Ecce Sententia

your brain is a two-faced liar

2009-05-22T04:37:00.001-07:00

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

2009-05-22T04:00:00.000-07:00

...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

2009-05-07T21:33:00.000-07:00

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

2009-04-01T00:21:00.000-07:00

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

2009-03-20T06:13:00.000-07:00

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

2008-12-14T20:46:00.000-08:00

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

2008-12-10T15:48:00.000-08:00

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.

sfn1

2008-11-19T19:15:00.000-08:00

So, if you haven't heard me rattling on about it 24/7 yet, I attended the 2008 Society for Neuroscience conference this past weekend, and... how should I put this?

It was amazing. Super natural. A neural orgy. A bona fide bacchanal of brains. Words fail me.

Seriously. During the course of this dense, nigh impenetrable semester, SfN was the breath of fresh air needed to reignite my faltering love for academics. That's not to say that I haven't been enjoying my classes, but there's something galvanizing about being in the midst of it all, talking face to face with brilliant, up and coming scientists about the work to which they dedicate their talents, and finding ourselves swept away by the eager excitement of our conversation. Yeah, some people prefer the symposia or the lectures, but for me, the real exhilaration was just to be downstairs navigating the endless rows of posters and speaking with impassioned scientists about everything I could possibly want. There was even a poster about Descartes. Apotemnophilia? The neural circuitry dedicated to integrating spatial and emotional memory? I'm Robert Downy Jr., and it just started snowing cocaine—pardon my French, but even royalty don't get it this good.

There's really too much to go through, but one of the highlights was speaking with people who work in Ramachandran's and Pineda's labs. Ramachandran! Pineda!! It turns out these titans are human after all (but by a narrow margin). Still, this doesn't undermine the sheer value of the experience; if anything, it only elevates it. All the literature search and abstract reflection of this semester culminated on that basement. Neurofeedback on autism finally materialized before my eyes as I spoke with Dr. Aragon, who works in Pineda's lab, discussing the potential clinical applications and theoretical implications. "Oh yeah." "How about the role of critical periods in treating these children." "That's fascinating." "You should come to my poster tomorrow." I'm melting in my shoes. At the end of the day, we go back and Frankie, Andrew, and I still can't stop talking about neuroscience.

And that's really my only regret — that I couldn't stay longer, so I couldn't attend Rizzolatti's lecture, talk to Dr. Aragon and Pineda more, or crash my professors' poster presentations when it was their turn. But the time will come—their time will come—for all of the above. Next year in Chicago. It's already been decided, between the UD neuroscience kids. We're going to start a neuroscience chapter for posterity—no neuro-neophyte can miss something this big—and have a reunion at the next meeting.

Eleven months and counting.

forging on

2008-11-19T10:26:00.001-08:00

So, after several months of investigating autism, I think I'm going to shift focus to amnesia and dementia. I'll still be posting about autism though, partly because I haven't even gotten half of my thoughts on it out here, but also because I've become so intrigued by it that I don't think I'll ever be able to leave it alone.

For now, though, the focus will be shifting to amnesia. I haven't done too much work on it yet, so I figured I'd throw a thought I had a while ago out there. The hippocampus is widely recognized as one of the critical areas in forming new memories — people with a badly lesioned hippocampus are afflicted with anterograde amnesia, so that they can't remember anything from that point on. Could this be why we often don't remember our dreams, then? I've heard that we only remember the parts of the dream immediately before waking up. Could this be a form of anterograde amnesia that every suffers? Yet at the same time, it's also said that our emotional memories are consolidated into long term memories during dreams. What could be going on? My first impulse is to suggest that specific input to the hippocampus is reduced, while output is actually increased. But it's just an intuition; I'll get back to you once I find some nice loot.

genetics of autism pt. 1

2008-11-15T22:21:00.000-08:00

(Note: This is also a dated post, but I heavily modified/rewrote it in light of Noah's comment in a previous post.)

So, as promised in the autism conspiracies post, I'm coming back to the "Extreme Male" theory of ASD. Since then, I've read some really fascinating papers that confront the genetic factors to be considered in autism, which really opens up a whole new world to explore. No kidding. Just when I thought I was getting exhausted from all the complex and more than a little muddled frameworks about autism, I started peeking into genetics and, to a lesser extent, epigenetics, and I think it blew half my brain away off the top.

So, to start off, there are several "odd" features of autism that I haven't been able to wrap my mind while equipped solely with frameworks and top-down models. One of the issues I've had is the point that males are afflicted with autism over 4 times as frequently as are females — how do the underconnectivity or broken mirrors hypothesis address this glaring fact? They don't, yet it's clearly something that needs to be explained. One famous jab at it was made by Baron-Cohen who, in researching autism, was so convinced by this lopsided ratio that he was compelled to formulate what he calls the EQ-SQ theory, which postulates that the "male" brain is better at systematic thinking while the "female" brain is better equipped for empathy, ingeniously accounting for both the gender statistics as well as two of autism's most prominent features: a deficiency in social cognition and a degree of systematic obsession.

To date, however, this theory remains in its infancy at best and is aborted at worst. There is little empirical evidence for this, with a large source of criticism aimed at the lack of controls in the few experiments that do seem to support it. My own criticism, however, is that it offers little scientific insight to the issue of autism. Let us grant that such a gradient between empathetic and systematic thought in humans; all this would tell us of someone is their preferential mode of thought. In the absence of an absolute metric, there is no way to definitively state whether or not a person is autistic or not. Thus, it would be possible for an individual to be highly intelligent and to excel in systematic thought—say, a mathematician—which could give him an E-S ratio within the autistic spectrum, but still exhibit normal social behavior. This very fact, I think, gives us ample reason to reject an attempt to characterize autism as a mere quotient between empathetic and systematic thought, even when we ignore the many subtle issues this theory skirts.

