1. 1 Memory and Amnesia Lecture 7 June 12th, 2006

2. 2 Learning & Memory “Life without memory is very unlike life as the rest of us know it; indeed, it is almost no life at all” Speaking, bicycling, multiplication by 7s, urinary control, taste of oranges, balancing when standing, anxiety associated with public speaking, smell of bananas, the appearance of your face, your mothers name, first day of school……………… Alzheimer’s Disease, Traumatic Brain Injury, Schizophrenia, Epilepsy, Dementia, Strokes, Tumors etc.

3. 3 Lecture Outline: Introduction Patient H.M. / Amnesia Deficits Episodic vs. Semantic long-term memory What is preserved? Short term memory Implicit memory What is the role of the hippocampus in memory? Basal ganglia and implicit learning

4. 4 What is Learning and Memory? Learning – relatively permanent change in an organism’s behavior as a result of experience Memory – is the acquisition and retention of, and the ability to retrieve information, personal experiences and procedures (skills and habits).

5. 5 Stages in Memory Formation and Retrieval 1.Encoding – processing of incoming information Acquisition – registers inputs in sensory buffers Consolidation – creation of a strong representation over time 2.Storage – the result of acquisition and consolidation 3.Retrieval – utilizes stored information to crate a conscious representation or to execute a learned behavior

6. 6 Are there Different Types of Memory? Temporal division Sensory memory (milliseconds to seconds) Short-term/working/on-line (seconds to minutes) Long-term memory (minutes to years) Content division Semantic (general knowledge) Episodic (personal memories) Skills

7. 7 Patient H.M. 1953 William Scoville & Brenda Milner William Scoville - bilateral medial temporal lobe resection Brenda Milner – neuropsychologist No language or perceptual deficits or motor deficits IQ unchanged (118) Intact digit span –short-term memory – can hold a conversation No language or perceptual deficits Remembered who he was Severe memory impairment - amnesia

8. 8 What is Amnesia? Amnesia - partial or total loss of memory Infantile amnesia Fugue state Transient Global Amnesia – short-lived neurologic disturbance characterized by memory loss (usually loss of old memories and an inability to form new memories) most often caused by ischemia

9. 9 Temporal Extent Anterograde amnesia Retrograde amnesia H.M.?

10. 10 Temporal Gradient Temporal gradient – a gradient in memory loss in which recent memories are affected to a greater degree than more remote memories Ribot’s Law “First-in-last-out” (e.g., childhood memories) Alzheimer’s disease

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12. 12 Global Nature of the Deficit In general, in cases of amnesia, memory deficit is multimodal However, there are cases of modality specificity For example, left hippocampal damage is associated with verbal memory deficits

13. 13 What Memory Functions are Spared in Amnesia? Short-term/Working/On- line memory Limited in capacity Consciously available Digit span - 7 ± 2 Serial position effect Primacy and recency effect

14. 14 Dorsolateral Prefrontal Cortex and Working Memory Delayed nonmatching to sample (DNMTS) Monkeys with with DLPFC lesions perform poorly in this working memory task Working memory does not depend on the hippocampus

15. 15 Brain Mechanisms of Working Memory Fuster, 1989 Single cell recording from DLPFC Delayed-response task DLPFC neurons show sustained activity during the delay until the response is made

16. 16 There are at least 2 types of short-term memory Phonological loop – deals with verbally based memory Visuospatial sketchpad – deals with object forms and locations

17. 17 Short Term Memory 6 2 3 4 5 1 Spatial Working Memory Spatial Span

18. 18 Implicit Learning H.M. could learn new motor tasks Could not remember doing the task before Hence he ‘implicitly’ learned but could not ‘explicitly’ remember doing the task

19. 19 Pursuit-rotor task Priming - The Gollin Incomplete Picture task

20. 20 Two Kinds of Long-Term Memory Explicit – conscious, intentional recollection of previous experience Declarative Fact Memory Knowing what Implicit – unconscious, non- intentional form of memory Non-declarative Skill Habit Knowing how

21. 21 Are There Different Types of Explicit Memory?

22. 22 Interview of G.O. by Dr. Levine Do you have a memory of when you had to speak in public? Well yes, I’m was a call centre trainer with Modern Phone Systems, so I did a lot of speaking because I did a lot, a lot of training all across Canada. I also went to parts of the States.

