the hippocampus and intelligence

Philosophical meanderings over the vastness of consciousness aside, one of the most intriguing and overwhelming aspects of the brain is the (paradoxically) incomprehensible computational power in its possession. For instance, animals with relatively "simple" brains are capable of catching a frisbee in their mouths with ease -- a dog's jaws rarely miss the mark. Quite to the contrary, however, even the most cutting edge computer algorithms struggle to achieve even object recognition, let alone the ability to react in a timely and accurate manner, yet they spit out answers to complex differential equations that would baffle the most seasoned of mathematicians in mere seconds. Thus arises a paradox: why is it that computers can master such complex mathematical functions, but not ostensibly simple perceptual tasks?

The simplest answer is: they're not simple! In other words, the hidden computational steps involved in "recognition" belie their incredible complexity.  Moreover, they may rely on more abstract algorithms that modern computer science and artificial intelligence has yet to tap into.  Theoretical models that deviate from the traditional view of "intelligence", such as Jeff Hawkins' memory-prediction framework, may hold the key to how computers could hypothetically emulate real, biological intelligence.

All of that aside, we may be living in an age where the neurological mechanisms by which our intelligence operates are finally dawning upon us. Last week, I read a chapter of a neuroscience book detailing the roles of several hippocampal subfields and their functional role in generating episodic memories, and I ran into some fascinating data. Remember K.C., from the previous post, who couldn't imagine himself in the future or evoke memories of the past--and the ensuing bewilderment? Perhaps there is a light at the end of this tunnel after all. To put it briefly, Eichenbaum formulates a model that proposes that the hippocampus performs--among other things--two tasks called pattern separation and pattern completion. The former describes the process of parsing out differencees between spatially related components and the latter is filling in a partial representations (i.e. perceptions, whether sensory or memory based) with a "complete" one from memory. This process is conducted performed--hypothetically--by the axon collaterals in CA3 of the hippocampus*. They proposed that the "whole event" is actually comprised of a number of "subevents" that are integrated by the hippocampus to form a coherent episode within a spatial context (and possibly non-spatial, depending on whether you're looking at the ventral or dorsal hippocampus).

What's especially relevant here to the amnesia researcher is that this specifically resolves the issue of why hippocampus damage does not merely inhibit semantic memory and destroy autonoesis, but obliterates all episodic experience altogether--by destroying CA3, you thereby also eliminate the ability to tie together the component pieces of an experience into a coherent story, which isn't actually stored in its entirety in your brain. Rather, each time you invoke a memory, you "recreate" it by the process of pattern completion. (One might also ponder if this could also explain why memories are so vulnerable to revision and error). To take this argument to its extreme would be to say that all episodic memories are not real memories, but rather fabrications reborn each time when the hippocampus transiently links them together and brings it into your conscious experience--after which they again fragment into their components memories. To lose your hippocampus entirely, then, you lose not merely the ability to form new or regurgitate old episodes, but much worse--you lack the neural machinery to create any story about yourself whatsoever, your memories doomed to neural isolation.

Poetic and tragic though it may be, this does not answer the initial inquiry. Does the hippocampus' role in pattern completion implicate it as a candidate for the neural correlate of intelligence? Or are there other structures or systems that perform similar functions for non-episodic memories? My own hunch is starting to tell me, Yes, but evidence--to my knowledge--is as of yet too lacking to assert anything defensible. Maybe getting an fMRI while thinking this out will pinpoint the next big engram.

*While there is currently no way to "prove" this conjecture, it seems the most reasonable candidate given its highly interconnected structure, permitting a wide range of different firing patterns with a high capacity for representing a variety of memory traces.

Episodes vs. Semantics v2.0

Time for another episode!

I have been perusing the labyrinthine literature on amnesic patients, and I have found that the consensus is often as confused as the patients themselves.  The specialists are often at odds with each other, depending on which patient they studied.

Endel Tulving, for instance, studied the fascinating (and oddly familiar) case of K.C., a patient who developed anterograde amnesia for episodic, but not semantic, memory due to a motorcycle accident.  His episodic deficit was so severe that he could no longer recall any autobiographical details of his life — he was, in fact, unable to envision himself beyond the confines of the present.  This then prompted Tulving to surmise that a key component to episodic memory is a property called autonoesis—the ability to mentally re-enact and re-experience an event that has previously occurred.  Despite KC's ability to reproduce a detailed spatial map of where he grew up, there was an apparent lack of any experiential component to any of his recollections.  He was, as it were, simply reciting facts about his life and his past without invoking first person details.  Thus, Tulving asserts, the definitive property of episodic memory is not merely the ability of recall, but the ability to relive.

