560 HM case study

Historical Vignette

The Legacy of Henry Molaison (1926e2008) and the Impact of His Bilateral Mesial

Temporal Lobe Surgery on the Study of Human Memory

Rimal Hanif Dossani, Symeon Missios, Anil Nanda

In 1953, neurosurgeon William Beecher Scoville performed a bilateral mesial temporal lobe resection on patient Henry Molaison, who suffered from epilepsy. The operation was novel as a treatment for epilepsy and had an unexpected consequence: a severe compromise of Molaison’s anterograde memory. In a landmark 1957 publication, Scoville and Milner concluded that mesial temporal lobe structures, particularly the hippocampi, were integral to the formation of new, recent memories. Over the next 5 decades, more than 100 researchers studied Molaison’s memory, behavior, and learning skills, making him one of the most famous patients in the history of cognitive neuroscience. Following his death in 2008, his brain was scanned in situ and ex vivo and then sectioned into 2401 sections. Histological evaluation of Molaison’s brain further elucidated which mesial temporal lobe structures were preserved or resected in his operation, shedding new light on the neuroanatomic underpinnings of short-term memory. Scoville regretted Molaison’s surgical outcome and spoke vigorously about the dangers of bilateral mesial temporal lobe surgery. This report is the first historical account of Molaison’s case in the neurosurgical literature, serving as a reminder of Molaison’s contributions and of the perils of bilateral mesial temporal lobe surgery.

Key words - Amnesia - Hippocampus - Mesial temporal lobe

Abbreviations and Acronyms AC: Anterior commissure H.M.: Henry Molaison IQ: Intelligence quotient MIT: Massachusetts Institute of Technology MNI: Montreal Neurological Institute MRI: Magnetic resonance imaging PC: Posterior commissure

From the Department of Neurosurgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA

To whom correspondence should be addressed: Anil Nanda, M.D., M.P.H. [E-mail: [email protected]]

Citation: World Neurosurg. (2015) 84, 4:1127-1135. http://dx.doi.org/10.1016/j.wneu.2015.04.031

Journal homepage: www.WORLDNEUROSURGERY.org

Available online: www.sciencedirect.com

INTRODUCTION

Henry Molaison (1926e2008) began suffering from epilepsy at the age of 10. His seizures started as petit mal but pro- gressed to generalized tonic-clonic type by age 15. The etiology of his seizures is un- clear. He had a history of epilepsy involving his father’s side of the family, and as a child, he sustained a minor head injury (8, 36). Despite high doses of a combination of several antiepileptic drugs, the seizures did not abate and caused se- vere limitation of his daily function. He dropped out of high school, lived at home with his parents, and became unable to hold steady employment (8). In 1953, after years of experiencing medi-

cally refractory seizures, Molaison under- went bilateral mesial temporal lobe resection, performed by William Beecher Scoville, “extending posteriorly for 8 cm from the midpoints of the temporal lobes,” an operation Scoville called “frankly experi- mental.” Following the operation, Molaison unexpectedly developed profound amnesia.

1878-8750/$ - see front matter Published by Elsevier Inc.

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In 1957, Scoville and Brenda Milner (Figure 1), then a neuropsychologist working with Wilder Penfield in Montreal, made a groundbreaking discovery linking bilateral mesial temporal lobe structures, particularly the hippocampi, to the formation of recent memories (33). Molaison’s postoperative amnesia chiefly

affected his long-term declarative memory, the ability to remember specific facts and autobiographical episodes after the opera- tion (1).His retrogradememorywaspartially affected, while his intellect and personality remained largely intact. More than 100 scientists examined Molaison and tried to identify the nature and extent of his memory deficits, making him the most extensively studied patient in the history of cognitive neuroscience (36). Magnetic resonance imaging (MRI)

(11, 29) was used to study Molaison’s brain. Following his death, his brain was sectioned into 2401 slices, each photographed at high resolution with selected corresponding slides prepared for histological study (4). MRI and direct brain examination precisely identified structures that were excised and

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spared in Molaison’s operation, further clarifying the association between the anatomy of the mesial temporal lobe and memory. This historical vignette offers a glimpse into Molaison’s life and chronicles the impact of his operation on the knowledge and study of memory.

