Readings

Gross and Functional Neuroanatomy Demonstration

Required Reading for Undergraduates and Graduate Students

• Gazzaniga, M.S., Ivry, R.B., & Mangun, G.R., “The substrates of cognition”, Cognitive Neuroscience: The Biology of the Mind, W. W. Norton & Co., New York, 1998, pp. 44-68. 

Methods in Cognitive Neuroscience

Required Reading for Undergraduates and Graduate Students

• Gazzaniga, M.S., Ivry, R.B., & Mangun, G.R., “The substrates of cognition”, Cognitive Neuroscience: The Biology of the Mind, New York, W. W. Norton & Co., 1998, pp. 23-44.
• Hannay, H.J., “Some issues and concerns in neuropsychological research:  an introduction”, Experimental techniques in human neuropsychology, H.J. Hannay (Ed.), New York, Oxford University Press, 1986, pp. 3-14.
• Weiskrantz, L., “Some traps and pontifications”, Analysis of behavioral change, L. Weiskrantz (Ed.), New York, Harper and Row, 1968, pp. 415-429.

Motor System Anatomy and Physiology

Required Reading for Undergraduates and Graduate Students

• Kandel, Schwartz & Jessell, “Voluntary Movement”, Principles of Neural Science, Norwalk, Appleton & Lange, 1991, pp. 609 – 625.
• Kandel, Schwartz & Jessell, “The Cerebellum”, Principles of Neural Science, Norwalk, Appleton & Lange, 1991, pp. 626 - 646.

Motor Control: Disorders

Required Reading for Undergraduates and Graduate Students

• Kandel, Schwartz & Jessell, “The Basal Ganglia”, Principles of Neural Science, Norwalk, Appleton & Lange., 1991, pp. 647-659.
• Growdon, J. H., Corkin, S. & Rosen, T. J., “Distinctive aspects of cognitive dysfunction in Parkinson’s disease”, Advances in Neurology, 53, 1990, pp. 365-376.
• Schmahmann, J.D. & Sherman J.C., “The cerebellar cognitive affective syndrome”, Brain, 121, 1998, pp. 561-579.
  • PubMed abstract:  Anatomical, physiological and functional neuroimaging studies suggest that the cerebellum participates in the organization of higher order function, but there are very few descriptions of clinically relevant cases that address this possibility. We performed neurological examinations, bedside mental state tests, neuropsychological studies and anatomical neuroimaging on 20 patients with diseases confined to the cerebellum, and evaluated the nature and severity of the changes in neurological and mental function. Behavioural changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis, and in some cases they were the most noticeable aspects of the presentation. These changes were characterized by: impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behaviour; and language deficits including agrammatism and dysprosodia. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. We have called this newly defined clinical entity the 'cerebellar cognitive affective syndrome'. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic cortices with the cerebellum.

Required Reading for Graduate Students (Recommended for Undergraduates).

• Alexander, G. E. & Crutcher, M. D, “Functional architecture of basal ganglia circuits: Neural substrates of parallel processing”, Trends in Neuroscience, 13(7), 1990, pp. 266-271.
  • PubMed abstract:  Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.

Supplementary Reading (Recommended for All)

• DeLong, M. R., “Primate models of movement disorders of basal ganglia origin”, Trends in Neuroscience, 13(7), 1990, pp. 281-285.
  • PubMed abstract:  Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorders (of which Parkinson's disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntington's disease and hemiballismus) at the other. Both extremes of this movement disorder spectrum can be accounted for by postulating specific disturbances within the basal ganglia-thalamocortical 'motor' circuit. In this paper, Mahlon DeLong describes the changes in neuronal activity in the motor circuit in animal models of hypo- and hyperkinetic disorders.
    
• Growdon, J. H, Clinical Aspects of Parkinson's Disease.
• Tanner, C. M., Ottman, R., Goldman, S. M., Ellenberg, J., Chan, P., Mayeux, R., Langston, J. W., “Parkinson disease in twins: an etiologic study”,  Journal of the American Medical Association, 281(4), pp. 341-346.
  • PubMed abstract:  CONTEXT: The cause of Parkinson disease (PD) is unknown. Genetic linkages have been identified in families with PD, but whether most PD is inherited has not been determined. OBJECTIVE: To assess genetic inheritance of PD by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. DESIGN: Twin study comparing concordance rates of PD in MZ and DZ twin pairs. SETTING AND PARTICIPANTS: A total of 19842 white male twins enrolled in the National Academy of Sciences/National Research Council World War II Veteran Twins Registry were screened for PD and standard diagnostic criteria for PD were applied. Zygosity was determined by polymerase chain reaction or questionnaire. MAIN OUTCOME MEASURE: Parkinson disease concordance in twin pairs, stratified by zygosity and age at diagnosis. RESULTS: Of 268 twins with suspected parkinsonism and 250 presumed unaffected twin brothers, 193 twins with PD were identified (concordance-adjusted prevalence, 8.67/1000). In 71 MZ and 90 DZ pairs with complete diagnoses, pairwise concordance was similar (0.129 overall, 0.155 MZ, 0.111 DZ; relative risk, 1.39; 95% confidence interval, 0.63-3.1). In 16 pairs with diagnosis at or before age 50 years in at least 1 twin, MZ concordance was 1.0 (4 pairs), and DZ was 0.167 (relative risk, 6.0; 95% confidence interval, 1.69-21.26). CONCLUSIONS: The similarity in concordance overall indicates that genetic factors do not play a major role in causing typical PD. No genetic component is evident when the disease begins after age 50 years. However, genetic factors appear to be important when disease begins at or before age 50 years.

Somatosensory System

Required Readings for Undergraduates and Graduate Students

• Goldstein, E.B., “The somatic senses”, Sensation and Perception (4th ed.), Wadsworth, 1996,  pp.459-487.

Vision: Anatomy and Physiology

Required Reading for Undergraduates and Graduate Students

• Kolb, B., and Whishaw, I.Q., “Organization of the Sensory Systems”, Fundamentals of human neuropsychology (4th ed)., New York, W.H. Freeman, 1996, Chapter 6, pp. 99-109.
• Kolb, B., and Whishaw, I.Q., “The Occipital Lobes”, Fundamentals of human neuropsychology (4th ed.), New York, W.H. Freeman, 1996, Chapter 11, pp. 243-251.
• Sereno, M.I., Dale, A.M., Reppas, J.B., Kwong, K.K., Belliveau, J.W., Brady, T.J., Rosen, B.R., and Tootell, R.B.H, “Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging”, Science, 1995, 268, 889-893.
  • PubMed abstract:  The borders of human visual areas V1, V2, VP, V3, and V4 were precisely and noninvasively determined. Functional magnetic resonance images were recorded during phase-encoded retinal stimulation. This volume data set was then sampled with a cortical surface reconstruction, making it possible to calculate the local visual field sign (mirror image versus non-mirror image representation). This method automatically and objectively outlines area borders because adjacent areas often have the opposite field sign. Cortical magnification factor curves for striate and extrastriate cortical areas were determined, which showed that human visual areas have a greater emphasis on the center-of-gaze than their counterparts in monkeys. Retinotopically organized visual areas in humans extend anteriorly to overlap several areas previously shown to be activated by written words.
    