23. 23 Do you remember one time that you were speaking? Can you tell us about one incident? Oh yes! Well I trained thousands and thousands of clients on a wide variety of topics including customer service, inbound and outbound telemarketing. Handling difficult customers. Do you remember one training session that you gave? Something that may have happened, a specific incident? Well for example I always recommended that people take customer service first. And I always had people come up with four things about themselves, three that were true and one that was false. Not necessarily in that order.

24. 24 But this was something ongoing, so every training session you would tell people this, right? Yes So what we’re looking for is one incident or one time that you gave a training session or any other speech that you want to tell us about. A specific incident. Oh well I customized a lot of material for many, many companies. And I also did lots of training at the home office OK, so what we’re asking is do you remember one time you gave a talk? Oh! Yes I do.

25. 25 One specific time not over a series of times, one time, can you tell us about that? Oh sure yes, it was at the home office and yes, many many people were there One occasion. When did it take place? When? Well I left Modern voluntarily in 1990. But this one occasion when did it take place? Ummm, well I started in the Modern home office.

26. 26 I’m getting the impression that you have a really good memory for all the training that you’ve done but you don’t seem to be able to come up with a specific talk that maybe stands out in your mind for any reason? Would you agree with that? Oh yes well I always trained customer service. So there was no talk that maybe something went wrong or something strange happened? No, no I was a very good trainer.

27. 27 Two Kinds of Explicit Memory Episodic Memory (personal experiences) Conscious awareness of past events Autobiographical memory Semantic Memory (facts about the world) What is the capital of Italy? Are rock and animals the same? Who are you parents? No episodic recollection of the specific circumstances surrounding this learning

28. 28 Dissociation Between Episodic and Semantic Memory Patient K.C. Motorcycle accident Subdural hematoma (a pool of blood under the dura mater) was surgically removed Short-term memory OK Retrograde and anterograde amnesia All episodic memories have been lost Semantic knowledge has been preserved

29. 29 K.C. could learn new semantic information but could not remember how he learned it Study: K.C. was given three-word sentences together with a related picture Tested 12 months later: perceptual test or conceptual test Hence, amnesics can acquire new semantic knowledge Can People with Amnesia Lear New Semantic Information?

30. 30 Summary of Major Points – Hippocampal Amnesia Global anterograde amnesia Explicit memory (episodic; semantic) Graded retrograde amnesia Ribbot’s law Intact implicit memory Motor learning Priming Intact short term memory

31. 31 The Role of Hippocampus in Memory H.M. case led neuropsychologist to focus on the hippocampus However, H.M.’s brain resection included several structures (hippocampus, amygdala, perirhinal cortex) making conclusions difficult 40% of H.M.’s hippocampus seems to be intact

32. 32 The Anatomy of The Hippocampus Two gyri: Ammon’s horn (CA1, CA2, CA3 and CA4) and dentate gyrus Two major pathways connecting it to the rest of the brain: perforant path and fimbria- fornix.

33. 33 Hippocampus Entorhinal cortex Perirhinal cortexPerahippocampal cortex Association neocortex

34. 34 Memory and the Hippocampus Hippocampus as a storage site for memory? Hippocampus consolidates new memories?

35. 35 The Hippocampus as a Storage Site for Memory? If memories are stored in the hippocampus more remote memories should be as likely to be lost as recent memories However, in most cases more remote memories, especially those acquired before the 20 th year of life, seem to be spared Most researchers do not think that the hippocampus is a place where memories are stored

36. 36 Hippocampus Consolidates New Memories? According to this theory, hippocampus consolidates new memories The memories are then stored somewhere else This would suggest that memories are held in the hippocampus for a long time This would explain why older memories are usually spared, whereas more recent memories are lost Problem is that retrograde amnesia can extend back for decades Consolidation is very slow??

37. 37 More Consolidation Evidence Patient R.B. –Dense anterograde amnesia - 1 to 2 years retrograde amnesia Autopsy – overall hippocampus looked intact Histological analysis indicated cell loss in CA1 region of the hippocampus Conclusion: CA1 important for consolidation of new memories

38. 38 Hippocampus and the Context Episodic memory is context dependent Associations between faces, names, places, events, time etc. Therefore, it has been suggested that the hippocampus is important for contextual learning (relations between items)

39. 39 Hippocampus and Relational Learning Paired-associate learning Apple-iron Horse-cow Children-sun Fault-squirrel Corkscrew-winter At test: Apple-? Horse-? Children-? Fault-? Corkscrew-? Amnesic patients are proportionally more impaired on this test

