Medium Spiny Neuron

J. David Sweatt, acrylic on canvas, 2008–2009

A. Amnesias

Amnesia is both frightening and fascinating to contemplate, so much so that Hollywood has turned to amnesia as a plot device on many occasions (see Table 1). The term amnesia is derived from mnemos, which is the Greek root for memory. Mnemos is derived from Greek mythology—Mnemosyne was one of the mythological Titans, and she was the goddess of recollection or remembrance—it was she who gifted humans the capacity for memory. Mnemosyne was one of Zeus’ lovers, and she gave birth to the nine muses. The muses are the source of inspiration for music, poetry, and stories. They also invented the combining of letters, i.e., writing, arguably the most useful technological development in the history of information storage.1

Table 1 Movies Using Amnesia as a Plot Device

Here are some personal comments, for what they are worth. Memento and Finding Nemo: outstanding movies that, without a doubt, are the most scientifically accurate movies ever made involving a character with a memory disorder. 50 First Dates: I have to admit I couldn’t stand to watch more than about 10 minutes of this—a chick-flick all the way. The Bourne Identity, Total Recall, Spellbound: pretty good action-type films. The disclaimer here is that these are probably the male equivalent of a chick-flick, whatever that’s called. Eternal Sunshine of the Spotless Mind: pretty creepy sci-fi for something that basically is a chick-flick. The Forgotten: the amnestic angry-mother variant of a chick-flick. Men in Black: OK, not much amnesia really, but at least it’s not a chick-flick. Mulholland Drive: Classic David Lynch, and if any movie qualifies as the antithesis of a chick-flick, this is it—seriously. If anybody understands what the heck was going on in this movie, please tell me. Product Liability Warning—never, ever try to watch Memento and Mulholland Drive in the same night—your brain will probably explode.

Thus, based on its Greek language roots, amnesia literally means “no memory.” As a clinical syndrome, amnesia is referred to as being either retrograde or anterograde. Retrograde amnesia is a loss of previously formed memory. Thus, it is the loss of memories that were formed before the memory-damaging insult. The term retrograde amnesia is reserved for profound loss of memory, and is distinct from normal forgetting. Retrograde amnesia is the classic plot device wherein the character wakes up and can’t remember who or where he is. Retrograde amnesia can result from injury, disease, or profound psychological trauma.

As a practical matter, it is extremely difficult to distinguish whether retrograde amnesia results from a loss of memory storage or a loss of the capacity for memory recall. We will return to this issue later on in Chapters 4 and 5 where we will discuss experimentally-induced amnesias.

Anterograde amnesia is a loss of the capacity to form new memories. Anterograde amnesia results from a lesion or deficit in the anatomical, cellular, or molecular mechanisms necessary to acquire and store information in the nervous system. In its purest form, anterograde amnesia leaves every previously formed memory still intact and available for recall. Individuals with anterograde amnesia typically have intact short-term memory, but lack the capacity to form long-term memories. Sadly, these individuals live a moment-to-moment existence because they are unable to remember anything that has happened to them for more than a few minutes.

B. Memory Consolidation

Studies with amnestic human subjects have identified a process that we now refer to as memory consolidation. Briefly stated, the idea of memory consolidation is captured in the theory that memory formation and stabilization proceeds as a time-dependent process, and that with time memories get stronger, i.e., less susceptible to disruption. The theory of memory consolidation is now ancient by modern scientific standards. One of the first observations to suggest memories need be consolidated came over a hundred years ago, using human subjects, where distraction and interference immediately after a training session could disrupt long-term memory formation, whereas the same distractions long after a training session had limited effects (1).

Physicians also had noted that patients that had an epileptic seizure could often experience a loss of memory for events immediately preceding the seizure, or that head trauma cases might experience the same effect. In a more recent and systematic study of this effect, Larry Squire and his colleagues studied retrograde memory effects (amnesia) in patients that had been given electroconvulsive shock, which triggers epileptic seizures. Note that the seizures in this case are triggered specifically, safely, and therapeutically—electroconvulsive therapy (ECT) is used clinically in cases of severe intractable depression. This iatrogenically-induced type of seizure allowed a unique opportunity to study retrograde amnesia in humans in a prospective and controlled memory study. Because the patients had the seizures at a predefined time, and were available both before and after the ECT treatment, this allowed Squire and his colleagues to systematically evaluate the retrograde amnestic effects of seizure (2). Their finding was that memories less than two years old were much more susceptible to seizure-associated transient loss than older memories. These findings were particularly compelling because the investigators were able to test memory in the same individual both before and after seizure. These findings and many others like them provide a compelling case that memories are differentially susceptible to disruption, depending on how old they are. The mechanistic implications of this are critically important—the finding implies that older memories are stored or recalled using different cellular/molecular mechanisms than newer memories. There is no other way they could be differentially susceptible to disruption.

We will return to animal studies of memory consolidation as a cellular and molecular process many times in this book, but human studies were the first to suggest the existence of the phenomenon. It should not escape your attention that the human studies also demonstrate the clinical relevance of understanding amnestic mechanisms.