H.M.'s contributions to neuroscience: a review and autopsy studies

Abstract

H.M., Henry Molaison, was one of the world's most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 μm isotropic anatomical scans. The next morning, H.M.'s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.'s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 μm isotropic. Based on the MRI data, the anatomical areas removed during H.M.'s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nuclei-central and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalo-transition-area, ∼2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and ∼2 cm of posterior parahippocampal gyrus. H.M.'s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI.

Keywords: amygdala; entorhinal cortex; hippocampus; parahippocampal cortex; perirhinal cortex.

FIGURE 1

Blockface images of medial temporal lobe structures from a control case (60-year-old, male). Nine levels represent the anterior-posterior extent of the medial temporal lobe. Level (A) temporal pole, (B) pyriform (olfactory) cortex, anterior-most entorhinal cortex, (C) anterior amygdala, (D) mid-amygdala, (E) anterior hippocampal head (pes), (F) posterior hippocampal head, (G) posterior hippocampal head and anterior hippocampal body, (H) hippocampal body, (I) posterior hippocampal body, hippocampal tail (not illustrated). Numerical labels correspond to Brodmann areas, and letter abbreviations are defined as: AAA = anterior amygdala area, AB = accessory basal nucleus of amygdala, B = basal nucleus of amygdala, CA = cornu ammonis (1–4), CAT = cortical amygdala transition area, Ce = central nucleus of amygdala, Co = cortical nucleus of amygdala, CS = collateral sulcus, DG = dentate gyrus, ES = endorhinal sulcus, fm = fimbria, HATA = hippocampal amygdala transition area, HF = hippocampal fissure, L = lateral nucleus of amygdala, LV = lateral ventricle, M = medial nucleus of amygdala, Pre = presubiculum, Par = parasubiculum, SUB = subiculum, TP = temporal pole, and Un = uncus. Magnification bar = 1 cm.

FIGURE 2

Photograph of the whole fresh brain (inferior surface) taken at H.M.’s autopsy. In the ventral view, the white arrows on both sides of the brain indicate the lines of cut in the coronal MRI slices in Figure 5. These slices (white arrows) correspond to the in situ MRI (Figs. 5A–L). Note the area of excision and additional fibrous tissue (i.e., scar tissue) bilaterally, and the residual medial most tissue (bilaterally but larger on the left) in the medial temporal area, next to cranial nerve III. Abbreviations: B = basilar artery, M = medulla, MB = mammillary bodies, OB = olfactory bulb, OC = optic chiasm, ON = optic nerve, TP = temporal pole, V = vertebral artery, and III = cranial nerve III (oculomotor nerve). White arrowheads point to posterior temporal artery on both right and left. Dashed white lines illustrate atrophy in the cerebellum. Note the black surgical clip on right temporal lobe. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIGURE 3

Close-up photographs of H.M.’s medial temporal lobe showing a ventral view of the right and left temporal regions (A and B). Tissue was splayed out (due to being unfixed) to reveal a slightly different viewpoint of the extent of the lesion. In A and B, the lesion extends from the temporal pole to the midparahippocampal gyrus. Note the absence of tissue and the abundant scar tissue bilaterally. The basilar and vertebral arteries contain several atherosclerotic plaques. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIGURE 4

Various MRI contrasts acquired at 3.0 T in situ. (A) multiecho MPRAGE (MEMPR), (B) T2-SPACE, (C) T2-SPACE FLAIR, (D) quantitative PD, (E) quantitative T1, (F) synthetic FLASH. Note the lesion in all contrasts, with the borders especially clear in the multiecho MPRAGE and synthetic FLASH images. T1 and T2-SPACE FLAIR revealed scar tissue faintly in addition to the lesion.

FIGURE 5

Twelve coronal MR images showing the anterior and posterior extent of H.M.’s medial temporal lobe lesion. Images were synthesized from multi-echo FLASH scans acquired in situ and are ordered from anterior (A) to posterior (L). In all images, note the enlarged ventricles, general atrophy, and a plethora of regional white matter signal abnormalities. We identify particular structures (present or absent) in each panel. A, B, C: medial temporal pole removed; D: anterior entorhinal cortex removed (i.e. piriform cortex), E: cortical amygdala and possibly central nucleus remained; F: gyrus ambiens or uncus remained; G and H: perirhinal cortex and damaged parahippocampal cortex; I: the body of the hippocampus visible; J: first full observation of parahippocampal cortex (right side) and fimbria; K: posterior tip of the lesion (right side is past the lesion), and L: the undamaged parahippocampal cortex posterior to the lesion. Magnification bar = 1 cm.

FIGURE 5

Twelve coronal MR images showing the anterior and posterior extent of H.M.’s medial temporal lobe lesion. Images were synthesized from multi-echo FLASH scans acquired in situ and are ordered from anterior (A) to posterior (L). In all images, note the enlarged ventricles, general atrophy, and a plethora of regional white matter signal abnormalities. We identify particular structures (present or absent) in each panel. A, B, C: medial temporal pole removed; D: anterior entorhinal cortex removed (i.e. piriform cortex), E: cortical amygdala and possibly central nucleus remained; F: gyrus ambiens or uncus remained; G and H: perirhinal cortex and damaged parahippocampal cortex; I: the body of the hippocampus visible; J: first full observation of parahippocampal cortex (right side) and fimbria; K: posterior tip of the lesion (right side is past the lesion), and L: the undamaged parahippocampal cortex posterior to the lesion. Magnification bar = 1 cm.

FIGURE 6

Ex vivo images of medial temporal lobe areas acquired at 7 T. Images at 210 µm isotropic show the extent of the lesion and remaining medial structures. For level-of-cut cross reference, see Figure 5. Panels A, B, and C correspond to the MRI slices in Figures 5E–G. A shows H.M.’s lesion approximately at the level of the amygdala. The lesion shape is relatively uniform at this level. Note the square corners at the dorsal-most part of the lesion. B demonstrates the lesion where the posterior amygdala-anterior hippocampal level would have been. Note the fornix columns medially in the hypothalamus and the irregular lesion shape. The large round black structures in C are regions of susceptibility surrounding air bubbles. C illustrates the lesion at the level of the mammillary bodies where the head of the hippocampus (i.e., pes hippocampus) would normally reside. At level C the lesion narrows. The shape of the lesion changes considerably from anterior to posterior, scar tissue is visible. The white arrowheads point to the collateral sulcus. Numbers represent Brodmann areas. Abbreviations: AC = anterior commissure, ES = endorhinal sulcus, FX = fornix, MB = mammillary bodies, OC = optic chiasm, RN = red nucleus, and SN = substantia nigra.

FIGURE 7

Axial view of the multiecho FLASH images. Line measurements were acquired in the axial plane to assess the anterior-posterior lesion size. The ablation on the right side measured 5.5 cm while the left measured 6.0 cm. The left temporal lobe lost considerably more cortex during surgery. Note the cerebellar atrophy due to Dilantin.