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

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.

Motor impulsivity in Parkinson disease: associations with COMT and DRD2 polymorphisms.

Parkinson disease (PD) is an age-related degenerative disease of the brain, characterized by motor, cognitive, and psychiatric symptoms. Neurologists and neuroscientists now understand that several symptoms of the disease, including hallucinations and impulse control behaviors, stem from the dopaminergic medications used to control the motor aspects of PD. Converging evidence from animals and humans suggests that individual differences in the genes that affect the dopamine system influence the response of PD patients to dopaminergic medication. In this study, we tested the hypothesis that patients taking dopamine replacement therapy who carry candidate alleles that increase dopamine signaling, exhibit greater amounts of motor impulsivity. We examined the relation between inhibitory ability (measured by the Stop Signal Task) and polymorphisms of COMT Val158Met and DRD2 C957T in patients with idiopathic PD. On the Stop Signal Task, carriers of COMT Val/Met and Met/Met genotypes were more impulsive than Val/Val carriers, but we did not find a link between DRD2 polymorphisms and inhibitory ability. These results support the hypothesis that the Met allele of COMT confers an increased risk for behavioral impulsivity in PD patients, whereas DRD2 polymorphisms appear to be less important in determining whether PD patients exhibit a dopamine overdose in the form of motor impulsivity.

Transformations in oscillatory activity and evoked responses in primary somatosensory cortex in middle age: a combined computational neural modeling and MEG study.

Oscillatory brain rhythms and evoked responses are widely believed to impact cognition, but relatively little is known about how these measures are affected by healthy aging. The present study used MEG to examine age-related changes in spontaneous oscillations and tactile evoked responses in primary somatosensory cortex (SI) in healthy young (YA) and middle-aged (MA) adults. To make specific predictions about neurophysiological changes that mediate age-related MEG changes, we applied a biophysically realistic model of SI that accurately reproduces SI MEG mu rhythms, containing alpha (7-14 Hz) and beta (15-30 Hz) components, and evoked responses. Analyses of MEG data revealed a significant increase in prestimulus mu power in SI, driven predominately by greater mu-beta dominance, and a larger and delayed M70 peak in the SI evoked response in MA. Previous analysis with our computational model showed that the SI mu rhythm could be reproduced with a stochastic sequence of rhythmic approximately 10 Hz feedforward (FF) input to the granular layers of SI (representative of lemniscal thalamic input) followed nearly simultaneously by approximately 10 Hz feedback (FB) input to the supragranular layers (representative of input from high order cortical or non-specific thalamic sources) (Jones et al., 2009). In the present study, the model further predicted that the rhythmic FF and FB inputs become stronger with age. Further, the FB input is predicted to arrive more synchronously to SI on each cycle of the 10 Hz input in MA. The simulated neurophysiological changes are sufficient to account for the age-related differences in both prestimulus mu rhythms and evoked responses. Thus, the model predicts that a single set of neurophysiological changes intimately links these age-related changes in neural dynamics.

False memory in aging: effects of emotional valence on word recognition accuracy.

Memory is susceptible to distortions. Valence and increasing age are variables known to affect memory accuracy and may increase false alarm production. Interaction between these variables and their impact on false memory was investigated in 36 young (18-28 years) and 36 older (61-83 years) healthy adults. At study, participants viewed lists of neutral words orthographically related to negative, neutral, or positive critical lures (not presented). Memory for these words was subsequently tested with a remember-know procedure. At test, items included the words seen at study and their associated critical lures, as well as sets of orthographically related neutral words not seen at study and their associated unstudied lures. Positive valence was shown to have two opposite effects on older adults' discrimination of the lures: It improved correct rejection of unstudied lures but increased false memory for critical lures (i.e., lures associated with words studied previously). Thus, increased salience triggered by positive valence may disrupt memory accuracy in older adults when discriminating among similar events. These findings likely reflect a source memory deficit due to decreased efficiency in cognitive control processes with aging.

What neural correlates underlie successful encoding and retrieval? A functional magnetic resonance imaging study using a divided attention paradigm.

