The long story of Patient H.M: a mile-mark in research on memory


Henry Gustav Molaison, born in 1926 and grown up in and around Hartford (Connecticut),has beenfor about half a century, until his death in December 2008, the most studied human being in the history of psychology, interviewed by at least 100 researchers and mentioned in thou­sands of journal articles.

Molaison began to suffer from a devastating seizure disorder at age 10. The cause of his seizures is uncertain, but his father's family had a history of epilepsy, and a colli­sion with a passing bicycle rider had once knocked Henry unconscious for several min­utes. The seizures worsened through his teens and 20s until frequent blackouts and increas­ingly severe convulsions left him unable to continue his work repairing electric motors, despite high doses of anticonvulsant drugs. He ended up in the care of William Beecher Scoville, a neurosurgeon at Hartford Hospital, who in 1953 decided to remove, via suction, a finger-sized piece of the temporal lobes on both sides ofMolaison's brain, including most of the hippocampus, amygdala, and nearby para­hippocampal gyrus. Scoville tried this experimental surgery because he had previously performed such bilateral medial temporal lobotomies on dozens of psychiatric patients, hoping to calm their psychosis without the personality changes associated with the more drastic frontal lobotomies. But this experimental brain surgery left Molaison, at age 27,unable to form new memories. In fact, although Molaison's seizures had diminished greatly, he now exhibited profound amnesia. He easily recalledevents, such as facts he'd learned and names of people he'd encountered, prior to his operation but had virtually no lasting memories of anything that had happened since. Evidently Molaison's ability to learn and retain new facts, what researchers now call declarative memory, had been devastated by removing a relatively small part of his brain.

Molaison cooperated with psycholo­gists and neuroscientists, and his case reshaped scientific thinking on the neural basis of memory, because helped establish several modern tenets of memory research, including the notion that there are different types of memory that depend on different brain regions, and the concept of memory consolidation, which holds that new memories formed by the hippocampus are later archived in the cerebral cortex for long-term storage.


The digital reconstruction of the brain of amnesic patient Henry Molaison made by Annese's team


When Molaison died of res­piratory failure at 5:05 p.m. on 8 December 2008, the plan for preserving his brain for perpetuity sprang into action. A hearse took his body to Massachusetts General Hos­pital (MGH) in Charlestown, where researchers began collecting anatomical magnetic resonance imaging (MRI) scans of his brain at about 9 p.m. and continued until 6 a.m. the next day, when Annese arrived on a special flight from San Diego, and assisted MGH neuropathologist Matthew Frosch in removing the brain. Two months later Molaison's brain fixed in formaldehyde, was carried by Annese in an ice-packed cooler on a reserved flight from Boston to San Diego. Here Molaison's brain for some months soaked in a mixture of formaldehyde and sucrose insideatube inarefrigerator of The Brain Observatory. This mixture helped prevent ice crystals from forming and poking holes in the tissue when Annese froze the brain for slicing in following July. Using a microtome, Annese and his team sliced the brain whole into very thin sectionsin a marathon 30-hour session, that was viewable online in real time. The procedure was followed by hundreds of thou­sands of people via the Internet and garnered attention and headlines around the world. Annese planned to slice the brain whole instead of first cutting it into smaller chunks as is more routinely done, because although small chunks are much easier to work with, the resulting slices are hard to keep in register with one another. Instead whole-brain slices keep more of the tissue intact and result in a more faithful reconstruction of the brain.

Annese and his colleagues ended up with about 2600 slices of Molaison's brain, each slice aboutthe thickness of a human hair. Then they mounted some of these, every 12th one to start, on extra-large glass slides - 13 by 18 centimeters - and treated them with a stain that colors cell bodies pur­ple. A camera attached to a microscope photographed each slice at 20x magnification, sufficient to distinguish different cell types. At that magnification, photographing a single slice requires a mosaic of about 40,000 individual images. An automated system carried out the job of moving the slice for each photo, focusing, triggering the shutter, and sending the shot to the San Diego SupercomputerCenter, which stored the data and stitched the images together into a composite for each slice. The MRI scans of Molaison’s head taken the night he died, once corrected, yielded a three-dimensional image Annese likens to the globe that appears on the open­ing screen of Google Earth - a starting point for navigation. Digital photographs and his­tological images provided more detailed neuroanatomical maps, down to the level of individual cells.