• Tootell R.B., Hadjikhani N.K., Mendola J.D., Marrett S., Dale A.M., “From retinotopy to recogntion:  fMRI in human visual cortex”, Trends in Cognitive Science, 2, 1998, 174-183.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Mason, C. and Kandel, E.R., “Central visual pathways”, Principles of Neural Science, Third Edition, E.R. Kandel, J.H. Schwartz, and T.M. Jessell (Eds.), Amsterdam, Elsevier, 1991, pp. 420-439.
• Ungerleider, L.G. and Haxby, J.V., “'What' and 'where' in the human brain”, Current Opinion in Neurobiology, 4, 1994, 157-165.
  • PubMed abstract:  Multiple visual areas in the cortex of nonhuman primates are organized into two hierarchically organized and functionally specialized processing pathways, a 'ventral stream' for object vision and a 'dorsal stream' for spatial vision. Recent findings from positron emission tomography activation studies have localized these pathways within the human brain, yielding insights into cortical hierarchies, specialization of function, and attentional mechanisms.

Recitation: Recovery of Function

Required Readings for Undergraduates and Graduate Students

• Kolb, B., and Whishaw, I. Q., “Recovery of Function”, Fundamentals of Human Neuropsychology (4th ed.), New York, W. H. Freeman, 1996, pp. 539-565.

Vision: Disorders

Required Reading for Undergraduates and Graduate Students

• Kolb, B., and Whishaw, I.Q., “Fundamentals of human neuropsychology (4th ed.)”, The Occipital Lobes, New York, W.H. Freeman, 1996, Chapter 11 (pp. 251-263)
• Farah, M.J., “The apperceptive agnosias”, Visual agnosia:  Disorders of object recognition and what they tell us about normal vision, MIT Press, 1990, pp. 7-33.
• Farah, M.J., “The associative agnosias”, Visual agnosia:  Disorders of object recognition and what they tell us about normal vision, MIT Press, 1990, pp. 57-92.
• Weiskrantz, L., “Blindsight”, Handbook of neuropsychology, Vol. 2, F. Boller and J. Grafman (Eds.), Amsterdam, Elsevier, 1989, pp. 375-385. 

Required Reading for Graduate Students (Recommended for Undergraduates)

• Etcoff, N.L., Freeman, R., and Cave, K.R., “Can we lose memories of faces?  Content specificity and awareness in a prosopagnosic”, Journal of Cognitive Neuroscience, 3, 1991, pp. 25-41.

Vision: Perception of Faces and Objects

Required Reading for Undergraduates and Graduate Students

• Moscovitch, M., Winocur, G. and Behrmann, M., “What Is Special about Face Recognition?  Nineteen Experiments on a Person with Visual Object Agnosia and Dyslexia but Normal Face Recognition”,  Journal of Cognitive Neuroscience, 9(5), 1997, pp. 555-604.
• Epstein, R. and Kanwisher, N., “A cortical representation of the local visual environment”, Nature, 392, pp. 598-601.
  • PubMed abstract:  Medial temporal brain regions such as the hippocampal formation and parahippocampal cortex have been generally implicated in navigation and visual memory. However, the specific function of each of these regions is not yet clear. Here we present evidence that a particular area within human parahippocampal cortex is involved in a critical component of navigation: perceiving the local visual environment. This region, which we name the 'parahippocampal place area' (PPA), responds selectively and automatically in functional magnetic resonance imaging (fMRI) to passively viewed scenes, but only weakly to single objects and not at all to faces. The critical factor for this activation appears to be the presence in the stimulus of information about the layout of local space. The response in the PPA to scenes with spatial layout but no discrete objects (empty rooms) is as strong as the response to complex meaningful scenes containing multiple objects (the same rooms furnished) and over twice as strong as the response to arrays of multiple objects without three-dimensional spatial context (the furniture from these rooms on a blank background). This response is reduced if the surfaces in the scene are rearranged so that they no longer define a coherent space. We propose that the PPA represents places by encoding the geometry of the local environment.
    
• Farah, M. J., “Is an Object an Object an Object?  Cognitive and Neuropsychological Investigations of Domain Specificity in Visual Object Recognition”, Current Directions in Psychological Science, 1992, pp. 164-169.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Kanwisher, Epstein, Downing and Kourtzi, “Functional Neuroimaging of Human Visual Recognition”, Handbook on Functional Neuroimaging of Cognition, To appear in Cabeza and Kingstone (Eds.), MIT Press, 1998.
• Aguirre, G. K., Zarahn, E. and D'Esposito, M., “Neural components of topographical representation”, Proceedings of the National Academy of Sciences, 95, 1998, pp. 839-846.

Vision: Attention

Required Reading for Undergraduates and Graduate Students

• Posner, M. I., “Attention in cognitive neuroscience: an overview”, The Cognitive Neurosciences, M. S. Gazzaniga (Ed.), Cambridge, MA, MIT Press, 1995, pp. 615-624.
• Rafal, R., and Robertson, L., “The neurology of visual attention”, The Cognitive Neurosciences, M. S. Gazzaniga (Ed.), Cambridge, MA, MIT Press, 1995, pp. 625-648. 

Required Reading for Graduate Students (Recommended for Undergraduates)

• Knight, R. T., “Distributed cortical network for visual attention”, Journal of Cognitive Neurosciences, 9, 1997, pp. 75-91.