There is, however, similar theory was recently proposed that offers more scientific appeal and has some empirical data to sustain it. In short, Bernard Crespi and Christopher Badcock collaborated to hypothesize that autism and schizophrenia are, in fact, on opposite ends of the "spectrum", with the autistics being more systematic and the schizophrenics being more psychotic and emotional. The exact location is determined by the balance of genetic contribution from the mother and the father, which in a way makes it an expansion of Baron-Cohen's EQ SQ model. You can find the news article version here, or you can just Google them individually and find their scientific publications on their websites.

First and foremost, we need to point out that this model does not suffer the same pitfall as Baron-Cohen's. By emphasizing the genetic component to brain development, Crespie and Badcock have already set a biological metric that Baron-Cohen lacks. Perhaps more intriguingly, their recruitment of epigenetics helps explain our difficulties in isolating the precise genes causing autism. They suggest that experience sometimes results in the methylation of genes, which results in reduced or halted expression, so even if you do have a gene that puts you at risk for autism, it may have been inherited a highly methylated sequence so it's not expressed.

I wonder, though, how Crespie and Badcock will cope with the doubtless criticism awaiting them. Their proposition that autism and schizophrenia exist on opposite ends of a spectrum may stand in opposition to the current view that each of these disorders alone exist with their own spectrums. Will it be possible to create a multidimensional map of their symptoms to confirm their predictions? Moreover, while a mom vs. dad model does fit nicely with the 4:1 male to female ratio in autism, why, then, is there no sex preference in schizophrenia? Even more disconcerting is the fact that while schizophrenics should exhibit erratic moods and autists should be less emotional, the opposite is true: one of the most common features of schizophrenia is blunted affect, and autistic children are notoriously emotionally unstable. Why, also, do symptoms from schizophrenia appear much later in life than autism?

In short, I still have my reservations. If this theory is to survive, it needs to undergo some dramatic revisions. Massive pedigree charts should be constructed following the inheritance of risk genes, statistically compared to the prevalence of autism and schizophrenia. Test the mu suppression in schizophrenics — do they exhibit more robust mirror neuron activity than controls, where autists are inhibited? Until we see some real concrete results, instead of abstract comparisons, I don't think there's much we can say about this theory.

Until next time,
Shuo

spinning girl

2008-11-10T11:37:00.000-08:00

(I was browsing through previous posts, and found this old, unpublished that I forgot about. I thought it's a cool example of top-top-down modulation, so I decided to put it up.)

Check it out. This is a pretty shocking example of top down modulation; the silhouette below can be perceived as spinning either clockwise or counterclockwise. It makes sense on an "intellectual" level, but it's hard to believe until you can actually see it go both ways. Give it a shot.

Did you get it? If you're still having trouble, try focusing entirely on the reflection of the foot to "convince" your brain it's going the other way. From what I gather, the reason that it's so hard to switch from one perspective to the other is that your higher-order areas fill in the features of the girl when you're looking at the more detailed parts of her body (like her face), so you'll get a very vivid perception of the direction in which she's turning. In reality, however, she's not turning in either direction. It's just a black image oscillating between two extremes, but your brain recognizes it as a human and imposes the perception of her pirouetting. What's cool is that this kind of represents a kind of "supra"-top-down modulation, where your higher-order visual processes are being directed by even higher areas.

Does this invalidate the argument that qualia are irrevocable—that once you perceive something, you can never take it back—as often exemplified using the dalmation image? You might think so at first, but it actually shades it with deeper nuance. Rather than describing it as irrevocable qualia, we can say that our brains are actively pursuing patterns to form coherent representations in our skulls — thus, placing some stimulus into a familiar category is its preferred path. However, when there are competing modes of perception or categorization, it can't entertain them simultaneously, so you can only see one at a time. The reason why it's hard to get the first switch, then, is because you have to wiggle out of the familiar category for a moment in order to reorganize it into a different pattern recognition—you have to "weaken" your perception of it a bit—which requires some higher-up input to catalyze. This is why it's easier to switch if the figure is spinning in the corner of your visual field than dead center.

At least, that's how I make sense of it. Whether you agree with my understanding or not, I think we can all agree that this is a pretty freakin' cool illusion. I've just gotta remember to freak out a few stoned hippies with this trick sometime.

autism conspiracies

2008-10-23T00:30:00.000-07:00

So, the history of autism research has certainly been an interesting one. Attempts to explain it have ranged from ingenious, like the broken mirror hypothesis, to the borderline (or maybe just outright) sexist, like the "extreme male brain" hypothesis. I've thus far focused on theories that I deem at least somewhat plausible, but it would be unfair to neglect the vast wealth of weirder ideas out there. More important, however, is the point that these theories have often led to enormous investments of resources for disproving them that could have otherwise been devoted to finding the real cause or effective therapies for it. My hope is that exposing the history of mistakes due to ignorance will show us the value of making informed judgments instead of railing on any wayward suggesting out of fear (because everyone on teh internets reads my neuro-blog).

So here are a few such theories, discussed and debunked:

1. MMR vaccine "theory".

As far as crazy autism theories go, this one's the mac daddy of them all. In 1998, Andrew Wakefield published a paper describing the disturbing observation that 8 out of 12 children in the study seemed to develop autistic symptoms soon after MMR vaccination. Moreover, they seemed to develop some odd gastrointestinal problems that Wakefield posited may be indicative of a new disorder created by the combined serum of measles, mumps, and rubella. In the subsequent years, the press started picking up on it and scared up a public storm, in the process generating the claim that the prevalence of autism has taken a sharp turn for the worse, coinciding with the advent of MMR. The mechanism for this, they claim, is due to an inability of the child's developing immune system to cope with the toxic triad of viral particles.