HENRY MOLAISON, THE PATIENT

Henry Molaison, or H.M., was born on February 26, 1926, in Mansfield, Con- necticut, USA, a small town about 10 miles east of Hartford (Figure 2). His father, Gustave Molaison, was of French lineage and hailed from Thibodaux, Louisiana, USA, a community 60 miles southwest of New Orleans. His mother, Elizabeth Molaison, was of Northern Irish origin, and was born in Manchester, Connecticut, USA (8, 19). Molaison was an only child and was

raised Catholic. Growing up, he learned to roller-skate and took banjo lessons at a local music house. During his young childhood, he was involved in a bicycle accident, the details of which are not

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Figure 1. William Beecher Scoville (left, Photograph courtesy of Lisa Scoville Dittrich) and Brenda Milner (right, Photograph courtesy of Neuro Media Services).

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clear. It is unlikely, however, that he incurred significant brain injury from this accident. Pneumoencephalograms per- formed in 1946 and 1953 were normal (8). At the age of 10, Molaison began having

petit mal, absence seizures. On his 15th

Figure 2. Henry Molaison in Hartford, Connecticut, USA, in 1975. (Photograph courtesy of Dr. Suzanne Corkin)

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birthday, while he was in the car returning home after visiting with relatives, he sus- tained his first grand mal, tonic-clonic seizure. The etiology of his seizures re- mains unclear, despite his frequently recounted head injury as a child and family history of seizures on his father’s side of the family (8, 11). Electroencepha- lographic studies were negative for a locus of seizure activity. Molaison’s classmates teased him about his seizure disorder, and he soon dropped out of high school. A couple of years later, at the age of 17, he enrolled at East Hartford High School, finally graduating at the age of 21 in 1947. Molaison enjoyed target shooting in the countryside and, with the help of his father, formed a collection of hunting rifles and pistols. Following high school, he repaired electric motors and worked on a typewriter assembly line. The seizures, however, progressively worsened, and he struggled to hold any employment for long. He lived at home with his parents, socially isolated and with few friends (8). Molaison’s family doctor, Harvey

Goddard, referred him to Scoville, a well- known neurosurgeon who had established the Department of Neurosurgery at Harford Hospital in 1939 and held a faculty position at Yale University Medical School. Scoville

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obtained his Bachelor of Arts degree from Yale University and his Doctor of Medicine degree from the University of Pennsylvania and was formidably trained at the top med- ical institutions of the time, including Cor- nell and Bellevue Hospital in New York City and Massachusetts General Hospital and Lahey Clinic in Boston (8). Molaison likely had his first appointment with Scoville in 1943, at the age of 17 (8). Scoville placed him on maximal medical therapy including a combination of antiepileptic medications: phenytoin, phenobarbital, tridione, and mesantoin. On September 3, 1946, when Molaison suffered yet another tonic-clonic seizure, he was admitted for the fourth time to Hartford Hospital and a pneumoencephalogram was obtained, which was negative for any intracranial abnormalities (8). Despite maximal medical management,

Molaison’s seizures progressed for over a decade. Exhausted by up to 10 seizure episodes daily, he was desperate for relief. Scoville offered Molaison the option of bilateral mesial temporal lobe resection. Scoville had previously resected varying amounts of bilateral mesial temporal lobes in 30 psychotic, schizophrenic patients (34). However, only 1 of these 30 patients had undergone a resection as radical as the one Scoville recommended to Molaison—an operation aiming to remove 8 cm of bilateral mesial temporal cortex from the temporal tips (33) (Figure 3), including “the anterior two- thirds of the hippocampus and hippo- campal gyrus bilaterally, as well as the uncus and the amygdala.” On August 25, 1953, Molaison became the first patient to undergo such an operation solely for epi- lepsy (33), a procedure Scoville referred to as “frankly experimental.” Molaison’s seizure frequency was

reduced after the operation, although he remained on antiepileptic medications (4, 11, 33). The operation created a deficit that Scoville did not anticipate: a profound loss of recent memories and inability to form new ones. Molaison was unable to recall routine daily events or recognize hospital staff taking care of him. He could converse normally but several minutes later would become oblivious to the con- tent of the conversation or whom he spoke to. Molaison’s memory loss, however, was not complete. Researchers found a disso- ciation of his remote memory capacities:

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Figure 3. (AeD). Scoville’s cross-sectional illustrations depicting his attempted bilateral medial temporal lobe resection. (Only one side shown for diagrammatic purposes.) (Reprinted with permission from Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20:11-21, 1957. BMJ Publishing Group Ltd).