Vision: Imagery and Neglect

Required Reading for Undergraduates and Graduate Students

• Farah, M. J., Brunn, J. L., Wong, A. B. Wallace, M. A. & Carpenter, P.A., “Frames of reference for allocating attention to space: Evidence from the neglect syndrome”, Neuropsychologia, 28, 1990, 335-347.
  • PubMed abstract:  With respect to what frames of reference, or spatial coordinate systems, is attention allocated to locations in space? We posed this question about the spatial attention system that has been damaged in neglect patients, distinguishing among three possible types of spatial reference frame: viewer-centered, according to which locations are coded with respect to the viewer, environment-centered, according to which locations or coded with respect to the environment, and object-centered, according to which locations are coded with respect to an object. The three candidate frames of reference were decoupled from one another by rotating either the viewer or the stimulus object. Visual search performance suggested that the neglected hemifield was defined with respect to both viewer-centered and environment-centered frames of reference, but not with respect to an object-centered frame of reference. The role of objects in the allocation of attention to space, and the relation between our findings and the "two cortical visual systems" hypothesis, are discussed.
    
• Meador, K.J., Loring, D.W., Bowers, D., and Heilman, K.M., “Remote memory and neglect syndrome”, Neurology, 37, 1987, 522-526.
  • PubMed abstract:  Three patients with right cerebral infarctions and neglect syndrome failed to recall left hemispatial remote memories, even when the imagined orientation was reversed by 180 degrees. One patient was retested 4 months later and, although improved, continued to consistently recall more right-sided items. He was tested at east and west mental orientations with his head/eyes oriented physically to each side. Recall for items imagined in left hemispace improved 26% when his head/eye orientation was physically shifted from right to left hemispace. Findings suggest that the engrams for left-sided visuospatial memories in neglect syndrome are not destroyed, but rather fail to be activated.
    
• Kosslyn, S.M., Alpert, N.M., Thompson, W.L., Maljkovic, V. et al., “Visual mental imagery activates topographically organized visual cortex: PET investigations”, Journal of Cognitive Neuroscience, 5, 1993, 263-287.
• Kosslyn, S.M., Thompson, W.L., Kim, I.J., and Alpert, N.M., “Topographical representations of mental images in primary visual cortex”, Nature, 1995, 378, 496-498.
  • PubMed abstract:   We report here the use of positron emission tomography (PET) to reveal that the primary visual cortex is activated when subjects close their eyes and visualize objects. The size of the image is systematically related to the location of maximal activity, which is as expected because the earliest visual areas are spatially organized. These results were only evident, however, when imagery conditions were compared to a non-imagery baseline in which the same auditory cues were presented (and hence the stimuli were controlled); when a resting baseline was used (and hence brain activation was uncontrolled), imagery activation was obscured because of activation in visual cortex during the baseline condition. These findings resolve a debate in the literature about whether imagery activates early visual cortex and indicate that visual mental imagery involves 'depictive' representations, not solely language-like descriptions. Moreover, the fact that stored visual information can affect processing in even the earliest visual areas suggests that knowledge can fundamentally bias what one sees.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Mesulam, M.-M., “A cortical network for directed attention and unilateral neglect”, Annals of Neurology, 10, 1981, 309-325.

Language: Phonological Processing and Syntax

Required Reading for Undergraduates and Graduate Students

• Gazzaniga, M.S., Ivry, R.B., & Mangun, G.R., “Language and the brain”, Cognitive Neuroscience: The Biology of the Mind, New York, W. W. Norton & Co., 1998, pp. 289-321.  
• Dronkers, N. F., “A new brain region for coordinating speech articulation”, Nature, 384, 1996, 159-161.
  • PubMed abstract:   Human speech requires complex planning and coordination of mouth and tongue movements. Certain types of brain injury can lead to a condition known as apraxia of speech, in which patients are impaired in their ability to coordinate speech movements but their ability to perceive speech sounds, including their own errors, is unaffected. The brain regions involved in coordinating speech, however, remain largely unknown. In this study, brain lesions of 25 stroke patients with a disorder in the motor planning of articulatory movements were compared with lesions of 19 patients without such deficits. A robust double dissociation was found between these two groups. All patients with articulatory planning deficits had lesions that included a discrete region of the left precentral gyrus of the insula, a cortical area beneath the frontal and temporal lobes. This area was completely spared in all patients without these articulation deficits. Thus this area seems to be specialized for the motor planning of speech.
    
• Levelt, W. J. M., & Indefrey, P., “The Speaking Mind/Brain: Where Do Spoken Words Come From?”, Paper presented at the First Mind Articulation Symposium on ‘Image, Language and Brain’, Tokyo, Japan, 1998.
• Phillips, C., Marantz, A., Yellin, E., Pellathy, T., McGinnis, M., Wexler, K., Poeppel, D., & Roberts, T., “Auditory Cortex Accesses Phonological Categories: an MEG Mismatch Study”,(Manuscript in Preparation), 1999.
• Sams, M., Aulanko, R., Haemaelaeinen, M., Hari, R., Lounasmma, O. V., Lu, S. T., & Simola, J., “Seeing speech: visual information from lip movements modifies activity in the human auditory cortex”, Neuroscience Letters, 1991, 127, 141-145.
  • PubMed abstract:   Neuromagnetic responses were recorded over the left hemisphere to find out in which cortical area the heard and seen speech are integrated. Auditory stimuli were Finnish/pa/syllables presented together with a videotaped face articulating either the concordant syllable/pa/(84% of stimuli, V = A) or the discordant syllable/ka/(16%, V not equal to A). In some subjects the probabilities were reversed. The subjects heard V not equal to A stimuli as/ta/ or ka. The magnetic responses to infrequent perceptions elicited a specific waveform which could be explained by activity in the supratemporal auditory cortex. The results show that visual information from articulatory movements has an entry into the auditory cortex.

Recommended Reading for Undergraduate and Graduate Students

• Grodinsky, Y., “The neurology of syntax:  Language use without Broca's area”, Behavioral and Brain Sciences, 23(1), 2000.  

Frontal Lobe Functions

Required Reading for Undergraduates and Graduate Students

• Kolb, B., and Whishaw, I.Q., “The Frontal Lobes”, Fundamentals of human neuropsychology (4th ed.), New York, W.H. Freeman, 1996, Chapter 14, pp. 305-331.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Stuss, D. T., Eskes, G. A., & Foster, J. K., “Experimental neuropsychological studies of frontal lobe functions”, Handbook of Neuropsychology (vol. 9, Section 12):  The Frontal Lobes, Boller & Spinnler, (Eds), 1994, pp. 149-185.