A pretty sound conspiracy theory, right? Right. That is, if you ignore the fact that several extensive epidemiological studies have demonstrated a blatant lack of correlation between autism and MMR. Not only that, but studies have actually shown MMR vaccine to strengthen the immune system, as any vaccine doubtlessly should. That's great and all, but what I want to know is how the heck damage to the immune system could result in immediate developmental deficits. No, really. If someone can come up with something, I'd love to hear it, because I've got nothing.

The truth of the matter comes out when it was revealed that Wakefield received anywhere from £55,000-£400,000 to invent a story undermining the credibility of the MMR vaccine, which he did not inform his co-authors. After this was publicly revealed, ten of the twelve co-authors of the original article retracted the argument that there may be a link between the vaccine and autism. As far as I'm concerned, this is case closed — except for the revolting taste left in my mouth by Wakefield's ulterior motives. Yecht.

2. Thiomersal causes mercury poisoning

The thiomersal controversy also concerns the relationship of a vaccine with autism, except it's deprived of a depraved figure in the center of the whole unnecessary fiasco. In this case, thiomersal contains mercury, so the CDC and FDA stated that it should be removed immediately until its toxicology has been more thoroughly explored. This was somehow blown out way beyond these humble beginnings, with several politicians supporting this theory. Anyway, what ended up happening was a lot of research time and money wasted dumped into this to assuage the public's uninformed worries, and today we know that there is indeed no link between thiomersal and autism.

3. Refrigerator mother

Ah, yes. The classic explanation that laid the blame on the mothers of autistic patients. While not a good explanation, I will tip my hat off to whoever coined the term. It's all in the name: what this hypothesis asserts is that autism is a psychologically generated disorder stemming from frigid, neglectful treatment from the mother. Many of the earlier proponents of this view were psychoanalysts, which should suffice to fully discredit an already dubious theory.

And indeed, we have long since debunked this wild, accusatory hypothesis — autism has an enormous genetic component. Yet, I can't help but wonder, what if a small subset of autistic cases are, if not caused by, to some extent exacerbated by parental neglect? This would only apply in the most extreme of cases, but it clearly played a significant part in Danielle's condition, which I talked about in a previous post. While a frigid mother is clearly not the primary force in the majority of autism, you can't help but wonder how much this obscure, nigh-untestable variable may factor into the fate of children predisposed for autism. I guess we may never know.

4. The extreme male theory.

I think I'm going to devote a whole post to this, but I may just come back and tack it on as an addendum to this post, so check back on this entry in the next few days!

upcoming articles and posts

2008-10-22T00:28:00.000-07:00

In case anyone wants to keep up with my adventures in cyber-neuroscience, here's a list of ten articles that I've read or will soon read that will be discussed in upcoming post. Like I said, I've gotten fed up with the theoretical propositions, so I've taken to more reductionist articles, which incidentally tend to be a bit more painful to work through:

1.) Modulation of mu suppression in children with autism spectrum disorders in response to familiar or unfamiliar stimuli: The mirror neuron hypothesis. Oberman, Ramachandran, and Pineda. Link.

2.) The Neuropathology of Autism. Casanova. Link.

3.) The teratology of autism. Arndt, Stodgell, and Rodier. Link.

4.) Animal models of autism. Klauck and Poustka. Link.

5.) Molecular genetics and animal models in autistic disorder. Andrew. Link.

6.) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Tabuchi et al. Link.

7.) The arg451cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. Comoletti et al. Link.

8.) Activity-dependent regulation of inhibitory synapse development by Npas4. Lin et al. Link.

9.) Autism's cause may reside in abnormalities at the synapse. Garber. Link.

10.) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. The Autism Genome Project Consortium. Link.

I'll probably post a quickie tomorrow or so dispatching the kookier theories of autism, like the MMR vaccine fiasco or the now classic refrigerator mother hypothesis, just for kicks.

synergy

2008-10-19T21:35:00.000-07:00

Sometimes, the biggest insights in your research come, not from immersing yourself in the sea of information, but from looking elsewhere.

Thus far, I've discussed autism both from the theoretical perspective, namely the broken mirrors hypothesis (I've also looked into the underconnectivity theory a bit, but I haven't posted about it here yet), and I've looked at more reductionist approaches — that is, approaches that have focused on specific features of autism rather than the "big picture". To date, all these theories have glaring flaws which leave me skeptical of their explanatory power, and the reductive approach has obviously failed to give us a clear answer as well.

Perhaps the most disconcerting fact is that autism exists as a constellation of disorders of varying severity. When a disorder is characterized by a dispersed spectrum of anomalies rather than a single definition, the possibility of multiple, symptomatically similar diseases arises. While true throughout medicine, this possibility is even more of a threat in psychiatric and neurological disorders, owing much to our ignorance of fundamental aspects of the brain's circuitry. Thus, we must surely begin to wonder, has this foreboding possibility—that autism spectrum disorders actually describes several distinct or at least not entirely related diseases—now become an inevitability? Apparently I am not alone in these apprehensions, as some researchers have made this exact assertion.

Someone needed to say it, but as for me, I've a while before I'm forced to settle upon any given theory. I did, however, read one article that gave me an idea and, God forbid, an opinion on this. As it so happens, this article is completely unrelated to autism; it's actually a review article that discusses the consequences of sensory deprivation on cortical development. What it argues (over and over and over) is that not only is top-down modulation a force to be reckoned with in the mature brain, but that it's also intimately related to development. The brain, as we all know and love it, consists of hierarchically connected nuclei that relay information both up from the lower, sensory end to the higher cortical areas. The higher areas, however, are not founded by genetics — they are complex, plastic, and experientally defined. It is the patterned activity of the sensory inputs, which are genetically mapped, that guides the patterning of these higher areas. The reason for the elaboration of these higher areas is so they can, when their turn comes, deconstruct, integrate, and guide the incoming information, allowing us to navigate through an ordered, valence-oriented representation of the world. Most critically, then, the paper culminates on this thesis: early developmental deprivation of lower bottom-up information impairs the formation of these higher areas, which consequently also impairs bottom-up signals. The reason these bottom-up signals are impaired is because while the lower areas are highly plastic during development, they lose this plasticity later on and require top-down modulation as they mature.

