Known for decades as patient H.M., Henry Molaison was familiar, indeed dear, to neuroscientists. In 1953, epilepsy surgery to remove a tiny part of his brain left him forever unable to acquire new facts and store them. His case gave the field its first solid evidence that the hippocampus was involved in memory (see Scoville and Milner, 1957). During Molaison's life, MRI scans gave low-resolution views of his brain after surgery, but could not resolve crucial details about the borders of the lesion or the underlying cellular structure of his medial temporal lobe. When Molaison died in 2008, scientists preserved, froze, and thinly sliced his brain. From the resulting images, researchers led by Jacopo Annese at The Brain Observatory, San Diego, in collaboration with Suzanne Corkin at the Massachusetts Institute of Technology, Cambridge, have digitally reconstructed a detailed three-dimensional map of his brain and now report in the January 28 Nature Communications that more of the hippocampus remained than had been believed. 

"The study of H.M. inaugurated the modern era of memory research," said Larry Squire, University of California, San Diego, who was not involved in the project. "With a case as important as this, we are going to want to know as much as we can about his brain."

Henry Molaison was just 10 years old when his seizures started. By age 27, in 1953, they were disruptive enough that doctors removed the affected portions of his brain: the medial temporal lobe structures, including part of the hippocampus. After the surgery, it quickly became apparent that he had lost the ability to form new declarative memories—ones involving facts and knowledge—though he retained his attentional and working memory capacity, as well as his intellectual abilities and personality. The surgeon's sketches approximated the removed areas, but not their true extent. With advances in brain MRI, Corkin's group later estimated that the resection included the medial temporal polar cortex, most of the amygdaloid complex, most if not all of the entorhinal cortex, and much of the hippocampus, including the dentate gyrus (see Corkin et al., 1997). 

When Molaison died from respiratory failure, researchers fixed his brain in formaldehyde, then froze it in gelatin. In a 53-hour procedure that took three days, Annese's group used a giant microtome to slice his brain into 2,401 sections 70 μm-thin (see a video of the painstaking process by clicking on the photo below). They photographed the surface before each slice was shaved off, used Nissl staining to visualize cell bodies in about every 20th slice, then digitally reassembled the brain in three dimensions to reveal structural details at the cellular level. All the slices have been cryogenically preserved in a secure freezer and the unstained ones will be reserved for forthcoming studies. 

Much analysis remains to be done on H.M’s brain map, but these initial published results suggest that his posterior hippocampal region was left intact. The first MRI images only allowed low-resolution, two-dimensional measurements of the length of the hippocampus. Later, three-dimensional MRI estimated the volume of the formation, but was still only approximate. 

The new map gives unambiguous measurements that indicate a slightly longer hippocampus with about double the previously estimated volume, Annese told Alzforum. It fits with Molaison's cognitive abilities, he added. For example, Molaison was able to hold a conversation with a visitor, but the next day would experience the same, returning visitor as meeting them for the first time. 

What's more, the neurons of the hippocampus are surprisingly intact, suggesting they remained connected to something even though the inputs from the entorhinal cortex were almost completely severed. People assumed that this tissue would have atrophied, Annese said. "I hope that the study stimulates memory researchers to go back and revisit the assumptions that were made based on the idea that H.M. had no hippocampus left." His group also found a previously unrecognized lesion in the left orbitofrontal cortex, likely a consequence of the original surgery, which they will study further. Researchers can explore H.M.'s brain in an interactive atlas on The Brain Observatory website.

Annese said that since publication, he has gotten hundreds of requests from all over the world to explore the atlas. In the future, outside researchers will be able to request access to certain slices for their own investigations. 

Some scientists contacted for this article commented that live imaging has already revealed the most important elements of Molaison's surgical lesion, but others said that his brain can still offer new insights into memory. For instance, scientists want to explore the intact hippocampal cells further, given that the surgery removed crucial inputs from the entorhinal cortex, Squire told Alzforum. Researchers are also curious to know the boundaries of the surgical lesions, to better understand some of H.M's difficulties. 

Squire added that neuropathologists will want to characterize the nature and extent of H.M.'s dementia, which started in the final decade of his life. Annese said his group stained for plaques in the hippocampus, but turned up nothing. Molaison's dementia looks to have been caused by microvascular disease instead, he said. So far, the preliminary findings change nothing about what researchers understand about Molaison's cognitive abilities or memory function in general, Squire said.

This "technical tour de force" reinforces the power of MRI images while showing how much more detail still remains in the classical histological approaches, Bradley Hyman of Massachusetts General Hospital, Charlestown, Massachusetts, wrote to Alzforum in an email. Hyman pointed out that the relative contributions to H.M.'s memory problems of surgery, deafferentation, seizures, aging, and potentially age-related changes will be hard to tease apart. "Nonetheless, the demonstration of this amazing three-dimensional reconstruction of a case of such historical importance is exciting," he added.Gwyneth Dickey Zakaib

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Comments on News and Primary Papers

  1. H.M. was the poster child of the lesion method for studying brain-behavior relationships and cognitive sequelae. His death provides the scientific community an opportunity to take an excruciatingly detailed investigation of the role of the anterior hippocampus and the entorhinal cortex in brain function and examine what part these critical brain regions have played in cortical and subcortical remodeling and compensatory functionality.

    What is even more fascinating for those of us in the dementia field is that H.M. was said to suffer from progressive cognitive decline in the later years of his life. It would be interesting to study the series of papers that will most certainly follow reporting the detailed immunohistochemical and stereological investigations of his brain. This is certainly one of the many significant publications that will result from in-depth investigation of H.M.'s famous brain. We will be tuned in for years to come.

  2. This is a fascinating paper, with three main points of interest: First, it is notable that H.M. has a near-complete ablation of the entorhinal cortex, yet there is remarkable preservation of many hippocampal regions (i.e., the dentate gyrus, the CA subfields, and the subiculum). The dentate gyrus receives nearly all its synaptic input from the entorhinal cortex. I am often asked how is it possible that the entorhinal cortex is affected first and foremost in Alzheimer's disease, yet the dentate gyrus is relatively preserved. This study suggests that the dentate gyrus can "survive" even without an entorhinal cortex.

    Second, that the anterior hippocampus was excised more than the posterior hippocampus is interesting. As the authors point out, the monosynaptic connections of the anterior hippocampus support its role in mood and behavior. And this might account for H.M.’s affect, as described in the paper. At the same time, the anterior hippocampus has been implicated in schizophrenia, and H.M. clearly did not have psychotic symptoms. This agrees with the observations that in schizophrenia, the anterior hippocampus is hyperactive—a sort of “toxic” gain of function. Thus, one would not expect that H.M. should manifest psychotic symptoms. In fact, the extreme view would maintain that without an anterior hippocampus, he could not develop schizophrenia. One thing that is not commented on is whether H.M. has evidence of tau or amyloid pathology in the neocortex. If he does, this would suggest that tau pathology in AD does not all emanate from the entorhinal cortex, as suggested by some. Hopefully, the authors will be able to address this very important question in a future study.

    View all comments by Scott Small

References

Paper Citations

  1. . Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957 Feb;20(1):11-21. PubMed.
  2. . H. M.'s medial temporal lobe lesion: findings from magnetic resonance imaging. J Neurosci. 1997 May 15;17(10):3964-79. PubMed.

External Citations

  1. The Brain Observatory

Further Reading

Primary Papers

  1. . Postmortem examination of patient H.M.'s brain based on histological sectioning and digital 3D reconstruction. Nat Commun. 2014;5:3122. PubMed.