Limbic System Anatomy and Historical Overview

Required Reading for Undergraduates and Graduate Students

• Eichenbaum, H., “Declarative memory: Insights from cognitive neurobiology”, Annual Review of Psychology, 48, 1997, 547-572.
  • PubMed abstract:   The discovery of declarative memory as distinct from other forms of memory is a major recent achievement in cognitive science. Basic issues about the nature of declarative memory are considered in this review from the perspective of studies on its underlying brain mechanisms. These studies have shown that declarative memory is mediated by a specific brain system including areas of the cerebral cortex and hippocampal region that make distinct functional contributions to memory processing. These processing mechanisms mediate the organization of memories in ways that can support the special properties of declarative or explicit memory expression. Furthermore, the basic properties of declarative memory in human beings can be viewed as evolving from a capacity for organized memory representation and flexible memory expression in animals.
    
• Dusek, J.A., & Eichenbaum, H., “The hippocampus and memory for orderly stimulus relations”, Proc. Nat. Acad. Sci. USA, 94, 1997, 7109-7114.
  • PubMed abstract:   Human declarative memory involves a systematic organization of information that supports generalizations and inferences from acquired knowledge. This kind of memory depends on the hippocampal region in humans, but the extent to which animals also have declarative memory, and whether inferential expression of memory depends on the hippocampus in animals, remains a major challenge in cognitive neuroscience. To examine these issues, we used a test of transitive inference pioneered by Piaget to assess capacities for systematic organization of knowledge and logical inference in children. In our adaptation of the test, rats were trained on a set of four overlapping odor discrimination problems that could be encoded either separately or as a single representation of orderly relations among the odor stimuli. Normal rats learned the problems and demonstrated the relational memory organization through appropriate transitive inferences about items not presented together during training. By contrast, after disconnection of the hippocampus from either its cortical or subcortical pathway, rats succeeded in acquiring the separate discrimination problems but did not demonstrate transitive inference, indicating that they had failed to develop or could not inferentially express the orderly organization of the stimulus elements. These findings strongly support the view that the hippocampus mediates a general declarative memory capacity in animals, as it does in humans.
    
• Wood, E.R.,  Dudchenko, P.A.  & Eichenbaum, H., “The global record of memory in hippocampal neuronal activity”, Nature, 397, 1999, 613-616.
  • PubMed abstract:   In humans the hippocampal region of the brain is crucial for declarative or episodic memory for a broad range of materials. In contrast, there has been controversy over whether the hippocampus mediates a similarly general memory function in other species, or whether it is dedicated to spatial memory processing. Evidence for the spatial view is derived principally from the observations of 'place cells'-hippocampal neurons that fire whenever the animal is in a particular location in its environment, or when it perceives a specific stimulus or performs a specific behaviour in a particular place. We trained rats to perform the same recognition memory task in several distinct locations in a rich spatial environment and found that the activity of many hippocampal neurons was related consistently to perceptual, behavioural or cognitive events, regardless of the location where these events occurred. These results indicate that nonspatial events are fundamental elements of hippocampal representation, and support the view that, across species, the hippocampus has a broad role in information processing associated with memory.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Lipton, P., Alvarez, P., and Eichenbaum, H., “Cross modal associative representations in the rodent orbitofrontal cortex”, Neuron, 22, 1999, 349-359.
  • PubMed abstract:   Firing patterns of neurons in the orbitofrontal cortex (OF) were analyzed in rats trained to perform a task that encouraged incidental associations between distinct odors and the places where their occurrence was detected. Many of the neurons fired differentially when the animals were at a particular location or sampled particular odors. Furthermore, a substantial fraction of the cells exhibited odor-specific firing patterns prior to odor presentation, when the animal arrived at a location associated with that odor. These findings suggest that neurons in the OF encode cross-modal associations between odors and locations within long-term memory.

Memory (Lecture I)

Required Reading for Undergraduates and Graduate Students

• Squire, L.R., “Memory”, Encyclopedia Americana, 18, 1997, 677-682.
• Squire, L.R., and Zola, S., “Memory, memory impairment, and the medial temporal lobe”, Cold Spring Harbor Symposia on Quantitative Biology, LXI, 1996, 185-195.
  • PubMed abstract:   The cognitive and neuroanatomical work described here should be viewed as a first step in analyzing how the brain has organized its memory functions, which can open the door to more detailed neurobiological analysis. With respect to declarative memory, it should soon be possible to study representations directly in neocortex with the technique of single-cell recording, to observe directly the development of neuronal plasticity important for declarative memory, and to determine how the medial temporal lobe interacts with neocortex during learning, consolidation, and retrieval. In this regard, the paradigms developed by Miyashita and his colleagues appear to hold particular promise (Sakai and Miyashita 1991; Higuchi and Miyashita 1996). With respect to nondeclarative memory, it is now possible to identify particular brain systems that are essential for particular kinds of memory. An important next step will be to determine whether these systems are essential for the acquisition, storage, or expression of memory, and to identify exactly where the synaptic changes occur that support each kind of memory.
    
• Corkin, S., Amaral, D.G., Johnson, K.A., and Hyman, B.T., “H.M.'s medial temporal lobe lesion: Findings from MRI”, Journal of Neuroscience, 17, 1997, 3964-3979.
  • PubMed abstract:   Although neuropsychological studies of the amnesic patient H. M. provide compelling evidence that normal memory function depends on the medial temporal lobe, the full extent of his surgical resection has not been elucidated. We conducted magnetic resonance imaging studies to specify precisely the extent of his bilateral resection and to document any other brain abnormalities. The MRI studies indicated that the lesion was bilaterally symmetrical and included the medial temporal polar cortex, most of the amygdaloid complex, most or all of the entorhinal cortex, and approximately half of the rostrocaudal extent of the intraventricular portion of the hippocampal formation (dentate gyrus, hippocampus, and subicular complex). The collateral sulcus was visible throughout much of the temporal lobe, indicating that portions of the ventral perirhinal cortex, located on the banks of the sulcus, were spared; the parahippocampal cortex (areas TF and TH) was largely intact. The rostrocaudal extent of the ablation was approximately 5.4 cm (left) and 5.1 cm (right). The caudal 2 cm, approximately, of the hippocampus body (normal length, approximately 4 cm) was intact, although atrophic. The temporal stem was intact. Outside the temporal lobes, the cerebellum demonstrated marked atrophy, and the mammillary nuclei were shrunken. The lateral temporal, frontal, parietal, and occipital lobe cortices appeared normal for age 66 years. The mediodorsal thalamic nuclei showed no obvious radiological changes. These findings reinforce the view that lesions of the hippocampal formation and adjacent cortical structures can produce global and enduring amnesia and can exacerbate amnesia beyond that seen after more selective hippocampal lesions.
    
• Moscovitch, M. and Nadel, L., “Consolidation and the hippocampal complex revisited: in defense of the multiple trace model”, Current Opinion in Neurobiology, 8, 1998, 297-300.