If you're versed at all in systems theory or the concept of emergence, then you may see where I'm trying to take this. If not, you may be thinking, "What the deuce does this have to do with autism?" Well, let's put it this way. One of my main gripes with several theories of autism is that they all set their sights on the consequences of a deeply developmental disease and assume looking at these symptoms will be sufficient to reveal the dysfunction. Put simply, the whole may be more than the sum of its parts. Secondly, in the last post, I suggested that autism may be the result of deficits in relaying information from sensory inputs to the higher areas, while Hamilton proposed that the culprit may be a dysfunction in top-down modulation. So which is it?* Is there a model that might be able to synthesize all these hypotheses about autism, all of which have valid points, but are still woefully incomplete?

Maybe. Recalling that autism is a developmental disorder, we can apply these findings and find a view that seems to reconcile both conjectures, and more: the elaboration of higher-order areas may be impaired by lower-order anomalies during early development, e.g. the interruption of some signals or modulatory elements. This, in turn, is exacerbated by the fact that top-down feedback plays a very important role in the guidance and analysis of sensory input, resulting in broad deficits spanning several levels of the hierarchy. The explanatory potential of this hypothesis really shines in its ability to account for the ominously broad range of symptoms and severity, which is a troublesome obstacle for a hypothesis restricted to any one higher-order system (e.g. the mirror neuron system). Because of emergence, there may be only one or a few pathways involved, but this could result in a global dysfunction in the neocortex. Or, it may involve a little bit of every pathway, which might be appealing, giving the morphological anomalies seen in multiple parts of the brain in autism.

I should catch myself before I read into this even more. At this point, this "emergent" hypothesis of autism is appallingly general and utterly unfalsifiable, so we should make some preliminary predictions and tests before taking it any further. The obvious question to pose is: what developmental problems, in particular, could result in this? My obvious answer is: I don't know. There are a bunch of genes implicated in autism, and it may well be the interactions between slight amino acid substitutions that results exponentially exaggerated autistic symptoms — yet another example of emergence. (Actually, I've probably just been doing too much biochemistry lately.) Which genes these might be, I will save for a later post. Which gives me ample time to load up on more research so I can fire off another storm inane conjectures. So, stay tuned!

Until next time,
neurophyte

*In all honesty, I favored the latter explanation. Problems in top-down modulation would explain why autistic subjects perform poorly at more complex tasks that require integration of multiple sensory modalities, while my hypothesis raises the question of why autists often respond vigorously to specific stimuli, but not to many normal ones.

Edited at 7:33 p.m, on 10/22/08

which came first, the man or the reflection?

2008-10-10T13:18:00.000-07:00

One thing that has troubled me about attempting to ascribe functions to the mirror neuron system is that we don't seem to know too much about its functional purpose. We've observed the neural correlates, but the first thing we learn in experimental techniques is that correlation does not imply causation. We can infer from fMRI scans and electroencephalography that a mirror neuron system exists in humans, but it's difficult to ascertain their specific computational role. Though far from conclusive, one study might give us a critical tip in developing a model for its purpose. They demonstrated that, in addition to the known property of mirror neurons firing both when performing and observing a particular action, they also fire when hearing their associated sounds. What this seems to suggest is that mirror neurons are a type of categorical, "name" cells that hold abstract representations of an action. If this is true, then, do the symptoms of autistic patients arise from an inability to conceive of actions or language? I find this somewhat hard to believe; if this were the case, it would be difficult to imagine how autistic patients could carry out actions at all.

While the broken mirrors theory is certainly not ruled out, it is far from our only option. An alternate possibility that comes to mind is a defect at an earlier stage of processing, which prevents information processing from even reaching mirror neurons (this may lend credence to the underconnectivity theory of autism, which I will discuss in the future). Information processing is achieved by hierarchical processing in the brain, so the lack of mirror neuron activation observed in autism could be indicative of the interruption of information relay up the hierarchy. That is, the information may never reach the mirror neurons in the first place. This seems like a highly plausible alternative explanation to the results from Obermann and Ramachandran's electrophysiological experiment that showed a deficiency of mirror neuron activity in autistic children when observing an action.

More tantalizing and ingenious an explanation was proposed by Hamilton. He proposes a "top-down modeulation hypothesis", in which the problem stems not from interrupted circuitry from lower levels, but even higher up in the hierarchy. He points out that this may account for why autistic patients may exhibit excess mimicry at times, as seen in echolalia or echopraxia.

At the present, no experiments to test these hypotheses comes to mind immediately. Perhaps more importantly, we must take caution making inferences about developmental disorders in which aspects of neural circuitry from the normal brain. While the gross symptoms of autism may manifest themselves as broken mirrors, underconnectivity, or cerebellar dysfunction, this may result from a much simpler problem earlier on in development. Inclusive of this is the possibility that the various theories may not be mutually exclusive; they may be incomplete individually and complementary together. So then, are mirror neurons dysfunctional because of underconnectivity, or is there underconnectivity because of a lack of patent mirror neurons to which connections can be made? It reminds me of the problem I face when trying to lose a bad habit. Did my personality predestine me for the habit, or did the habit shape my personality? Which, then, do I attempt to change? As long as we're talking about growth and development, the critical question always comes down to correlation vs. causation.

broken mirrors: a broken theory?

2008-10-09T13:28:00.000-07:00

It's bloggerin' time!

