The personal tragedy of the famous amnesic patient known for more than 50 years only by the initials H.M. revolutionized the science of memory. In a special lecture during the annual meeting of the Society for Neuroscience in San Diego last month, researcher Suzanne Corkin summarized what H.M., whose full name was Henry Molaison, has taught us about memory, and what we may still learn from him now that he has died.
“His contributions to science continue,” said Corkin, “and just as we learned so much from him during his life, we will continue to do so after his death.”
Corkin, professor of behavioral neuroscience at MIT, is one of more than a hundred people who studied Molaison over the years. He has “taught us a great deal about the neural and cognitive organization of memory,” she said, and “probably contributed more than all of the scientists put together.” And yet, despite working with him for more than 45 years, she said, “he never knew who I really was.”
Molaison began to have frequent epileptic seizures around age 15; the exact cause of the seizures is unknown. He had suffered a minor head injury after falling off his bicycle at age 7, but he also was genetically predisposed to the condition—his father had two cousins and a niece who had it. During high school, Molaison's seizures became progressively more severe and could not be eased with anti-convulsant drugs.
In 1953, at 27, he gave consent for a radical neurosurgical procedure—a bilateral medial temporal lobe resection—to be performed on him as a last resort. Described by William Scoville, the surgeon who performed the operation, as “a frankly experimental procedure,” it involved removing brain tissue from the inner surface of the temporal lobes, including the anterior half of the hippocampus, the perirhinal and parahippocampal cortices, and most of the amygdalae, small structures involved in emotions. The entire entorhinal cortex from both hemispheres also was removed, which severed the pathways that send information to the hippocampus.
The operation significantly reduced the frequency and severity of his seizures, but tests performed subsequently by neuropsychologist Brenda Milner showed that it came at a huge cost. Milner found that Molaison had profound anterograde amnesia, or an inability to form new memories, and could only retain small amounts of information for short periods of time. His amnesia was “pure,” leaving other mental processes, such as perceptual skills and lexical and grammatical processing, unaffected. He also had an IQ that was above average, and showed no adverse psychiatric symptoms.
Earlier studies of other people with amnesia had suggested that the hippocampus is necessary for memory formation; Milner's data on Molaison provided the first direct evidence that this is the case. It also showed that memory consists of distinct short- and long-term components, an idea that dates back to psychologist William James. Milner and Scoville described their findings in a groundbreaking 1957 paper that set the stage for modern memory research. (See also "Memory as a Life’s Work," an interview with Brenda Milner.)
Discovering the workings of memory
Corkin joined Milner’s lab in 1962 as a Ph.D. student, and continued to test Molaison’s memory function. Her work revealed more about his memory impairments, and about the workings of memory in general. She found that he could remember some types of information but not others. He could remember specific details about World War II, for example, but not what he had done earlier on the day or what he had for breakfast or lunch.
Corkin found that Molaison could draw an accurate floor plan of the house he had moved into after his operation, but he had great difficulty finding his way around in real time using maps. He could learn to perform simple motor tasks, such as tracing a figure while looking at its reflection in a mirror, and could remember facts about a small number of celebrities when presented with them repeatedly, but could not learn the meaning of new words.
His experiences showed that there are distinct types of memory, each of which has a different neural substrate. Molaison could not form new memories, or recall facts and events that occurred during his life, because his hippocampi were missing. His ability to learn new motor skills remained, however, because motor learning is dependent on a structure called the striatum, which was left intact. And he could retain information about a handful of celebrities because the connections between his remaining parahippocampal gyrus and other neocortical areas were functional.
Corkin’s findings illustrated the distinction between declarative memory (knowing what and when) and non-declarative memory (knowing how). They support the hypotheses that structures in the medial temporal lobe, especially the hippocampus, are required for the retrieval of autobiographical memories; that factual knowledge becomes independent of the hippocampus with time; and that memory retrieval involves the reactivation of cellular ensembles in the medial temporal lobe and neocortex whose activity constitutes a “memory trace.”
Of course, many questions about memory remain, and although Molaison has now died he may yet provide further insight into its mysteries. In 1992, Corkin asked Molaison and his relatives to donate his brain upon his death. They agreed, and 10 years later she and her colleagues made step-by-step plans to preserve the organ after his death. When Molaison died, on Dec. 2, 2008, his brain was removed, scanned by functional magnetic resonance imaging, and later transported to The Brain Observatory at the University of California, San Diego.
“H.M. wanted his brain to be beneficial to science," says Jacopo Annese, director of The Brain Observatory, "and we are trying to make it as beneficial as possible. By looking at the anatomy in detail we can elaborate on our assumptions about memory, because the exact anatomical mapping will show just how much of each section of his brain was removed.”
Phase I of Project H.M. began exactly one year after Molaison's death. Partly funded by The Dana Foundation, it involved using specially designed equipment to freeze the brain and then slice it into 2,401 sections, each just 70 thousandths of a millimeter thick.
Annese and his colleagues plan to digitize the data and make it available to other memory researchers. He says that this shared resource will probably be put online in February 2011, along with new software that can integrate the different types of anatomical data. “The two-dimensional data sets [from the cutting] and three-dimensional data sets [from brain scans] are two separate entities, so it would be desirable to create an interface viewer that would combine them both," he says.
Phase II of the project started in January 2010, once the sectioning was completed and the researchers had cryo-protected all the slices, Annese said. “It involves histopathological tests [microscopic examination] for analyzing the brain. We have already stained two series of sections for cell bodies and myelin, and will reconstruct that region of the brain from the images we acquired during the cutting.”
"Obviously everyone is interested in knowing the extent of the lesion,” he said, “and here at the meeting I have talked with other anatomists who are interested in examining what is left of the hippocampus. I am also working with Matthew Frosch, a neuropathologist at Massachusetts General Hospital, to evaluate the damage done by his hypertension and the strokes he suffered.”
Knowing the extent of the hippocampal lesion, Corkin says, is “important in relation to any preserved memory he had—like motor skill learning. Also, we would like to know about his residual perirhinal and parahippocampal cortices, which we know are critical for different kinds of memory.”
Annese calls The Brain Observatory “a central neurological library,” and to the collection of brains held within it as being “like rare books.” Molaison’s brain, he says, “is definitely one of the most important books in this library, a very rare manuscript that we have to preserve.”