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his preoperative semantic memory, gen- eral knowledge of the world, was intact, but his autobiographical memory for preoperative events was destroyed (37). Nevertheless, his personality remained largely unchanged, his language skills were sharp, and he maintained an above-average IQ (10, 33). Subsequent

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neurocognitive testing demonstrated that he had preserved ability to acquire new motor skills (6, 24). At the 1953 Harvey Cushing Society

meeting, Scoville reported the profound memory loss in the cases of Molaison and a psychotic patient who underwent the same radical operation (11, 32). Around that time,

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Wilder Penfield, founder and director of Montreal Neurological Institute at McGill University, had performed two standard unilateral temporal lobe resections that had shocking results: the patients were rendered amnesic and manifested a deficit similar to Molaison’s (11, 23). Further workup revealed that one patient on autopsy had a lesion in the contralateral hippocampal formation (27), while the other patient on electroencephalography had a presumed lesion involving the contralateral mesial temporal lobe (11, 14). Thus both patients inadvertently had bilateral mesial temporal lesions. Brenda Milner, a graduate psychology student at McGill working under Penfield at the time, studied both patients and noted their memory deficits. Given their experience with such patients, Scoville invited Milner and Penfield to test his patients in an attempt to decipher a potential connection between mesial temporal lobe structures and memory. Scoville and Milner described 10 patients,

including Molaison, who underwent varying degrees of temporal lobe resection. Their results demonstrated for the first time that bilateral mesial temporal lobe resection involving the hippocampus and its associated structures lead to anterograde memory loss (31). Their results were published in one of the most cited papers in neuroscience. Molaison’s deficit was pure—restricted to his inability to remember new episodic, autobiographical events and not confounded by other neurological or psychological disorders. The purity of his deficit intrigued neuroscientists studying the memory processes of the human brain and increased Molaison’s popularity among famous patients studied in the history of cognitive neuroscience (8, 36). Suzanne Corkin, Molaison’s most dedi-

cated researcher, met him in 1962, when she was a graduate student at McGill working in Milner’s laboratory. She continued her study of Molaison after she founded her neuroscience laboratory at the Massachusetts Institute of Technology (MIT). Between 1966 and 2000, Molaison visited Corkin’s laboratory 50 times for neurocognitive testing (36). His medical chart listed Corkin as “the only interested relative, friend, or contact.” By the late 1970s, Corkin oversaw research access to Molaison, and researchers had to submit their proposals to Corkin for a chance to

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study Molaison. She instructed the staff at his care facility to safeguard his identity from interested callers. Her association with Molaison lasted 46 years (36). Immediately following his death, she arranged for detailed in situ and ex vivo MRI and a postmortem examination of his brain. She wrote a biography of Molaison and recounted his legacy to the study of memory in Permanent Present Tense, published in May 2013 (8). In the years following his operation,

Molaison continued to live with his parents. After his father’s death in 1966, Molaison spent his time at a workplace for mentally challenged men and women, where he per- formed such repetitive tasks as attaching key chains to a cardboard display stand. As he grew older and his mother’s health deterio- rated, he moved with his mother to the home of a nurse who was a distant relative. Hismothermoved to a nursinghome in 1977 (8). In 1980, the nurse was no longer able to care for him, and she moved Molaison to Bickford Health Care Center, a long-term- care facility in Windsor Locks, Con- necticut, USA, where he lived until his death on December 2, 2008, at the age of 82 (19).

OPERATION

Early in his career, Scoville performed fractional orbital frontal lobotomies on schizophrenic patients who were re- fractory to other forms of treatment (34). He believed that fractional lobotomies had a therapeutic advantage in treating psychosis and minimized undesirable side effects. Scoville modified his fractional lobotomy procedure when he learned of the close association between orbital frontal and medial temporal areas. In 30 schizophrenic patients, he performed bilateral medial temporal lobe resections of varying distances with or without orbital undercutting (35). In a 1953 publication, Scoville described

his mesial temporal lobotomy technique in meticulous detail. The temporal lobes were approached through bilateral 3.8 cm supraorbital trephine holes (11, 34). Once the temporal lobes were adequately exposed, Scoville made a “cortical incision . just anterior to the middle cerebral vessels under the midpoint of the sphe- noidal ridge so as to bisect the tips of the temporal lobes.” The middle cerebral artery was retracted posteriorly and