If attention is divided during learning, memory suffers. Nevertheless, individuals can learn information with divided attention. This event-related functional magnetic resonance imaging (fMRI) study (n = 17) investigated what neural processes support (1) learning with divided attention and (2) retrieval of information learned with divided attention. Participants encoded words (Is the word abstract or concrete?) while performing an auditory discrimination task (press a button whenever an auditory pattern changes). The auditory task was easy or hard, depending on the similarity of the patterns. A behavioral study indicated that detailed ("recollective") information was more likely to be present for words encoded with the easy versus the hard concurrent task. Words encoded with the hard versus the easy concurrent task, in contrast, were more likely to rely on less detailed ("familiarity"-based) information. fMRI revealed encoding-related activation in the left prefrontal cortex (PFC) and left hippocampus that was linked to successful memory formation only for items encoded with the easy task. In contrast, activation in the right PFC and left parahippocampal gyrus was linked to successful memory for all items. Thus, successful encoding with the hard concurrent task was supported by a subset of the regions recruited for successful encoding with the easy task. The neural processes recruited for successful retrieval also depended on the encoding condition: The left PFC was disproportionately recruited for retrieval of items encoded with the easy task, whereas the right PFC was disproportionately recruited for retrieval of items encoded with the hard task. These findings may reflect left-sided specialization for recollective memories and right-sided specialization for familiarity-based traces.

Medial temporal lobe structures are needed to re-experience remote autobiographical memories: evidence from H.M. and W.R.

The nature and extent of retrograde amnesia in patients with medial temporal lobe (MTL) lesions is currently under debate. While some investigators propose a temporally limited role for the MTL in episodic and semantic memory, others claim that MTL structures are needed for episodic memories of one's entire lifetime, and that only semantic memory becomes independent of the MTL. To address this issue, we tested two amnesic patients, H.M. and W.R., with bilateral MTL lesions on a series of remote memory tests that together distinguished episodic memory from semantic memory performance. Notably, we used a new method to assess autobiographical memory that measured the degree of re-experiencing of personal happenings from the past. Both patients showed relatively spared semantic memory, but severe impairment on measures of autobiographical memory, with no temporal gradient. Our data support the view that MTL structures play a significant role in recalling specific personal episodes, not only from the recent past but from the distant past as well.

Memory for contextual details: effects of emotion and aging.

When individuals are confronted with a complex visual scene that includes some emotional element, memory for the emotional component often is enhanced, whereas memory for peripheral (nonemotional) details is reduced. The present study examined the effects of age and encoding instructions on this effect. With incidental encoding instructions, young and older adults showed this pattern of results, indicating that both groups focused attention on the emotional aspects of the scene. With intentional encoding instructions, young adults no longer showed the effect: They were just as likely to remember peripheral details of negative images as of neutral images. The older adults, in contrast, did not overcome the attentional bias: They continued to show reduced memory for the peripheral elements of the emotional compared with the neutral scenes, even with the intentional encoding instructions.

Effects of Alzheimer disease on memory for verbal emotional information.

In healthy young and older adults, emotional information is often better remembered than neutral information. It is an open question, however, whether emotional memory enhancement is blunted or preserved in Alzheimer disease (AD). Prior studies of emotional memory in AD have included small samples of patients. In addition, studies that failed to find an enhancement effect in AD used stimuli lacking semantic coherence (e.g. lists of unrelated words, some that were emotional and others that were neutral). To circumvent these limitations, the present study examined a large number of AD patients (N=80) and investigated whether AD patients would show better memory for a verbal description of an emotional event as compared to a neutral one. AD patients were equivalent to young and older control participants in rating the emotional descriptions for valence and arousal. Unlike the control groups, however, memory in AD patients did not benefit from the emotional narratives. We conclude that AD disrupts memory enhancement for at least some types of verbal emotional information.

Role of the anterior temporal lobe in repetition and semantic priming: evidence from a patient with a category-specific deficit.

Neuroimaging studies in healthy participants have implicated anterior temporal lobe regions and the fusiform gyrus in repetition priming and semantic priming. Only the investigation of patients with selective lesions, however, can establish the necessity of these particular regions. To this end, we administered three tests of repetition priming (pseudoword identification; masked-form priming; category-exemplar generation) and a test of semantic priming to a patient (J.P.) with a category-specific deficit stemming from bilateral damage to the anterior fusiform gyrus and anterior temporal regions. On all of the repetition priming tasks, J.P. showed priming effects within 1 S.D. of 10 age- and education-matched CON; ANOVAs indicated no interaction between group and prime condition. These findings suggest that the anterior fusiform and anterior temporal lobe are not required for these priming effects. J.P. also showed normal repetition priming even for items that he had never been able to name or to provide semantic information about. On the semantic priming task, J.P. showed normal levels of priming across categories. When we separately analyzed his priming for items he could never name or access information about versus items that he had been able to name on at least two testing sessions, we found priming for the latter items, but not for the former. This result suggests that category-specific deficits resulting from damage to the anterior temporal lobes may disrupt the automatic, rapid access of semantic information of some items.

Questioning the living/nonliving dichotomy: evidence from a patient with an unusual semantic dissociation.