Memory (Lecture II)

Required Reading for Undergraduates and Graduate Students

• Nadel, L. and Moscovitch, M., “Memory consolidation, retrograde amnesia and the hippocampal complex”, Current Opinion in Neurobiology, 7, 1997, 217-227.
  • PubMed abstract:   Results from recent studies of retrograde amnesia following damage to the hippocampal complex of human and non-human subjects have shown that retrograde amnesia is extensive and can encompass much of a subject's lifetime; the degree of loss may depend upon the type of memory assessed. These and other findings suggest that the hippocampal formation and related structures are involved in certain forms of memory (e.g. autobiographical episodic and spatial memory) for as long as they exist and contribute to the transformation and stabilization of other forms of memory stored elsewhere in the brain.
    
• Milner, B., “Memory and the human brain”, How We Know, Shafto, Ed., San Francisco, Harper & Row, 1985, pp. 31-59. 
• Murray, E., “Memory for objects in nonhuman primates”, The Cognitive Neurosciences (2d. ed.), Gazzaniga, M., Cambridge, MA, MIT Press, (In Press).
• Murray, E. and Bussey, T., “Perceptual-mnemonic functions of the perirhinal cortex”, Trends in Cognitive Science, (In Press).  

Memory (Lecture III)

Required Reading for Undergraduates and Graduate Students

• Baddeley, A., “Recent developments in working memory”, Current Opinion in Neurobiology, 8, 1998, pp. 234-238.
  • PubMed abstract:   Research on the visual and verbal subsystems of working memory has shown vigorous development, with PET, fMRI and behavioral data all supporting separate systems, with further fractionation being likely. Analysis of executive processes is revealing a range of subprocesses, providing a very fruitful field for the interaction of cognitive psychology, neuropsychology and functional imaging.
    
• Petrides, M., “Lateral frontal cortical contribution to memory”, The Neurosciences, 8, 1996, pp. 57-63.
• Owen, A. M., Morris, R. G., Sahakian, B. J., Polkey, C. E., and Robbins, T. W., “Double dissociations of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions, or amygdalo-hippocampectomy”, Brain, 199, 1996, pp. 1597-1615.
  • PubMed abstract:   Thirty-two neurosurgical patients with unilateral or bilateral frontal lobe excisions, 41 patients with unilateral temporal lobe lesions and 19 patients who had undergone unilateral amygdalo-hippocampectomy were compared with matched controls on a computerized test of spatial working memory. A significant deficit was observed in the frontal lobe group, even at the least challenging level of task difficulty and this impairment was found to relate to the inefficient use of a particular searching strategy shown to improve performance on this task. In contrast, deficits in the temporal lobe group and the amygdalo-hippocampectomy group were only observed at the most difficult level of the task and in neither group could the deficit be related to the inefficient use of any particular searching strategy. In a follow-up study, the three patient groups were compared on analogous computerized tests of visual and verbal working memory. No deficits were observed in the frontal lobe group. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy group were significantly impaired in the visual working memory condition but not in the verbal working memory condition. These deficits were clearly evident at all levels of task difficulty and were not related to any particular searching strategy. The data are discussed in terms of the relative contributions of "executive' and "mnemonic' mechanisms to the contrasting, material dependent deficits observed in the frontal and temporal lobe groups.
    
• Owen, A. M., Evans, A. C., and Petrides, M., “Evidence for a two-stage model of spatial working memory processing within the lateral frontal cortex: A positron emission tomography study”, Cerebral Cortex, 6, 1996, pp. 31-38.
  • PubMed abstract:   Previous work in nonhuman primates and in patients with frontal lobe damage has suggested that the frontal cortex plays a critical role in the performance of both spatial and nonspatial working memory tasks. The present study used positron emission tomography with magnetic resonance imaging to demonstrate the existence, within the human brain, of two functionally distinct subdivisions of the lateral frontal cortex, which may subserve different aspects of spatial working memory. Five spatial memory tasks were used, which varied in terms of the extent to which they required different executive processes. When the task required the organization and execution of a sequence of spatial moves retained in working memory, significant changes in blood flow were observed in ventrolateral frontal cortex (area 47) bi-laterally. By contrast, when the task required active monitoring and manipulation of spatial information within working memory, additional activation foci were observed in mid-dorsolateral frontal cortex (areas 46 and 9). These findings support a two-stage model of spatial working memory processing within the lateral frontal cortex.

Memory (Lecture IV)

Required Reading for Undergraduates and Graduate Students

• Schacter, D. L., “Implicit memory: a new frontier for cognitive neuroscience”, The Cognitive Neurosciences, M. S. Gazzaniga, 1995, Chapter 52, pp. 815-824.
  • PubMed abstract:   Amnesic patients often exhibit spared priming effects on implicit memory tests despite poor explicit memory. In previous research, we found normal auditory priming in amnesic patients on a task in which the magnitude of priming in control subjects was independent of whether speaker's voice was same or different at study and test, and found impaired voice-specific priming on a task in which priming in control subjects is higher when speaker's voice is the same at study and test than when it is different. The present experiments provide further evidence of spared auditory priming in amnesia, demonstrate that normal priming effects are not an artifact of low levels of baseline performance, and provide suggestive evidence that amnesic patients can exhibit voice-specific priming when experimental conditions do not require them to interactively bind together word and voice information.
    
• Keane, M. M., Gabrieli, J. D. E., Mapstone, H. C., Johnson, K. A., and Corkin, S., “Double dissociation of memory capacities after bilateral occipital-lobe or medial temporal-lobe lesions”, Brain, 118, 1995, pp. 1129-1148.
  • PubMed abstract:   Memory for recently encountered information can be reflected in conscious recall and recognition of that material, or in facilitated reprocessing of that material, an effect known as repetition priming. Repetition priming may be perceptual (form-based) or conceptual (meaning-based). A patient with bilateral occipital-lobe lesions (L.H.) and a patient with bilateral medial-temporal lobe lesions (H.M.) showed a double dissociation between visuoperceptual priming (impaired in L.H. and intact in H.M.) and visual recognition memory (intact in L.H. and impaired in H.M.). L.H. showed intact conceptual priming for visually presented words; his pattern of impaired visuoperceptual priming and intact conceptual priming is the reverse dissociation to that observed in prior studies of patients with Alzheimer's disease, in whom occipital cortices are relatively spared. These double dissociations suggest that a memory system localized to the occipital lobe mediates visuoperceptual priming effects, and that this system is independent of neural circuits mediating conceptual priming effects, and independent of the limbic-diencephalic system supporting conscious recognition of recently encountered information.
    