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superiorly using a flat spatula. The mesial tip of the temporal lobes was resected using fine suction. Intraoperative electro- encephalography was performed on the uncus, amygdala, and hippocampus, structures known to be commonly epilep- togenic, and no seizure activity was noted. The middle cerebral vessels were then retracted superoposteriorly, and the resection was extended to areas mesial to the temporal horns, including the “amyg- daloid nucleus, periamygdaloid cortex, and anterior portion of the hippocampus (34).” Molaison remained awake and conversant during the procedure (34). Scoville removed varying lengths of

bilateral mesial temporal lobes. In one group of patients, resection was limited to the “uncus and underlying amygdaloid nucleus (33).” In another group, resection was carried back “5 cm or more after bisecting the tips of the temporal lobes.” In one psychotic patient, all tissue was removed “medial to the temporal horns for a distance of at least 8 cm posterior to the temporal tips . which presumably included the anterior two thirds of the hippocampal complex bilaterally (33).” Molaison’s operation was unique for two reasons: The indication was epilepsy, and the removal of bilateral temporal lobes was as radical as the most extensive resection described by Scoville (33). Scoville carefully considered the deci-

sion to perform the more elaborate pro- cedure on Molaison. Before the operation, he had known Molaison for nearly 10 years, trying him on maximal doses of multiple antiepileptic medications (8). Electroencephalograms did not help in localizing seizure focus, showing instead diffuse abnormalities not clinically correlating with time of seizure activity (33). Scoville was familiar with the epileptiform tendencies of the uncus and hippocampal areas, and he noted “near absence of postoperative seizures” in his temporal lobe resection as compared with lobotomies in other cortical areas (33, 34). Finally, Molaison and his family’s desperation for any relief from the relentless seizure activity compelled Scoville to operate in such a radical manner (8). Scoville quickly realized the importance

of Molaison’s postoperative deficits for the study of memory. He invited Brenda Milner to perform tests of memory and

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intelligence on 10 patients who underwent varying degrees of temporal lobe re- sections. In addition to Molaison and a psychotic patient who underwent a similar 8-cm resection posterior to the temporal tip, the operative sample included “one bilateral removal of the uncus, extending 4 cm posterior to the temporal tips, and six bilateral medial temporal lobe resections in which the removal was carried back 5 or 6 cm to include also a portion of the anterior hippocampus. . One unilateral case was also studied in which right infe- rior temporal lobectomy and hippo- campectomy had been carried out for the relief of incisural herniation due to ma- lignant edema (33).” Scoville and Milner classified the mem-

ory deficit in these 10 patients in three cat- egories: severe memory loss, moderately severe memory loss, and no persistent memory loss. They noted that the degree of memory loss was proportionate to the length of bilateral mesial temporal lobe resection. Patients who underwent unilat- eral temporal lobe resection for herniation and bilateral uncinectomy had no persis- tent memory deficits. Those who under- went 4.5 to 6 cm of bilateral mesial lobe resection including the anterior portion of the hippocampus were classified in the moderately severe deficit category. Three patients were labeled as having severe memory deficit: two patients, including Molaison, who underwent the extensive 8 cm resection including the anterior two thirds of the hippocampal complex and one patient who had a 5.5-cm resection. Scoville and Milner were the first researchers to observe that bilateral mesial temporal lobe resections extending “far enough posteri- orly to damage portions of the anterior hippocampus and hippocampal gyrus” resulted in a “persistent impairment of recent memory (33).” Their work established the role of the hippocampus and the mesial temporal lobe as the neural structure responsible for the formation of new memories. The correlation, however, between the

extent of hippocampal resection and mem- ory deficits was not perfect because one pa- tient with a 5.5-cm resection had as grave a memory loss as Molaison’s. Scoville esti- mated the extent of temporal lobe resection on the basis of his intraoperative judgment, not on imaging studies (unavailable at the time) or histological analysis of resected

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brain tissue. Scoville remarked that “in the absence of necropsy material we cannot be sure of the exact area removed (33).” In later years, researchers were able tomap the exact contours of Molaison’s temporal lobe resection due to advances in neuroimaging and the availability of his brain for postmortem imaging and histological analysis (4, 5, 11, 29).

Figure 4. Axial T1-weighted magnetic resonance image obtained in 1992 showing extent of medial temporal lobe resection bilaterally. (Photograph courtesy of Neuro Media Services)