In this article the authors describe a patient (J.P.) whose category-specific naming deficit eluded the classical dichotomies between living versus nonliving items or visual versus functional attributes. At age 22, he had herpes simplex encephalitis followed by a left temporal lobectomy. J.P. was tested on measures of visual perception, category naming, fluency, and name-picture matching. He showed a severe impairment naming and identifying fruits, vegetables, and musical instruments. His performance with animals and birds was spared inconsistently, meaning that even the preserved categories were, at some point, affected. J.P.'s unusual deficit supports the hypothesis that semantic knowledge is organized in the brain on the basis of object properties, which can cut across the living-nonliving categorical distinction.

Working memory in mild Alzheimer's disease and early Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) impair working memory (WM). It is unclear, however, whether the deficits seen early in the course of these diseases are similar. To address this issue, the authors compared the performance of 22 patients with mild AD, 20 patients with early PD and without dementia, and 112 control participants on tests of inhibition, short-term memory, and 2 commonly administered tests of WM. The results suggest that although mild AD and early PD both impair WM, the deficits may be related to the interruption of different processes that contribute to WM performance. Early PD disrupted inhibitory processes, whereas mild AD did not. The WM deficits seen in patients with AD may be secondary to deficits in other cognitive capacities, including semantic memory.

Puzzling thoughts for H. M.: can new semantic information be anchored to old semantic memories?

Researchers currently debate whether new semantic knowledge can be learned and retrieved despite extensive damage to medial temporal lobe (MTL) structures. The authors explored whether H. M., a patient with amnesia, could acquire new semantic information in the context of his lifelong hobby of solving crossword puzzles. First, H. M. was tested on a series of word-skills tests believed important in solving crosswords. He also completed 3 new crosswords: 1 puzzle testing pre-1953 knowledge, another testing post-1953 knowledge, and another combining the 2 by giving postoperative semantic clues for preoperative answers. From the results, the authors concluded that H. M. can acquire new semantic knowledge, at least temporarily, when he can anchor it to mental representations established preoperatively.

Perceptual organization in Alzheimer's disease.

The ability of 16 AD patients and 16 age-matched control Ss to discriminate degraded forms was compared. Also examined were the effects of aging on perceptual organization by comparison of performance of normal Ss ranging in age from 20 to 86 years. Ss discriminated 2 forms, a circle and a square, each composed of randomly distributed dots concurrently embedded in visual noise. By means of a forced-choice procedure, the threshold signal-to-noise ratios at 4 levels of figure degradation were obtained, each presented at 3 durations. Performance by the normal Ss did not vary with age for long-duration stimuli, but did decline with age for briefly presented stimuli. Relative to age-matched control Ss, AD patients had significantly elevated thresholds at all form densities. Disruption of visual processing at the level of perceptual organization is likely a contributing factor to impairment of high-order visual function.

Effect of negative emotional content on working memory and long-term memory.

In long-term memory, negative information is better remembered than neutral information. Differences in processes important to working memory may contribute to this emotional memory enhancement. To examine the effect that the emotional content of stimuli has on working memory performance, the authors asked participants to perform working memory tasks with negative and neutral stimuli. Task accuracy was unaffected by the emotional content of the stimuli. Reaction times also did not differ for negative relative to neutral words, but on an n-back task using faces, participants were slower to respond to fearful faces than to neutral faces. These results suggest that although emotional content does not have a robust effect on working memory, in some instances emotional salience can impede working memory performance.

Effects of normal aging and Alzheimer's disease on emotional memory.

Recall is typically better for emotional than for neutral stimuli. This enhancement is believed to rely on limbic regions. Memory is also better for neutral stimuli embedded in an emotional context. The neural substrate supporting this effect has not been thoroughly investigated but may include frontal lobe, as well as limbic circuits. Alzheimer's disease (AD) results in atrophy of limbic structures, whereas normal aging relatively spares limbic regions but affects prefrontal areas. The authors hypothesized that AD would reduce all enhancement effects, whereas aging would disproportionately affect enhancement based on emotional context. The results confirmed the authors' hypotheses: Young and older adults, but not AD patients, showed better memory for emotional versus neutral pictures and words. Older adults and AD patients showed no benefit from emotional context, whereas young adults remembered more items embedded in an emotional versus neutral context.

Postmortem examination of patient H.M.'s brain based on histological sectioning and digital 3D reconstruction.