Other memory researchers are very interested for a better look at Molaison’s brain, that is where the boundaries of the surgical lesion were exactly. MRI scans lack the resolution to determine with certainty which bits of tissue survived Scoville's surgery and may have provided a residual memory function. In fact, despite his well-documented declara­tive memory deficits, Molaison every once in a while surprised researchers with a newly learned fact. Annese's postmortem anatomical studies provide a much clearer view, revealing more precisely the extent of surgical lesions, as well as subsequent degeneration.

Moreover, comparing Molaison's brain with those of other amnesic patients, that have agreed to donate their brains, may yield additional insights. Subtle behavioraldifferences among Molaison and other amnesic patients with injuryto themedialtemporal lobes, paired with anatomical comparisons, might help clarify the function of different regions within the temporal lobes. So preserving the donated brains of such unique patients and those with a variety of unusual neurological conditions has both historical and scientific great value.


The Digital Brain Library aims to collect the brains of 1,000 donors


But H. Molaison has been just the beginning. Annese and his colleagues are now poised to dramatically expand the scope and the goals of the UCSD Digital Brain Library. The challenge over the next decade is to collectthe brains and personal medical profiles of up to 1,000 donors. Unlike H.M. and other notable neuropsychological cases that have been referred by doctors, the vast majority of UCSD Digital Brain Library donors will be ordinary people. The Brain Observatory is currently collaborating with local donors or their families to produce the first series of cases that will offer truly holistic representations of different brain conditions. Some donors suffered from neurological diseases like Alzheimer’s and Parkinson’s, but others enjoyed apparent good brain health up until the day they passed. Neurologically healthy individuals are equally interesting and informative, because they provide context and a basis for making comparison with disease states.

The goal is boosting knowledge of how the human brain is wired and how disease and aging act upon it, then using that information to improve medical treatments and the lives of the patients.

With a large enough catalog of brains preserved as virtual models, scientists can explore and visualize them in novel ways that may provide glimpses into the governing principles of brain design and help scientists decipher the personal patterns of maturation and disease. A byproduct of this research will be 1000 personal neurological portraits: immense digital canvases that map precisely some of the biological complexities of individual (and social) behaviors.

Currently, the best way to peer inside a living human brain is through an MRI, which is a powerful diagnostic tool but cannot reveal the fine structural detail underlying brain function and neurological conditions. To do that requires the examination of the brain ex vivo; an undertaking that at a large scale presents obvious challenges.

Then the Digital Brain Library at UC San Diego has developed new protocols that combine the advantages and benefits of both of these approaches, and then transcends them.

Using innovative technologies, researchers preserve in the Digital Brain Library each brain in one piece, transforming it into an unabridged collection of sequential images that can be visualized at different levels of resolution, reassembled into three-dimensional models, or inspected with virtual dissection tools — all without compromising the integrity of the original dataset. Moreover, these images are corroborated by additional medical, neuropsychological, and even biographical data. So the final product isn’t just a series of slides, but a “neurological portrait” that describes not just the brain, but its owner too.

Some of the material is cryogenically preserved and protected for future, still-unimagined questions and experiments, while many very thin slices are cut at regular intervals, stained to reveal different features, and mounted onto postcard-sized glass slides. These slides are digitized, which allows them to be accessed and observed by countless researchers simultaneously, anywhere in the world, over and over again.

With microscope scanners designed at The Brain Observatory, each slide is an incredible source of information. Slides can be viewed microscopically down to a resolution of less than one-half of a micron per pixel. Each digitized slice requires a terabyte of disk storage (1 trillion bytes of information).

This deep digitization process also permits researchers to pull back for a more global view of the brain. They can even reassemble whole human brains in three dimensions and view them from multiple angles. So the Digital Brain Library takes the brain imaging process innovative, producing interactive images that can be studied and manipulated online anywhere in the world, and not just by specialists, but amateur neuroscientists too. In fact, Annese sees his project as an experiment in open-access science, and according to him amateur neuroscientists might make discov­eries that have eluded experts.

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