MAGNETIC RESONANCE IMAGING FINDINGS

A computed tomography (CT) scan of Molaison’s brain published in 1984 was not of sufficiently high resolution to define the boundaries of temporal lobe resection (7). MRI scans were not performed until 1992 due to concerns regarding compatibility of dural clips that were placed during the operation. Further investigation revealed that the clips were made of nonferromagnetic materials and did not pose a risk to patients undergoing MRI (11). Prior analyses of the hippocampal for-

mation showed that the entire rostrocaudal distance from the temporal pole to the caudal limit of the hippocampal formation is 7 cm (3, 11). If Scoville’s resection actually involved 8 cm ofmedial temporal cortex, he would have extended into the calcarine cortex. In his reports, however, Scoville noted that the posterior boundary of his resection was the anterior two thirds of the hippocampal complex (33). MRI scans obtained in 1992 were the first to reveal that the length of temporal lobe resection (11) was indeed overestimated. MRI demonstrated that the surgical resection was symmetrical bilaterally and largely correlated with Scoville’s written description. The major discrepancy was in the length of the rostrocaudal extent of temporal resection. Scoville reported a measurement of 8 cm, but liberal measurement criteria accounting for structures with minor damage on MRI calculated the rostrocaudal extent of temporal removal at 5.4 cm on the left and 5.1 cm on the right (Figure 4) (11). High-resolution in situ and ex vivo MRI

scans obtained shortly after Molaison’s death in 2008 showed damage to signifi- cant “portions of the medial temporopolar, pyriform, entorhinal, perirhinal, and para- hippocampal cortices, as well as the subiculum, presubiculum, parasubiculum,

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amygdala, hippocampal fields CA1, CA2, CA3, and CA4 (in the hippocampal head and body), and dentate gyrus (posterior head and body).” Among the residual areas, various areas of the amygdala, a small portion of the uncus, the hippo- campus tail (posterior 2 cm), a small part of the perirhinal cortex, the entire ectorhinal cortex (Brodmann area 36), and 2 cm of the posterior parahippocampal gyrus were preserved (5). The entorhinal cortex supplies most of the sensory input into the hippocampus via the perforant and direct pathways; therefore the preserved caudal half of the hippocampus was likely devoid of function as a result of damage to the entorhinal cortex (4, 5, 39).

POSTMORTEM BRAIN EXAMINATION

Shortly after his death in 2008, Molaison’s body was sent to the Massachusetts Gen- eral Athinoula A. Martinos Center for Biological Imaging in Charlestown, Mas- sachusetts, USA. He underwent 9 hours of

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in situ MRI scanning, and then an autopsy was performed. The brain, weighing 1300 g, was removed and fixed in formalin for 10 weeks. After fixation, further MRI im- aging using 3T and 7T scanners was per- formed. In February 2009, his brain was transported to the University of California, San Diego, USA, where it was fixed in formaldehyde for 2 more months (4). Using a microtome, Jacopo Annese serially sectioned Molaison’s brain into 2401 slices at 70-micrometer intervals over 53 hours. Selective slices were pre- pared for histological analysis. A camera mounted on the microtome acquired high- resolution digital images of each slice that were reconstructed three-dimensionally. Sectioning of the brain into 70 micro- meter slices provided significantly more clarity and information as compared with 4- to 5-mm slices on 1992 MRI (4). The goal of acquiring three-dimensional

images was to reconstruct Molaison’s brain to identify the exact boundaries of Scoville’s surgical resection. Images were

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obtained in the coronal plane in alignment with the anterior and posterior commis- sures (AC-PC line). The linear measure- ments, based on the AC-PC line, compared well with previous measure- ments obtained on MRI. The residual linear length of the hippocampus was 23.6 mm on the left and 24.3 mm on the right hemisphere, compared with 19 mm and 22 mm, respectively, on the 1992 MRI scans. The volume of residual entorhinal cortex was 0.03 cm3 and 0.11 cm3 for the left and right hemispheres, respectively, corre- sponding to about 1.7% and 6.5% of the normal volume. Linear calculations, however, are not a reflection of the three- dimensional anatomy of the hippocam- pus. Taking the curvature of the posterior hippocampus into account, Annese et al. calculated a residual hippocampal length of 45.4 mm on the right and 47.2 mm on the left hemispheres (4). Histological tissue samples obtained at

1.26-mm intervals and stained with thio- nin showed preservation of neuronal cell bodies in CA1, CA2, CA3, CA4, and the subiculum of the hippocampal formation posterior to the surgical resection (4). The entorhinal cortex is the major channel for the transmission of sensory input to and from cortical and subcortical nuclei (39). Bilateral removal of the entorhinal cortex deafferented the residual posterior hippocampus from other critical connections, thus causing Molaison’s profound anterograde amnesia. Brain examination also showed a lesion

involving the left lateral orbitofrontal gy- rus, possibly as a result of the surgical approach to the temporal lobes through the frontal trephine holes (4, 5). Multiple white matter lesions were considered to be secondary to hypertension and lacunar infarctions (4, 29). Cerebellar atrophy, likely due to chronic phenytoin use (4, 12), was also noted.