Modern scientific knowledge of how memory functions are organized in the human brain originated from the case of Henry G. Molaison (H.M.), an epileptic patient whose amnesia ensued unexpectedly following a bilateral surgical ablation of medial temporal lobe structures, including the hippocampus. The neuroanatomical extent of the 1953 operation could not be assessed definitively during H.M.'s life. Here we describe the results of a procedure designed to reconstruct a microscopic anatomical model of the whole brain and conduct detailed 3D measurements in the medial temporal lobe region. This approach, combined with cellular-level imaging of stained histological slices, demonstrates a significant amount of residual hippocampal tissue with distinctive cytoarchitecture. Our study also reveals diffuse pathology in the deep white matter and a small, circumscribed lesion in the left orbitofrontal cortex. The findings constitute new evidence that may help elucidate the consequences of H.M.'s operation in the context of the brain's overall pathology.

New MRI Biomarkers Advance the Characterization of Parkinson Disease.

The pathophysiology of idiopathic Parkinson disease (PD) is traditionally characterized as substantia nigra degeneration, but careful examination of the widespread neuropathological changes suggests individual differences in neuronal vulnerability. A major limitation to studies of disease progression in PD has been that conventional MRI techniques provide relatively poor contrast for the structures that are affected by the disease, and thus are not typically used in experimental or clinical studies. Here, we review the current state of structural MRI as applied to the analysis of the PD brain. We also describe a new multispectral MRI method that provides improved contrast for the substantia nigra and basal forebrain, which we recently used to show that these structures display different trajectories of volume loss early in the disease.

Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease.

OBJECTIVE: To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. DESIGN: Matched case-control study. SETTING: The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. PATIENTS: Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1-3) and 27 matched healthy control subjects. MAIN OUTCOME MEASURES: We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. RESULTS: Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. CONCLUSION: Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF.

Cognition in healthy aging is related to regional white matter integrity, but not cortical thickness.

It is well established that healthy aging is accompanied by structural changes in many brain regions and functional decline in a number of cognitive domains. The goal of this study was to determine (1) whether the regional distribution of age-related brain changes is similar in gray matter (GM) and white matter (WM) regions, or whether these two tissue types are affected differently by aging, and (2) whether measures of cognitive performance are more closely linked to alterations in the cerebral cortex or in the underlying WM in older adults (OA). To address these questions, we collected high-resolution magnetic resonance imaging (MRI) data from a large sample of healthy young adults (YA; aged 18-28) and OA (aged 61-86 years). In addition, the OA completed a series of tasks selected to assess cognition in three domains: cognitive control, episodic memory, and semantic memory. Using advanced techniques for measuring cortical thickness and WM integrity, we found that healthy aging was accompanied by deterioration of both GM and WM, but with distinct patterns of change: Cortical thinning occurred primarily in primary sensory and motor cortices, whereas WM changes were localized to regions underlying association cortices. Further, in OA, we found a striking pattern of region-specific correlations between measures of cognitive performance and WM integrity, but not cortical thickness. Specifically, cognitive control correlated with integrity of frontal lobe WM, whereas episodic memory was related to integrity of temporal and parietal lobe WM. Thus, age-related impairments in specific cognitive capacities may arise from degenerative processes that affect the underlying connections of their respective neural networks.

Posterior parahippocampal place learning in H.M.

In a previous experiment with patients who had undergone unilateral temporal thermocoagulation lesions to alleviate intractable epilepsy, we demonstrated that the right parahippocampal cortex was critical for the performance of a spatial memory task (Bohbot et al. (1998) Neuropsychologia 36:1217-1238). Based on this evidence, we predicted that H.M., whose caudal parahippocampal cortex was structurally intact (Corkin et al. (1997) J Neurosci 17:3964-3979), would be able to learn the spatial memory task. This task was designed to be a human analogue of the Morris water maze in that it measured participants' ability to learn the location of a target, which was an invisible weight sensor placed under a carpet (Bohbot et al. (1998) Neuropsychologia 36:1217-1238). H.M. was first tested with the sensor under a small carpet (162 cm x 150 cm). Then, interspersed with the first sensor location, he was tested with the sensor in a second location, covered by a larger carpet (250 cm x 210 cm). He found the second target location in a direct path on only 10% of the trials. In contrast, when tested on the first sensor location, he walked directly toward the center of the testing area in 19/35 trials and from there found the sensor in a direct path on 15 of the 19 trials (80%). The number of direct hits at the first target location was significantly greater than chance (P < 0.0005). An analysis of H.M.'s paths showed that they were characteristic of fast learning, and that he did not rely on egocentric, short-term, or working memory strategies to learn the task. H.M's ability to locate the sensor is remarkable given his severe amnesia and his inability to explicitly recollect the testing episode. These findings underscore the role of the parahippocampal cortex in spatial memory.