But first, I must issue my apologies for such a long delay between posts. Sometimes I forget that this blog is for a class — in my mind, I think of it as "play time", so I set it behind cramming for tests or confabulating presentations. Not a very good excuse, but I hope the utterly fascinating articles I've been checking out lately will make up for this in this post.

Last post, I talked about the "Broken Mirrors" theory of autism, which basically asserts that a dysfunctional mirror neuron system (MNS) accounts for most of the symptoms of autism. I was so impressed with this theory that I decided to devote my attention to articles addressing either mirror neurons, their relation to autism, or the broken mirror theory. In this post, I address articles and work done by Hamilton, among others, that scrutinizes broken mirrors theory, which ultimately rejects it. You can find the review article here if you want to take a look at it.

The foundation for the criticism is as follows. The mirror neuron system is integral in generating behaviors serving a goal, e.g. lifting a glass of water to one's mouth to drink from it, as well as in imitation tasks (demonstrated also by Fogassi et al. in 2005). Thus, it's been shown that damage to the MNS results in apraxia. Thus, they assert that if the pathophysiology of autism is fundamentally a global dysfunction of the MNS, they should exhibit impairments in their abilities to carry out purposive tasks and imitate the actions of others. However, a series of experiments by Hamilton et al. in 2007 showed that while autistic children do indeed fail miserably at Theory of Mind tasks, they could imitate goal-directed tasks (Hamilton uses this to define emulation) just fine. Moreover, they passed as normal when given tests for apraxia, suggesting that at least some aspect of the MNS was functional. Yet, it's become an increasingly obvious fact that autistic children fail at the imitation of apparently meaningless actions (he calls this mimicry); why, then, the dichotomy between such tasks?

Thus crumbles the hypothesis of global mirror neuron dysfunction, according to Hamilton. The argument in essence is thus: (1) the MNS is involved in understanding intentions and executing purposive behaviors, (2) autistic subjects have been shown to have the capacity for these functions, ergo, (3) the theory in its current formulation is wrong.

To sort out this mess, the MNS must be broken up. Instead of regarding it as a single, unitary system, there's been evidence that it should be addressed as three separate systems, the inferior frontal gyrus (IFG), the medial temporal gyrus (MTG), and the inferior parietal lobule (IPL) divisions. To get to the point, the primary assertion is that the IFG mediates the motor output, while the MTG mediates visual input and the IPL is an in-betweener which colors behaviors with goal orientation, but a shortcut pathway exists between the IFG and the MTG that bypasses the goal-orienting region that directs mimicry. To make a long story short, the explanation behind the ability of autistic subjects to emulate, but not mimic, actions is because there is some disruption along the shortcut pathway.

It's getting late; I'll up the evidence and implications for this along with my thoughts tomorrow morning.

broken mirrors

2008-09-19T08:19:00.000-07:00

I'm back!

Phew, what a week it's been! It culminated in me giving a terrible presentation in neurobio, which resulted in me skipping my next class in mindless abandon to eat some greasy, nasty cheese steaks on the green, followed with the best crab bisque ever. It was worth the waste. I am refreshed and ready for blogging now.

I've read quite a few articles recently, including those mentioned in my previous post. One of the coolest was Oberman et al., which investigated the involvement of mirror neuron dysfunction in high-functioning autistic children. The experiment is simple and elegant, coming from a very rational premise. Mirror neurons are, in the strictest terms, neurons that fire both when a subject is performing an action as well as when observing someone else perform it. It takes a moment for the importance of this to sink in — I myself had heard of it a while ago, but it was not until I read some of Ramachandran's articles about its implications that its implications hit me full force. Taken in another way, these neurons are a gateway between "self" and "other". We understand the actions of others because, by computation of mirror neurons, they are transposed into ourselves. It is suggested, then, that it is by mirror neurons that we can learn motor skills through merely watching others, acquire language, understand the intentions of others, and perhaps even formulate a theory of other minds. (Interestingly, Ramachandran argues the opposite — self-awareness came as a consequence of understanding other minds, which you can read about here.) Looking over these putative functions, any autism researcher would surely jump off of their chair — these are the very same traits that are dysfunctional in autistic patients! The obvious task at hand, then, is to find a way to investigate the relationship between mirror neuron dysfunction and autism.

Oberman et al. found a simple, ingenious way of testing this. Mirror neuron activity has been shown to be correlated with mu frequency suppression in EEG band oscillations, which presents a simple, noninvasive way of measuring mirror neuron activity in active subjects. What this lab did, then, was compare the mu wave suppression in high-functioning autistic children to those of non-autistic children while watching videos of a moving hand, a bouncing ball, and nonsense stimulus, as well as while moving their own hand. What they found was that the autistic children showed mu suppression in response to moving their own hand, but not while watching the video of the moving hand, which stood in stark contrast to the control group, which showed mu suppression in both instances. They interpreted these results as evidence that mirror neurons were not firing when the autistic children were watching the videos, possibly due to dysfunction of the mirror neuron system. A first shred of evidence for the involvement of mirror neurons in the pathology of autism.

As a kid who used to think science involved little more than looking at a line of ants under a magnifying glass, this article came as a welcome break from the dense, nigh-impenetrable neurobiology papers I'd been gnawing on lately. It told us that something is wrong with mirror neurons, but it's not clear what. Despite all the hopeful conjectures about the role of mirror neurons, they remain relatively enigmatic due to their inaccessibility — we cannot perform lesion tests because they have a dispersed distribution in the cortex. What they do and how they do it are essentially unknown to us. So as excited as we all are about what mirror neurons could mean, we must tread cautiously. Not only are we uncertain about the role or computational basis of mirror neurons, but we have yet to verify them as the cause of the symptoms in autism. It remains a possibility that other neurons, lower down in the cortical hierarchy, are the real culprits that contribute to broader range, higher-up dysfunction.