• Clark, R. E. and Squire, L. R., “Classical conditioning and brain systems: The role of awareness”, Science, 280, 1998, pp. 77-81.
  • PubMed abstract:   Classical conditioning of the eye-blink response, perhaps the best studied example of associative learning in vertebrates, is relatively automatic and reflexive, and with the standard procedure (simple delay conditioning), it is intact in animals with hippocampal lesions. In delay conditioning, a tone [the conditioned stimulus (CS)] is presented just before an air puff to the eye [the unconditioned stimulus (US)]. The US is then presented, and the two stimuli coterminate. In trace conditioning, a variant of the standard paradigm, a short interval (500 to 1000 ms) is interposed between the offset of the CS and the onset of the US. Animals with hippocampal lesions fail to acquire trace conditioning. Amnesic patients with damage to the hippocampal formation and normal volunteers were tested on two versions of delay conditioning and two versions of trace conditioning and then assessed for the extent to which they became aware of the temporal relationship between the CS and the US. Amnesic patients acquired delay conditioning at a normal rate but failed to acquire trace conditioning. For normal volunteers, awareness was unrelated to successful delay conditioning but was a prerequisite for successful trace conditioning. Trace conditioning is hippocampus dependent because, as in other tasks of declarative memory, conscious knowledge must be acquired across the training session. Trace conditioning may provide a means for studying awareness in nonhuman animals, in the context of current ideas about multiple memory systems and the function of the hippocampus.
    
• Shadmehr, R., Brandt, J., and Corkin, S., “Time-dependent motor memory processes in amnesic subjects”, Journal of Neurophysiology, 80, 1998, pp. 1590-1597.
  • PubMed abstract:   Functional properties of motor memory change with the passage of time. The time-dependent nature of memories in humans has also been demonstrated for certain "declarative" memories. When the declarative memory system is damaged, are the time-dependent properties associated with motor memories intact? To approach this question, we examined five subjects with global amnesia (AMN), including subject H.M., and a group of age-matched control subjects. The task was to make reaching movements to visually presented targets. We found that H.M. (but not the other subjects) was significantly impaired in the ability to perform the visuomotor kinematic transformations required in this task, to accurately move the hand in the direction specified by a target. With extensive practice, H.M.'s performance improved significantly. At this point, a force field was imposed on the hand. With practice in field A, H.M. and other AMN subjects developed aftereffects and maintained these aftereffects for 24 h. To quantify postpractice properties associated with motor memories, subjects learned field B on day 2 and at 5 min were retested in field A. In both subject groups, performance in field A was significantly worse than their own naive performance a day earlier. The aftereffects indicated persistence of the just-learned but now inappropriate motor memory. After 4 h of rest, subjects were retested in B. Performance was now at naive levels. The aftereffects at 4 h indicated a reduced influence of the memory of field A. The time-dependent patterns of motor memory perseveration, as measured at 5 min and 4 h, were not different in the AMN and normal control groups.
    
• Knowlton, B. J., Squire, L. R., and Gluck, M. A., “Probabilistic classification learning in amnesia”, Learning and Memory, 1, 1994, 106-120. 
  • PubMed abstract:   Amnesic patients and control subjects participated in a study of probabilistic classification learning. In each of three tasks, four different cues were each probabilistically associated with one of two outcomes. On each trial, the cues could appear alone or in combination with other cues and subjects selected the outcome they thought was correct. Feedback was provided after each trial. In each task, the amnesic patients learned gradually to associate the cues with the appropriate outcome at the same rate as control subjects, improving from 50% correct to approximately 65% correct. Presumably because the cue-outcome associations were probabilistic, declarative memory for the outcomes of specific trials was not as useful for performance as the information gradually accrued across trials. Nevertheless, declarative memory does appear to make a contribution to performance when training is extended beyond approximately 50 trials, because with further training control subjects eventually outperformed the amnesic patients. It was also demonstrated that performance on the probabilistic classification task was not the result of holding knowledge of cue-outcome associations in short-term memory, because both control subjects and amnesic patients demonstrated significant savings when testing was interrupted by a 5-min delay (experiment 2). Probabilistic classification learning appears to provide an analog in human subjects for the habit learning tasks that can be acquired normally by animals with hippocampal lesions.

Working Memory in Nonhuman Primates

Required Reading for Undergraduates and Graduate Students

• Roitblat, H.L., “Working memory”,  Introduction to Comparative Cognition, New York, Freeman, 1987, Chapter 5, pp. 146-189,  READ pp. 166-189.
• Miller, E.K., “The neural basis of top-down control of visual attention in the prefrontal cortex”, Attention and Performance, 18, Monsell & Drivers, in press, 1999.  
• Rushworth, M.F.S & Owen, A.M., “The functional organization of the lateral frontal cortex: conjecture or conjuncture in the electrophysiology literature”, Trends in Cognitive Science, 2, 1998, 46-53.

Spatial Memory and Plasticity

Required Reading for Undergraduates and Graduate Students

• Wilson, M.A., & McNaughton, B.L., “Dynamics of the hippocampal ensemble code for space”, Science, 261, 1993, 1055-1058.
  • PubMed abstract:   Ensemble recordings of 73 to 148 rat hippocampal neurons were used to predict accurately the animals' movement through their environment, which confirms that the hippocampus transmits an ensemble code for location. In a novel space, the ensemble code was initially less robust but improved rapidly with exploration. During this period, the activity of many inhibitory cells was suppressed, which suggests that new spatial information creates conditions in the hippocampal circuitry that are conducive to the synaptic modification presumed to be involved in learning. Development of a new population code for a novel environment did not substantially alter the code for a familiar one, which suggests that the interference between the two spatial representations was very small. The parallel recording methods outlined here make possible the study of the dynamics of neuronal interactions during unique behavioral events.
    
• Wilson, M.A., & Tonegawa, S., “Synaptic plasticity, place cells and spatial memory: study with second generation knockouts”, 1997.
  • PubMed abstract:   The use of genetically engineered mice has been a major development in neuroscience research. Genetic engineering is an undoubtedly powerful technique; however, the value of this approach has been debated, particularly in relation to its use to probe the underlying bases of complex behaviors, such as memory. A recent new development of the technique is the ability to target a specific gene knockout to a particular subregion or even to specific and limited cell types of the mouse brain. An example of this approach is the knockout of the NMDARI gene in only CAI-pyramidal cells of the hippocampus. The resulting animals can be tested by several methods, including in vivo multielectrode recording during behavioral tasks. The data provide strong evidence in favor of the notion that NMDA receptor-dependent synaptic plasticity at CAI synapses is required for both the acquisition of spatial memory and the formation of normal CAI place fields. This relationship suggests that robust place fields may be essential for spatial memory.
    