MOLAISON’S MEMORY

Scoville and Milner’s landmark 1957 pub- lication describing Molaison’s operation documented for the first time the connection between mesial temporal lobe structures, particularly the hippocampus, and loss of anterograde long-term declar- ative memory, the ability to remember specific facts and episodes. Scoville and Milner tested Molaison’s memory using

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the Wechsler Memory Scale, on which he obtained a below average score. Each time he was tested with a new task, he was unable to recall or recognize the previous task (33). Milner’s studies demonstrated that Molaison’s anterograde declarative memory loss was pervasive—impaired regardless of type of memory test or the sensory modality through which information was presented (25). Gabrieli et al. tested Molaison on several

aspects of semantic memory, including un- derstanding of the meaning, perception, and pronunciation of words, and showed that semantic memory acquired before the operation was normal compared with that encountered postoperatively (16). Molaison’s inability to collect new semantic information did not affect his ability to carry normal conversations using the words he knew preoperatively. Molaison continued to have a sense of humor and understood complex sentences with ambiguous syntax. Longitudinal studies conducted over a period of 48 years showed consistency in scores obtained on four Wechsler subtests (Information, Comprehension, Similarities, and Vocabulary) (10, 20). Despite the profound loss of declarative

and semantic memory, Molaison on rare occasions would uncannily recall episodic events occurring after the operation. In a visual picture recognition experiment, Molaison saw colored magazine pictures for 20 seconds and achieved normal recognition at 10 minutes, 24 hours, 72 hours, and 1 week after the stimulus, performing within one standard deviation of the control average 6 months later (5, 15). One hypothesis attributes the ability to recognize pictures “to the engagement of familiarity-based processes supported by his residual perirhinal and parahippocampal cortices in communica- tion with his preserved cortical circuitry (5).” Molaison moved with his parents to a new home in Hartford 5 years after the operation. In subsequent visits to MIT in 1966 and 1977, Molaison was able to accurately draw the floor plan of his home and remembered the address (10). The recollection of spatial memories of his home can be explained by functional MRI studies linking topographical memory formation to cortical areas outside the medial temporal lobe (2, 10, 22). Molaison recognized a few notable

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celebrities and politicians who became famous after his operation, such as John F. Kennedy, Ray Charles, and George Bush (5, 10). It is possible that the residual perirhinal and parahippocampal cortices sustained the formation of certain declarative memories after years of repeated exposure to the same stimuli. Molaison spent hours looking at magazine pictures of celebrities and politicians, which likely explains the gradual formation of his memories of a few notable people. Molaison’s declarative memory loss was

in sharp contrast to his preserved cognitive abilities. Shortly after the operation in 1953, his intelligence quotient (IQ) was normal at 104 on the Wechsler-Bellevue Intelligence Scale, improving to 118 upon retesting in 1962, likely due to the reduced frequency of seizures (7). Longitudinal analysis of his intelligence based on the Intelligence Scale showed that his IQ was maintained (10, 20, 25). Molaison’s short-term mem- ory was relatively unimpaired, as noted in number span tests requiring recall of six digits forward and five back (25). Molaison’s capacity for registration of sensory information in the short term was intact. For example, on the Tonal Memory Test, in which a sequence of three to five notes are played twice in succession and the subject is tested on the ability to discern which note in the second playing was different, Molaison performed normally (28). Molaison was unable to convert information gathered in the short- term to long-term memory, a deficit attributed to the damage to the hippo- campus and associated mesial temporal lobe structures. Molaison also demonstrated an ability

to acquire motor skills. In a pivotal study conducted by Milner in 1959, Molaison performed 39 trials on a mirror-drawing task, showing improvement over a 3-day period (6, 24). In later experiments, Cor- kin confirmed Milner’s findings using three motor tests repeated serially over the course of days and compared his perfor- mance to other right-handed male sub- jects. Molaison exhibited improvement from one session to the next on each of the three motor tasks, although his per- formance was below average compared with control participants (9). His ability to learn new motor skills was independent of the declarative memory system and mesial

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temporal lobe structures. Studies in Parkinson disease, Huntington disease, and cerebellar degeneration have linked the striatum and cerebellum to motor learning (5, 21, 30). Indeed, MRI of Molaison’s brain showed that the striatum was intact and that the cerebellum, although atrophied, was grossly normal (22). Molaison became anosmic after his pro-

cedure as a result of resection of the primary olfactory cortex in the temporal lobe (piri- form cortex and periamygdaloid cortex), although his olfactory bulbs and tracts remained intact. He was able to detect odor but unable to distinguish odor quality (13). Scoville’s surgery significantly damaged various portions of the amygdala. As a result, Molaison did not exhibit fear, was asexual, expressed no change in level of hunger or thirst following a meal, and had a reduced perception of pain (18).