Perhaps there is a way to refine these results though. Let us assume for a moment that their proposed framework for autism is correct, that mirror neuron dysfunction is one of the primary factors in autism. Have we also, by understanding the cause, found a cure? Perhaps. A fundamental principle in neurobiology is that cells that fire together wire together (and cells that are out of sync, lose their link). Assuming that mirror neurons are not actually absent in autistic children, would it be possible to condition them to emulate mirror neuron activity? Could we, by simultaneously showing an autistic child a video of a hand opening and closing and telling him to perform that action in synchrony, alleviate some of its symptoms? The answer probably depends on how impaired their mirror neuron system is with respect to how sophisticated a normal one is. If the mirror neuron system is highly extensive — say, if emotional systems were involved in addition to motor tasks — then the amount of therapy may be too complex and rigorous to serve as a practical form of treatment. This is not to mention that there could be collateral associations formed that could prove deleterious enough to outweigh whatever benefits it may provide. More problematic would be the ethical issues in such an experiment. Is emotional conditioning, especially fear and pain condition, justifiable in cases like these, or would this become the leading edge of the footsteps towards the Brave New World of Our Ford? It is hard to say, but either way, an experiment on the efficacy of neurofeedback in motor tasks for treating autistic symptoms may tip us off on whether it would be plausible as a therapy not only for autism, but for other neurological or psychiatric disorders as well.

too busy to blog

2008-09-16T18:29:00.000-07:00

I have been incredibly busy lately. I have not, however, been neglecting my autism work; I just haven't had a chance to put together my reflections from my readings in blogoform yet. After my presentation tomorrow, I should be quite a bit more free. I'll definitely have the time between Thursday and Sunday to give this poor, malnourished blog the attention it deserves.

In the meanwhile, I'll list the articles that I've been reading or will be reading up my next post. They can be found here, here, here, and here, in case any readers would like to get the detailed story, but I'm also going to start my article posts with a quick synopsis that'll hopefully provide enough background to allow you to understand where I'm coming from even without reading the article.

Oooook, back to work. See you soon!

Phantom Limbs, Pessimism, and Free Will

2008-09-11T14:53:00.000-07:00

I've been slightly unfaithful recently. I've been voraciously chomping down articles and info on mirror neurons, developmental neuro, and genetics on autism, but a few days ago, I read an article that made my day. It was for my integrative neuroscience class, called "Phantom limb pain, cortical reorganization, and the therapeutic effect of mental imagery". You can find it here if you want to read it. Its target topic is the cortical reorganization that coincides with phantom limb syndrome, but its results have other, somewhat more philosophical, implications as well.

At the risk of sounding a sadist, I love phantom pain. I think it profoundly illustrates so many abstruse topics in neuroscience. For starters, pain is not something that we really understand in neurobiological terms. There are different hypotheses about what level on the neural axis it occurs, but generally speaking, it contains some very elusive circuitry. One of the main hypotheses behind phantom pain is the disruption of inhibitory neurons by amputation of a limb, leading to an exaggeration of pain sensation. A very sensible hypothesis, and likely true, though in my somewhat naive opinion, unlikely the entire truth. The first thought that had the inertia to rattle my thick skull when I read this, however, was how ostensibly macabre this view is. We need to inhibit pain, or it will become persistent. This stands in stark contrast to the intuition that pain is something that is elicited by some stimuli, but if this hypothesis holds true, it may be the opposite -- we are constantly holding pain at bay until some stimulus tells us to release it. I would advise you not to inform the emo kid about this, lest you wish to release a complimentary torrent of painful gloating and sulking.

But when I thought about it some more, perhaps that's not quite right. The possibility that pain is regulated by inhibitory connections does not preclude the concurrence of excitatory connections as well. Perhaps, like many other perceptual systems, the nociceptory system is constantly adjusting itself to the sensory input in a complex feedforward/feedback loop, rather than sending information up a one way escalator up. If this is the case, then what this case would illustrate is not the cruelty of the world, but the incredibly sophisticated fine modulation that is occurring throughout your nervous system, and indeed your body as well. I'll definitely have more on this later, so I should probably hold off on fine-tuning until then.

That was the tangent. The reason the article made my day is because of its technique. The experiment used meditation and mental imagery to treat the symptoms of phantom limb syndrome, which not only significantly reduced phantom pain, but, would you believe it, significantly altered cortical organization. In other words, they "thought" the pain away. How beautiful is that! Mentally constructed techniques that originated from the "top", flowing down the cortical hierarchy and reorganizing the cortex so profoundly as to alter an inferior pathway like nociception. This, I think, exemplifies free will at its finest -- the ability to effect a noticeable change on your cortical architecture by merely thinking. I've actually sent this article to several friends who've mentioned how glum they are about the impending demise of free will because of neuroscience. But here we are, compelling evidence from neuroscience that we can, in fact, exercise control over lower steps in the hierarchy by overt activity -- free will!* One can only wonder how much power we have to control destructive habits, neuroses, or even mental disorders if we have the patience and dedication to effect change.

*For the philosophers that may be reading this: I know that this doesn't necessarily mean free will is "real", because part of the problem of free will seems to be the lack of a precise definition. Is our ability to control any aspect of our behavior, cognition, or mind to any degree required for free will? Then clearly, we do not have it. Only an omnipotent being could boast free will given such demanding criteria. Alternatively, how does free will stand up to the fact that we are essentially an unimaginably complex chemical reaction stretched across the thin layer of organic matter that glazes the surface of the earth? Or how about the random fluctuations of electrons at the quantum level -- is quantum indeterminacy also the capricious executioner of any hope for free will? In the end, an inquiry about such an abstract, hypothetical construct is encased by what lens through which we choose to view it. Thus, whether this article can be construed as evidence for free will is not only conditional, but irrelevant. What I enjoyed about it is not that it provides a strong inductive argument for free will, but rather that it informs us of the incredible influence we have over the regions of our mind traditionally considered inaccessible to conscious effort, given the determination and patience to effect an end.