• Wilson, M.A., & McNaughton, B.L., “Reactivation of hippocampal ensemble memories during sleep”, Science, 265, 1994, 676-679.
  • PubMed abstract:   Simultaneous recordings were made from large ensembles of hippocampal "place cells" in three rats during spatial behavioral tasks and in slow-wave sleep preceding and following these behaviors. Cells that fired together when the animal occupied particular locations in the environment exhibited an increased tendency to fire together during subsequent sleep, in comparison to sleep episodes preceding the behavioral tasks. Cells that were inactive during behavior, or that were active but had non-overlapping spatial firing, did not show this increase. This effect, which declined gradually during each post-behavior sleep session, may result from synaptic modification during waking experience. Information acquired during active behavior is thus re-expressed in hippocampal circuits during sleep, as postulated by some theories of memory consolidation.

Alzheimer's Disease

Required Reading for Undergraduates and Graduate Students

• Cummings, J.L, Vinters, H.V., Cole, G.M. and Khachaturian, Z., “Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities”, Neurology, 51, 1998, S2-S17.
  • PubMed abstract:   Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.
    
• Gómez-Isla, T., Price, J.L., McKeel, Jr., D. W., Morris, J.C., Growdon, J.H., and Hyman, B.T., “Profound loss of layer II entorhinal cortex neuron occurs in very mild Alzheimer's disease”, The Journal of Neuroscience, 16, 1996,  4491-4500.
  • PubMed abstract:   The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.
    
• Locascio, J.J., Growdon, J.H., Corkin, S., “Cognitive test performance in detecting, staging, and tracking Alzheimer's disease”, Arch. Neurol., 52, 1995, 1087-1099.
• Mayeux, R., Saunders, A.M., Shea, S., Mirra, S., Evans, D., Roses, A.D., Hyman, B.T., Crain, B., Ming-Xin Tang and Phelps, C.H., “Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease”, New England Journal Medicine, 1998, 338, 506-511.
  • PubMed abstract:   BACKGROUND: The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain. METHODS: We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS: Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.
    
• Price, D.L. and Sisodia, S.S., “Mutant genes in familial Alzheimer's disease and transgenic models”, Ann. Rev. Neuroscience, 21, 1998, 479-505.
  • PubMed abstract:   The most common cause of dementia occurring in mid- to late-life is Alzheimer's disease (AD). Some cases of AD, particularly those of early onset, are familial and inherited as autosomal dominant disorders linked to the presence of mutant genes that encode the amyloid precursor protein (APP) or the presenilins (PS1 or PS2). These mutant gene products cause dysfunction/death of vulnerable populations of nerve cells important in memory, higher cognitive processes, and behavior. AD affects 7-10% of individuals > 65 years of age and perhaps 40% of individuals > 80 years of age. For the late-onset cases, the principal risk factors are age and apolipoprotein (apoE) allele type, with apoE4 allele being a susceptibility factor. In this review, we briefly discuss the clinical syndrome of AD and the neurobiology/neuropathology of the disease and then focus attention on mutant genes linked to autosomal dominant familial AD (FAD), the biology of the proteins encoded by these genes, and the recent exciting progress in investigations of genetically engineered animal models that express these mutant genes and develop some features of AD.

Effects of Aging on Memory

Required Reading for Undergraduates and Graduate Students

• Huppert, F. A., “Age-related changes in memory: Learning and remembering new information”, Handbook of Neuropsychology, Vol. 5, Boller, P. & Grafman, J. (Eds.), St. Louis, MO, Elsevier Science Publishers B. V. (Biomedical Division), 1991, pp. 123-147.
• Craik, F. I. M., Morris, R. G., Morris, L. W., & Loewen, E. R., “Relations between source amnesia and frontal lobe functioning in older adults”, Psychology and Aging, 5, 1990, 148-151.
  • PubMed abstract:   A study is reported in which the relations among normal aging, source amnesia, and frontal lobe functioning were explored. Twenty-four older adults (aged 60-84 years) were tested on their ability to remember where they had acquired new factual information; they were also given the Wisconsin Card Sorting Test (WCST), a test of verbal fluency, and other psychometric tests. The degree of source amnesia in this normal sample correlated with age, verbal fluency, and some measures from the WCST. Source amnesia was not related to Performance IQ, however, or to a measure of fact recall. The implications for the relations among aging, memory, and frontal lobe functions are discussed.
    
• Loewen, E. R., Shaw, R. J., & Craik, F. I. M., “Age differences in components of metamemory”, Experimental Aging Research, 16, 1990, 43-48.
  • PubMed abstract:   Young adults (N = 58) and older adults (N = 55) answered 30 questions extracted from three dimensions of the Metamemory in Adulthood (MIA) questionnaire: Capacity, Task and Strategy. The older participants scored significantly lower on the Capacity dimension, indicating that they report having greater difficulty in everyday memory situations. There was no age difference on any item in the Task dimension; both groups were equally knowledgeable about memory task demands. Responses to Strategy items varied with type of strategy: younger adults were more likely than older adults to report the use of encoding strategies, while older adults reported significantly more use of strategies which involved planning and organization. A further group of employed young adults (N = 26) was added to clarify the respective roles of aging and environmental demands on strategy use. The findings suggest that both changes in lifestyle and the effects of aging per se play some part in the use of particular memory strategies.
    
• Wingfield, A., Stine, E. A. L., Lahar, C. J., & Aberdeen, J. S., “Does the capacity of working memory change with age? “, Experimental Aging Research, 14, 1988, 103-107.
  • PubMed abstract:   We studied the topographic distribution of Alzheimer's disease (AD)-type pathologic changes in the brains of 25 presumed nondemented elderly individuals. Neurofibrillary tangles (NFT) and senile plaques (SP) were evaluated quantitatively in nine to 20 cytoarchitectural fields using thioflavine S, Alz-50, and anti-beta/A4 amyloid immunohistochemistry. Our observations suggest that (1) most individuals over the age of 55 have at least a few NFT and SP; (2) the topographic distribution of NFT and SP in nondemented elderly individuals follows a consistent pattern of vulnerability in different cytoarchitectural areas; (3) NFT occur most frequently in the entorhinal and perirhinal cortices and the CA1/subiculum field of the hippocampus, while neocortical areas are less frequently affected; (4) immunohistochemically defined subtypes of SP have distinct patterns of distribution. beta/A4 immunoreactive SP are present in neocortical areas much greater than limbic areas. Alz-50 immunoreactive SP are infrequent and limited to those areas that contain Alz-50-positive neurons and NFT. These patterns closely match the hierarchical topographic distribution of NFT and SP observed in AD, suggesting a commonality in the pathologic processes that lead to NFT and SP in both aging and AD.