OTHER CASES OF BILATERAL TEMPORAL LOBE RESECTION, INJURIES, AND EXPERIMENTS

A review of scientific and historical liter- ature presents a few cases linking bilateral temporal lobe structures with the forma- tion of recent memories. Wilder Penfield described profound memory deficit anal- ogous to Molaison’s in two of his patients, F.C. and P.B. (28). A 28-year-old epilepsy patient, F.C. presented to Montreal Neurological Institute (MNI) in October, 1952, suffering from progressively wors- ening seizure activity refractory to anti- convulsant medications. Preoperatively, F.C. complained of mild forgetfulness, but he could perform work-related tasks, recognize people, and remember daily events. Although several electroencepha- lograms (EEGs) indicated a left temporal epileptic focus, they also suggested bitemporal involvement with generalized electrical activity. Penfield performed a left temporal osteoplastic craniotomy and partial temporal lobectomy, resecting the anterior temporal lobe including all of the uncus and hippocampal gyrus. In total, the extent of temporal ablation from the anterior wall of the temporal fossa was 5.5 cm along the Sylvian fissure and 6.5 cm along the inferior temporal surface. Post- operatively, F.C. suffered from fluent aphasia, which improved over the course of his hospitalization, and a severe deficit

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in recent memory formation with retro- grade amnesia of events occurring up to 4 years before the operation. Penfield’s second patient, P.B., was a

41-year-old civil engineer who presented to MNI in 1946 (28). Like Molaison, P.B. had a history of head injury at a young age, but no abnormalities attributable to trauma were noted on skull radiograph and pneumoencephalogram. His seizures were characterized by staring spells and periods of automatism manifested in stereotypical chewing and hand movements. Because preoperative EEG showed a definite seizure focus in the left temporal lobe, Penfield decided to perform a left temporal craniotomy. Guided by abnormalities on intraoperative EEG, Penfield removed 4 cm of the anterior temporal lobe. Postoperatively, P.B. had a transient fluent aphasia, but his memory was intact. His seizures, however, continued with similar features of automatism, but they were shorter in length and reduced in frequency. He was readmitted to MNI in September 1951. Repeat EEG showed persistent left temporal epileptiform activity. Upon reoperation, Penfield noted a yellowish appearance of the uncus and hippocampus, and EEG stimulation of the hippocampal area reproduced seizure symptoms. Penfield thus proceeded to remove the uncus and hippocampal area of the left temporal lobe. Postoperatively, P.B. became severely amnesic to recent events, and his memory loss affected his ability to work. Later in life, he was demoted from the position of department manager to that of draughtsman, and he had difficulty remembering names of new business clients. Penfield and Milner performed detailed

psychological testing in more than 80 pa- tients on whom he performed unilateral temporal lobectomy for treatment of epi- lepsy. Except for F.C. and P.B., none of his patients demonstrated generalized mem- ory loss. Penfield assumed that there must be a destructive lesion in the right hip- pocampal region in both patients who developed severe memory deficit following left hippocampal resection. His assump- tion was supported by three observations. First, EEG studies in both patients showed postoperative evidence of continuing epileptiform activity in the right mesial temporal cortex. Second, in both cases, Penfield described the left hippocampus

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as sclerotic due to apparent inferior mesial temporal cortex herniation across the tentorial notch. Penfield believed that temporal herniation in both patients likely occurred at birth and caused ischemic damage to both hippocampal areas. Third, memory loss in Scoville’s operative series of patients with bilateral mesial temporal lobe resection supplemented Penfield’s hypothesis about the connection between bilateral mesial temporal lobe structures and memory. Penfield’s assumptions regarding

unanticipated injury to the right temporal lobe were confirmed several years later. Patient P.B. died in 1964 from massive pulmonary embolism, and his brain was studied at autopsy. Penfield had retired at the time, but at the urging of the Editor of the Archives of Neurology and Theodore Rasmussen, former director of MNI, Pen- field reviewed the autopsy and published his thoughts in 1974. In the left temporal region, surgical excision included the entire amygdala, and resection of the hippocampus spared 22 mm of its poste- rior portion. Histological examination of the remaining hippocampus showed an intact pyramidal cell layer without cell loss. In comparison, the right hippocam- pus appeared pale, sclerotic, and shrunken with reduced surface area. Microscopic examination showed marked cell loss in the pyramidal cell layer and a depletion of neurons in the dentate gyrus (27). Penfield commented that the right mesial temporal lobe findings fit the pattern of Ammon horn sclerosis occurring “almost certainly” due to ischemia from incisural herniation during birth (27). Numerous experiments involving the