Environment and Autism

2008-09-08T16:03:00.000-07:00

I've been going through a bit about autism, but I haven't gotten to any of the hypothetical frameworks or precise neurobiology, so this entry is going to be somewhat of a cop out entry. A good way to start the Fall.

What I've been reading about autism, however, is that it's (roughly) defined as a developmental disorder characterized by poor social development, impairment of communicative skills, and ritualistic behavior. Research in twin studies has implied that genetics account for much of autism, but the question of what role environment plays hovers in my head. One issue that comes to mind is that if genetics plays a large role in explaining autism, how many of the studies were conducted on adopted children. After all, nurture clearly plays an enormous role in the social and behavioral development of humans; if genes are a significant factor, this may imply that a parent or both parents have the potential for possessing alleles that place them in the proximity (if not within the range) of autism-spectrum disorders insofar as their behavior deviates slightly beyond the average, though not to such an extent as to be classified as a disorder. The behavior of these parents may have a significant effect on the social, communicative, and behavioral tendencies, which then exacerbate an existing genetic propensity for abnormality.

I am reminded of feral children, who often display similar symptoms to autistic children. One case does more to capture this more than any other: a few years ago, a child named Danielle was discovered to be the subject of such profound neglect that she has not been able to learn a language to this day -- the term "environmental autism" was coined to describe her. She was found in revolting conditions, malnourished and isolated, and would not make eye contact or respond to the typical stimuli. You can find an article about her here. Aside from the profound moral aversion of this case, it also illustrates the intimate role the environment plays in how we respond to and cope with the world. This is obviously a most extreme case, but the point remains of how much influence the parent-child interactions have influenced the course of disorder in autistic children.

But maybe I'm attacking the genetic basis because I'm a little biased. Another topic that's occupied a prominent portion of my thoughts is the organizing principle of the nervous system, from proliferation of neuroblasts to differentiation and finally to maintenance of synaptic integrity. Vernon Mountcastle, the discoverer of the cortical column, described it as the organizing principle of the neocortex. The idea that the principles by which the neocortex is organized are uniform throughout the cortex is integral to the memory-prediction framework, which asserts that each column is computationally equivalent in the cerebral hierarchy. So instead of a lot of genes being transcripted that are specific to different aspects of intelligence, the neocortex is by virtue of its computational properties uniformly intelligent. What happens is that information is fed back and forward among the hierarchies, but the tasks that are executed by the neocortex is the same all over; it's just the inputs and outputs that are different. This seemed to make sense to me not only because of the structural similarity seen throughout the neocortex, but also given the fact that (1) humans only have approximately 25,000 genes and (2) because the neocortex displays an extraordinary degree of plasticity. A congenitally blind person will, for example, be born with a brain that is structurally similar to a normal person, but their visual areas will adopt different roles.

Overall, this view is a very ingenious way of unifying all these different traits. The thing is, autism and other congenital brain disorders set off a warning signal in my head. If the neocortex's functions are so plastic and so uniform, why does autism have such a specific constellation of symptoms? This fact seems to suggest that there are certain genes that code for certain functions, unless autism can be said to be primarily an environmental disorder -- but that doesn't seem to be the case. How can this apparent discrepancy be account for, I wonder... or will it simply go down as a strike against the idea of organizational principles ubiquitous in the neocortex?

I'll think about it some more as I delve deeper into the world of autism -- I have a hunch that tells me the answer may lie in the details.

a quickie

2008-07-24T16:36:00.000-07:00

I have been reading "On Intelligence" by Jeff Hawkins. It's really immensely interesting and captures the path I think the neurosciences should start pursuing. I'll post about it when I'm completely through with the book -- I'm taking my time with it, chewing it over, so I don't miss any important connections, especially with the material that I'm moving through now.

Speaking of which, I have a lot of stuff on Alzheimer's now! Too much, in fact, for the brief few weeks I can devote to it, so I think I might have to take it easy on its biochemistry. The two major competing hypotheses on it have libraries of information, details, and research on it, many of which lend support for their own research and sometimes deface the alternate hypothesis. I am definitely not going to be able to sort through all that stuff and decide which hypothesis, if either, accurately detail the mechanisms underlying the disease, especially since I've run to several articles that bluntly contradict others. Ironic, I find, that I sought refuge in the empricism of science from the confounding, befuddling argumentation of philosophers, only to come upon another community who is constantly in conflict. At least, in my mind, science continues to build its empire upwards, slowly and deliberately, while philosophers still struggle with even the most basic, fundamental beliefs. I'm sure we'll solve the problem of Alzheimer's in time, as evidence accumulates.

Anyway, all that philoso-babbling aside, I did find a book on the cognitive neuropsychology of Alzheimer's, which will be stand in pretty contrast to the rest of all the dense biochemical reading I have on it. I'm looking forward to it!

Also, I'm going to China on August 10, so I won't be able to do much in that time, but I think I should be fine, as far as not trailing behind.

And I think that about does it for this short update.

2008-07-16T11:22:00.000-07:00

Ah, man. I am in love with V. S. Ramachandran. I think that should be the preface to all of my entries.

Actually, I have been making progress in shaping the way of this course in my head as well as in terms of research. I have decided that the focus of my study will be on epilepsy, Asperger syndrome/autism spectrum disorders, schizophrenia, amnesia, and Alzheimer's. I am not sure about the order yet, but I think I would like to keep epilepsy paired with ASD and amnesia with Alzheimer's. The rationale behind the latter pairing should be somewhat obvious, but the one behind the former is little more than an intuitive nudge. Perhaps it has something to do with how often savant-like abilities are associated with them. Or perhaps it's because I fancy them as insightful peepholes into this mysterious idea called "intelligence" that's locked inside our heads.