Required Readings for Graduate Students (Recommended for Undergraduates)

• Arriagada, P. V., Hyman, B. T., & Marzloff, K., “Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease”, Neurology, 42, 1992, 1681-1688.
  • PubMed abstract:   We studied the topographic distribution of Alzheimer's disease (AD)-type pathologic changes in the brains of 25 presumed nondemented elderly individuals. Neurofibrillary tangles (NFT) and senile plaques (SP) were evaluated quantitatively in nine to 20 cytoarchitectural fields using thioflavine S, Alz-50, and anti-beta/A4 amyloid immunohistochemistry. Our observations suggest that (1) most individuals over the age of 55 have at least a few NFT and SP; (2) the topographic distribution of NFT and SP in nondemented elderly individuals follows a consistent pattern of vulnerability in different cytoarchitectural areas; (3) NFT occur most frequently in the entorhinal and perirhinal cortices and the CA1/subiculum field of the hippocampus, while neocortical areas are less frequently affected; (4) immunohistochemically defined subtypes of SP have distinct patterns of distribution. beta/A4 immunoreactive SP are present in neocortical areas much greater than limbic areas. Alz-50 immunoreactive SP are infrequent and limited to those areas that contain Alz-50-positive neurons and NFT. These patterns closely match the hierarchical topographic distribution of NFT and SP observed in AD, suggesting a commonality in the pathologic processes that lead to NFT and SP in both aging and AD.

Developmental Cognitive Neuroscience

Required Reading for Undergraduates and Graduate Students

• Diamond, A., “Frontal lobe involvement in cognitive changes during the first year of life”, Brain maturation and cognitive development: Comparative and cross-cultural perspectives, K. R. Gibson & A. C. Petersen (Eds.), New York, Aldine de Gruyter, 1991, pp. 127-180.
• Diamond, A., “Differences between adult and infant cognition:  Is the crucial variable presence or absence of language?”, Thought without language, L. Weiskrantz (Ed.), Oxford, England, Oxford University Press, 1988, p. 337-370.
• Bachevalier, J., & Mishkin, M., “An early and a late developing system for learning and retention in infant monkeys”, Behavioral Neuroscience, 98, 1984, 770-778.
  • PubMed abstract:   On the evidence that memory formation and habit formation represent two qualitatively different learning processes based on separate neural mechanisms, the functional development of these two processes was followed ontogenetically. Separate groups of rhesus monkeys of different ages were tested in delayed nonmatching-to-sample and 24-hr concurrent discrimination learning, considered to be measures of recognition memory and discrimination habit formation, respectively. The youngest group of infant monkeys failed to learn the nonmatching task until they were approximately 4 months old. With further maturation, learning ability on this task gradually improved, yet it did not reach adult levels of proficiency even at 1 year of age. Postlearning evaluation with long delays and lists confirmed this slow ontogenetic development of recognition memory to adult levels of function. By contrast, infant monkeys 3-4 months old learned to discriminate long lists of object-pairs about as quickly as adult monkeys despite the use of 24-hr intertrial intervals. This striking dissociation in the ability of infants on the two tasks closely resembles the dissociation first found in adult monkeys rendered amnesic by limbic lesions. The results suggest that whereas the nonlimbic habit system matures early in infancy, the limbic-dependent memory system develops only slowly.

Required Reading for Graduate Students (Recommended for Undergraduates)

• Diamond, A., “Evidence for the importance of dopamine for prefrontal cortex functions early in life”, Philosophical Transactions of the Royal Society (London) Series B, 351, 1996, 1483-1494.
  • PubMed abstract:   There is considerable evidence that dorsolateral prefrontal cortex subserves critical cognitive abilities even during early infancy and that improvement in these abilities is evident over roughly the next 10 years. We also know that (a) in adult monkeys these cognitive abilities depend critically on the dopaminergic projection to prefrontal cortex and (b) the distribution of dopamine axons within dorsolateral prefrontal cortex changes, and the level of dopamine increases, during the period that infant monkeys are improving on tasks that require the cognitive abilities dependent on prefrontal cortex. To begin to look at whether these cognitive abilities depend critically on the prefrontal dopamine projection in humans even during infancy and early childhood we have been studying children who we hypothesized might have a selective reduction in the dopaminergic innervation of prefrontal cortex and a selective impairment in the cognitive functions subserved by dorsolateral prefrontal cortex. These are children treated early and continuously for the genetic disorder, phenylketonuria (PKU). In PKU the ability to convert the amino acid, phenylalanine (Phe), into another amino acid, tyrosine (Tyr), is impaired. This causes Phe to accumulate in the bloodstream to dangerously high levels and the plasma level of Tyr to fall. Widespread brain damage and severe mental retardation result. When PKU is moderately well controlled by a diet low in Phe (thus keeping the imbalance between Phe and Tyr in plasma within moderate limits) severe mental retardation is averted, but deficits remain in higher cognitive functions. In a four-year longitudinal study we have found these deficits to be in the working memory and inhibitory control functions dependent upon dorsolateral prefrontal cortex in PKU children with plasma Phe levels 3-5 times normal. The fact that even infants showed these impairments suggests that dopaminergic innervation to prefrontal cortex is critical for the proper expression of these abilities even during the first year of life. To test the hypothesis about the underlying biological mechanism we have created the first animal model of early and continuously treated PKU. As predicted, the experimental animals had reduced levels of dopamine and the dopamine metabolite, homovanillic acid (HVA), in prefrontal cortex and showed impaired performance on delayed alternation, a task dependent on prefrontal cortex function. Noradrenaline levels were unaffected; however some reduction in serotonin levels and in dopamine levels outside the prefrontal cortex was found. If prefrontal cortex functions are vulnerable in children with a moderate plasma Phe:Tyr imbalance because of the special properties of the dopamine neurons that project to prefrontal cortex, then other dopamine neurons that share those same properties should also be vulnerable in these children. The dopamine neurons in the retina share these properties (i.e. unusually high firing and dopamine turnover rates), and we have found that PKU children with plasma Phe levels 3-5 times normal are impaired in their contrast sensitivity, a behavioural measure sensitive to retinal dopamine levels.