mesial temporal lobe in primates and several case reports further delineate the role of the hippocampus in memory for- mation. Glees and Griffith described au- topsy findings in a patient with anterograde and retrograde memory loss. On gross appearance, the tips and medial parts of both temporal lobes were damaged and replaced with cystlike structures commu- nicating with the temporal horns of the lateral ventricle. Only the left hemisphere was examined histologically, and the hip- pocampal gyrus, Ammon’s horn, and parts of the lingual and fusiform gyri were ab- sent. The left posterior cerebral artery was partially occluded due to atherosclerosis,

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RIMAL HANIF DOSSANI ET AL. THE LEGACY OF PATIENT HENRY MOLAISON ON THE STUDY OF HUMAN MEMORY

and the fornix was gliotic with a decreased number of fibers (17). Zola-Morgan and colleagues described

anterograde amnesia in patient R.B., who suffered an ischemic episode that pro- duced a bilaterally symmetrical lesion confined to the CA1 region of the hippo- campus (41). Psychologist Heinrich Kluver and neurosurgeon Paul Bucy studied the effects of radical bilateral temporal lobectomy in rhesus monkeys (38). Their findings became known as the Kluver- Bucy syndrome, characterized by antero- grade and retrograde amnesia among other symptoms of docility, hyperphagia, and hypersexuality. In 1955, Terzian and Dalle Ore discussed a patient with Kluver- Bucy syndrome following radical bilateral temporal lobectomy (38). In addition to the memory deficit from hippocampal resection, the patient likely developed other features of Kluver-Bucy syndrome from destruction of bilateral lateral tem- poral cortices. Several studies involving primate models of amnesia have shown that destruction of bilateral lesioning of the hippocampal and entorhinal cortices causes severe and long-lasting memory deficits (40, 42-44).

CONCLUSION

In his 1957 paper, Scoville commented that hewas eager to report hisfindings “partly for their theoretical significance and partly as a warning to others of the risk to memory involved in bilateral surgical lesions of the hippocampal regions.” Molaison’s opera- tion weighed heavily on Scoville, and he repeatedly cautioned neurosurgeons about the risks of removing the hippocampus bilaterally. According to his wife, he deeply regrettedMolaison’s outcome, and in a 1974 lecture, lamented Molaison’s operation as a tragic mistake (8). Penfield noted that the impetus for his analysis of F.C. and P.B. stemmed from “remorse that two of our patients should have suffered a complication” (27). Learning from his errors, Penfield changed his practice such that if an EEG showed involvement of bilateral mesial temporal lobe regions, he would not operate on either hippocampal region. It was Scoville and Penfield’s earnest intention to educate neurosurgeons about the memory function of the hippocampal region and to caution them

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of the perils of bilateral mesial temporal lobe resection. In a 2007 National Public Radio segment,

when asked about how he spends his time, Molaison responded, “see, that’s what I don’t—I don’t remember things” (26). Molaison demonstrated insight into his own condition, yet he failed to remember the most routine details about his daily life. Paradoxically, Molaison’s heartbreaking loss of memory resulted in a tremendous gain of knowledge for neurosurgery and cognitive neuroscience. Following Molaison’s case, neurosurgeons became aware of the dangers of bilateral mesial temporal lobe injury. Now, during the planning of a unilateral temporal lobectomy, neurosurgeons ensure the integrity of the contralateral hippocampus using various diagnostic studies, such as the Wada test and functional MRI. Molaison’s selfless participation in

dozens of neuropsychological studies led to the discovery of different types of memory and elucidated neural structures responsible for memory formation. For example, Molaison’s case highlighted that the neural structures underlying formation of recent memory are different from those responsible for motor learning. As a result of Molaison’s direct contributions, the field of cognitive neuroscience has grown tremendously, and the gift of his brain for anatomic and histological study will continue to inform the science of memory for a long time to come.

ACKNOWLEDGEMENT

The authors thank Dr. Suzanne Corkin for her helpful comments on the manuscript.

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Conflict of interest statement: The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Received 7 April 2015; accepted 14 April 2015

Citation: World Neurosurg. (2015) 84, 4:1127-1135. http://dx.doi.org/10.1016/j.wneu.2015.04.031

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