Before I decided upon the topics of my study, I grazed lightly on a much wider number of neuropathologies to get a feel for what they're like, how they're categorized, the basic principles, etc. I wonder now, however, how useful they will be for this course. The only thing is, their focus is primarily medical, and understandably so. As such, their pathologies are grouped in such a way as to maximize diagnostic efficiency and treatment. And while I am not trying to rail against medical conventions, my purposes are to investigate these diseases on a more etiological level (how they arise) before exploring their psychological, cognitive implications. So diagnosis and medication are not that useful to me. I'll be looking for the underlying mechanism to understand how treatments work and, using that, attempt to suggest possible alternative methods of treatment. So as far as producing models are concerned, I'm going to prefer to set pathologies that are mechanistically (and, in a different vein of thought, cognitive) similar side by side. Again, theoretic rather than medical. It might even be necessary to split what's often considered a single disease into multiple categories if different mechanisms produces similar symptoms. This would be especially likely in much more complex diseases that have higher-order, developmental components like schizophrenia or autism, which already have several different competing theories that are often just as valid as the others.

Why is this important? Well, I'm writing a Wiki for this class, so how I characterize and categorize pathologies are going to be one of the primary concerns. More importantly, though, doing a little rearranging and cleaning on these pretty aged medical terms might help shed light on them. Revolutions in scientific paradigm are often initiated by simple shifts in perspective. Understanding this, questions like, "Should ASD be thrown next to epilepsy or is it more illuminating to stick it beside ataxia or mental retardation?" does not seem as trivial. If you still think it's trivial, well, the Wiki is for a grade, so there's another reason to do it well... and if you still think it's trivial, then I applaud you, but I wonder why you're here at all.

Er, anyway. In summary, I've been looking into autism a lot. Mirror neurons are fascinating. I'll have more soon!

2008-06-14T05:49:00.000-07:00

I am back at my parents' house in Virginia. For some reason, whenever I get home, even when I tell myself I'm going to work diligently, I always end up slothing around like a lazy bum. I was reflecting about this last night, and a thought hit me.

Last semester, I did a presentation on an article that both differentiated long-term depression (LTD) from long-term depotentiation and investigated the behavioral effects of LTD inhibition. (LTP and LTD, for those of you who don't know, are essentially changes in the strength of connections between neurons; check here for some more info on it). It made me wonder, since depotentiation is merely the reverse process of potentiation, would there be a corollary for LTD? Not only would it give neurons an aesthetically pleasant mechanistic symmetry, it would make sense, too, for neurons to reserve a return point in case the LTD lose its usefulness. In doing so, a neuron can revert to its original state rather than potentiating too much. This way, not only are neurons free to potentiate or depress, but they have set previous state in case the behavior is no longer effective.

This would serve me well in explaining my plight. Why do I study so much better in my room at Delaware than in my room in Virginia? Stimulus wise, they are both desks with computers in them. Their chairs are equally comfortable, and I am comparably isolated from distractions in them. Yet, whenever I go to Virginia, a "no-studying" switch seems to be flipped, preventing me from doing any real studying. Could it be because I almost always go home to take a break from studying? Furthermore, could the mechanism for contextual conditioning be depotentiation and/or "de-depression"? Perhaps this is not something we can directly answer, but science has always relied in the kindness of indirect approaches. Experimentally, we would first determine whether such a thing as de-depression really exists. The methodology for this would be pretty straightforward: (1) inhibit LTP (so we know that it's not actually LTP doing this, but rather a distinct mechanism), (2) induce LTD, (3) use a tetanizing stimulus to encourage LTDD. From here, if there is an increase in synaptic efficacy, then we can assume that LTDD exists. If there isn't, well, it could still exist if it shares some part of its mechanistic pathway with LTP, and we've inadvertently inhibited it. So to confirm it thoroughly, we might have to inhibit LTP in several ways.

Taking it one step further, every student learns in psyc100 that addiction is merely a form of learning. This is relevant to us, because addiction is a testable, reliable form of learning. Moreover, the reversion point hypothesis presented here seems to correspond closely with cases of ex-drug addicts who quit for years or even decades, but try it "just once" and get sucked back into the addiction as badly as ever. Could this be due to a reversion point? A very unethical way of testing this would be to disable LTDD in the mesolimbic system (whose function is reward and is heavily implicated in addiction) in ex-heroin addicts and then giving them a shot of the drug. After that, observe. Do they freak out and spiral back into a cycle of junk and drugs? Or do they just go euphoric for a while, but then return to their normal, clean lives without much of a struggle?

This is, by the way, highly unethical, so maybe we shouldn't start on humans. But either way, it could be pretty cool, so I'll do some research and mulling and see if anything turns up.

Hello!

2008-06-11T10:45:00.000-07:00

And welcome! Since this is the first post, I suppose the proper way of starting this is by introducing myself as I am presently. On today, June 11, 2008, I'm a neuroscience undergraduate at the University of Delaware. (If there are any changes to the above, you will be duly notified). I've started this blog as a journal of my thoughts and reflections related to topics concerning neuroscience, with emphasis on those pertaining to my independent study on neuropathology this fall. I probably won't start posting regularly until my class is about to begin, but I will drop a thought every now and then during the summer.

I guess it's also worth mentioning that, while this is a professedly neuro-blog, I'll try to keep this from being too esoteric to retain some appeal to a broader audience. So if you're not an adamant neuro-nerd, stick around anyway -- you may find something interesting yet!

always,
your friendly neighborhood neurophyte