40. 40 Hippocampus and Relational Learning Eye movement while viewing pictures Target picture viewed Same picture Same picture with altered item relations Novel picture Intact subjects: Reduction in movements after identical repeat Increase in movements if: novel picture or if items are moved Hippocampal patients: Reduction in movements after identical repeat Increased movements for novel picture No increase in movements if items are moved

41. 41 Hippocampus and Relational Learning Spatial memory - hippocampal lesions impair performance (Morris et al., 1982)

42. 42 Hippocampus and Relational Learning Egocentric Learning – no impairment after hippocampal lesions

43. 43 Knowing Where and Getting There Maguire et al., (1998) investigated, with functional neuroimging, navigation through a virtual town Hippocampus was activated if the regular route was blocked and the subjects had to find alternative routes Maguire et al., 1998

44. 44 Anterior and Lateral Temporal Lobes and Memory If memories are distributed throughout the cortex than damage to the cortex will lead amnesia Lesions of the lateral cortex of the anterior temporal lobes (entorhinal and parahippocampal cortex also) produce retrograde amnesia Alzheimer’s disease and herpes simplex encephilitis – anterograde and retrograde amnesia Is this where the memory is stored? Medial temporal lobe - anterograde amnesia Temporal and frontal cortex – retrograde amnesia

45. 45 The Role of Diencephalon - Korsakoff’s Syndrome Damage to diencephalon (dorsomedial thalamus and mammillary bodies) causes amnesia Strokes, tumors, trauma, and metabolic problems (associated with alcoholism) (vitamin B1 deficiency) Korsakoff’s syndrome: 1) retrograde amnesia, 2) anterograde amnesia, 3) lack of insight, 4) apathy, 5) meager content in conversation, 6) confabulations. Confabulations – the recitation of imaginary experiences to fill gaps in memory

46. 46 The Neural Basis of Explicit Memory

47. 47 Encoding vs. Retrieval HERA Model “Hemispheric encoding-retrieval asymmetry”

48. 48 Neural Mechanisms for Episodic Memory

49. 49 Patient J.K. – Parkinson’s disease (DA cells in substantia nigra die) On one occasion, he stood at the door of his bedroom frustrated by his inability to recall how to turn on the lights. He remarked “I must be crazy. I’ve done this in my life, and now I can’t remember how to do it!” Huntington’s Chorea (degeneration of basal ganglia cells) mirror drawing task – no improvement The Neural Basis of Implicit Memory

50. 50 The Neural Basis of Implicit Memory Motor-based implicit memory is thought to be mediated by a circuit separate from limbic structures (explicit memories)

51. 51 Basal Ganglia and Habits Using well learned routes (versus relying on a cognitive map) is associated with caudate (basal ganglia) activation Maguire et al., 1998

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53. 53 What is the relationship between the Medial Temporal Lobe (MTL) and Basal Ganglia (BG) Memory Systems? MTL – episodic, declarative, relational memory (relation between multiple cues) Basal ganglia – procedural, habit, nondeclarative (learning based on individual cues) Are these two systems independent, cooperative or competitive?

54. 54 Relationship Between MTL and BG Memory systems? Virtual environment 8-arm radial maze Extra maze cues (trees, landscape, sunset, mountains) At the end of 4 arms there were objects (not visible from the central platform) SPATIAL – USING AT LEAST 2 EXTRA-MAZE LANDMARKS (SPATIAL GROUP) NON-SPATIAL – COUNTING THE ARMS FROM A SINGLE STARTING POINT (NON-SPATIAL GROUP) Poldrack & Rodriguez, 2004

55. 55 Relationship Between MTL and BG Memory systems? The use of a spatial strategy was associated with right hippocampal activation The use of a non-spatial strategy was associated with caudate nucleus activation In both cases there was activation in frontal cortex Poldrack & Rodriguez, 2004

56. 56 Relationship Between MTL and BG Memory systems? Win-shift task No particular stimulus is consistently paired with the correct response (spatial learning) Win-stay Single stimulus consistently paired with the correct response Lit arms are baited Packard et al., 1989

57. 57 Relationship Between MTL and BG Memory systems? Packard et al., 1989 Win-shift task – Spatial task Fornix lesions – deficits Caudate lesions = control Win-stay task – Non-Spatial task Caudate lesions –deficits Fornix lesions better than control