The patient R.B., however, demonstrates a drastically divergent view of amnesia.  After suffering highly specific bilateral hippocampal lesions, he developed an anterograde amnesia covering both episodic and semantic memories — yet, he was capable of retrieving pre-brain damage autobiographical memories in colorful, episodic detail.  Moreover, his brain damage was, unlike previous cases, restricted to CA1 of the hippocampus, its main output region, rather than encompassing much of the medial temporal lobe.  His hippocampus was, in other words, largely dysfunctional, despite retaining most of his tissue.  The conflict arises, however, from the fact that he was unable to form new episodic memories, despite apparently possessing autonoesis.  Does this, then, invalidate Tulving's ambitious constructs?  What's more, is how could KC's lesions possibly spare semantic memory, though the extent of his lesions encompass those of RB?

Alas, that I cannot supply a meaningful solution.  All I can suggest is perhaps there is a drastic difference in the nature of the lesions between the two patients, with RB's hippocampus lesions supporting the classical view of amnesia, as first formulated through studies with HM, and with KC's lesions indicating that the perihippocampal areas may contribute to the full integration of "imagining" an experience.

What an unsatisfying answer.  Maybe something more satiating will come up this afternoon so that I can make reparations...

revival, rule-based memory, recursion

I am back. Hello! I will be making a few successive posts about what I've done from December to now. Also, I will be making the majority of my posts more concise and less elaborate so that I can post more regularly in the future. Hopefully. Anyway, here's the meat of it.

Historically, the study of amnesia has relied on the kindness of lesion studies. From the most famous case of Henry Molaison (HM), who recently passed away, and lesser known patients like EP, KC, or CL, the unfortunate but fortuitous consequences of brain lesions has been an indispensable pillar in the development of modern neuropsychology.

One of the cases I've dedicated special interest to is the patient KC, who was involved in a major motorcycle accident that resulted in major brain injury to his hippocampus, he lost his ability to form episodic memories, but—most crucially—retained his capacity for semantic memory. Unlike previous neuropsychological cases like HM and RB, who exhibit a loss of both types of memory, the case of KC shows us that there is some degree of independence between episodic and semantic memory, such that semantic memory is not, for the most part, dependent upon episodic memory. Later on, another patient, CL, confirmed this with similar sparing of semantic despite loss of episodic memory. One attribute of KC, however, stands out in its peculiarity: when asked about his future—even 24 hours ahead—he is utterly unable to conceive of it, yet he is capable of looking several moves ahead in a chess game. The paradox, then, is how can KC look prospectively into a chess game but not a day into the future?—after all, with respect to the general population, the difficulty is reversed.

As perplexing as it may seem, it is not beyond our means of explanation. In Tapestry of Memory, the great neuropsychologist Ray Kesner gives us not only a fascinating account of his career, but also a framework for memory that hints at a resounding explanation. He argues that there are three different types of memory—event-based, knowledge-based, and rule-based—that apply to all of our "higher-order" modalities, from language to space and time. Of particular interest here is the "rule-based" memory, which operates by "integration of information from the event-based and knowledge-based memory systems for the use of major processes that include the selection of strategies and rules for maintaining or manipulating information for subsequent action as well as short-term or working memory for new and familiar information." In a sense, then, it is syntax that governs how different objects in our memory can interact.

How, then, does Kesner aid us in explaining why poor KC can play chess, but not look into the future? In short, what his brain trauma resulted in was an inability to form new memories--including rule-based memories--but it spared the regions where his already established "rules of chess" memories are stored. We can thus make a prediction about this case: KC, while retaining his ability to play chess, will not be able to improve his ability to any significant degree because he lacks the adaptive neural machinery to guide it. One could liken him to a computer program that can retains the original program, but does not have the programmer to improve or even alter it.

Conversely, the question of what he will be doing tomorrow does not invoke a solidified rule-based system because of the endless amount of options available at any given moment. This takes the liberty of assuming that he did not have a highly ritualistic daily routine prior to his accident, which would render this process far more rule-dependent than adaptive. Here, we can make a second prediction that, if someone highly ritualistic were to receive KC's lesions, this hypothesis would predict that the subject would be able to speak of the future because the question would be addressed more directly as a rule-based inquiry.

[Edited 10:35 2/19/09]

wider than the sky

Sorry about the big gap again, but I'm gonna get right back onto posting tomorrow evening or so, after I finish my essay. And—just to keep the topics here neuroflavored—here's a poem by one of my favorite writers of ye olde high school English days, Emily Dickinson:

The Brain—is wider than the Sky—
For—put them side by side—
The one the other will contain
With ease—and You—beside—

The Brain is deeper than the sea—
For—hold them—Blue to Blue—
The one the other will absorb—
As Sponges—Buckets—do—

The Brain is just the weight of God—
For—Heft them—Pound for Pound—
And they will differ—if they do—
As Syllable from Sound—

—

I guess that makes me a theologian.  But better.