Hippocampal Damage and Semantic Memory

1. Impaired recognition memory in monkeys after damage limited to the hippocampal regionZola SM, Squire LR, Teng E, Stefanacci L, Buffalo EA, Clark RESemantic memory and the human hippocampusManns JR, Hopkins RO, Squire LR Hippocampal Damage and Semantic Memory

2. Semantic Memory MEMORY DECLARATIVE (EXPLICIT) FACTS (Semantic) EVENTS (Episodic) Recall Recognition Visual-paired comparison Multiple choice Delayed non-matching to sample Free-response MEDIAL TEMPORAL LOBE Milner B, Squire LR, Kandel ER: "Cognitive neuroscience and the study of memory". Neuron 1998, 20:445-468.

3. MTL lesion

4. Medial Temporal Lobe (MTL) 2) Entorhinal cortex 4) Parahippocampal Cortices 1) Hippocampus 3) Perirhinal Cortex

5. What is the Role of the Hippocampus Semantic Memory? How might you test your hypothesis? • Some Examples: Lesion studies • Stroke damage in humans. Chemical lesion in animals. Record Activity • fMRI, electrical recording Stimulation • Electrical stimulation (e.g. Penfield)

6. Part I Formation of long-term semantic memory after monkey hippocampal lesions

7. Part I: Overview FACTS (Semantic) Sensory Input Frontal Lobe (short term) Recognition Hippocampus (long-term) Visual-paired comparison Multiple choice Delayed non-matching to sample Cortex (long-term memory storage

8. Part I: Goal Study the role of the hippocampus in recognition (semantic) memory with a highly localized lesion. • Natural ischemia (loss of blood supply) may produce undesired side effects • Ibotenic acid (IBO) selectively destroys cell bodies and leaves surrounding white matter intact • Radiofrequency (RF) and ischemia (ISC) lesions were also analyzed

9. Characterize the lesion

10. Delayed nonmatching to sample (recognition memory) Standard Setup Animals are presented with an object for a period of time. The animal is blocked from viewing the object. After a delay, they are presented with the original object and a new one. The animal has to choose the new object to get a food reward. 8 sec - 40 min delay

11. Delayed nonmatching to sample (recognition memory) IBO = ibotenic acid; RF = radiorequency; ISC = ischemia

12. Visual paired-comparison task (recognition memory) Animals have a natural tendency to look at new images more often than familiar images FAMILIARIZATION TESTING 1 sec - 40 min delay 5 sec 25 sec of viewing time 1 sec delay 5 sec

13. Visual paired-comparison task (recognition memory)

14. Combined data for all forms of hippocampal lesions (recognition memory)

15. Part I Conclusions • The hippocampal region is crucial for the formation of recognition (semantic) memory after a period of time • But this period might vary depending on the task. Possible role for other structures, attention, food deprivation in semantic memory formation? Difficult to tell with a lesion alone

16. Part II The storage of long-term recognition and recall memory after hippocampal lesions in humans

17. Part II: Overview Sensory Input FACTS (Semantic) Frontal Lobe (short term) Recall Recognition Hippocampus (long-term) Free-response Multiple choice Cortex (long-term memory storage

18. Characterization of Damage

19. Group Average Age Years of Education Patients (n=6) 48.5 ± 5.1 yrs 13.7 ± 3.3 yrs Controls (n=12) 52 ± 3.3 yrs 13.4 ± 3.3 yrs Controls Each patient was matched with 2-3 controls

20. Recall Task • Data was analyzed in five year intervals starting from the onset of amnesia • (e.g. J.S. from 1999-1994, 1993-1988, etc.) • Questions ranged from 1950 to present • Sample Questions that might apply to 22 year olds: • Who was the famous rock musician that committed suicide in 1994? • Which famous rapper remarried his ex wife and then filed for divorce 3 months later?

21. Recall Task • Patients with hippocampal damage (H) were impaired at learning notable news events compared to controls (CON). • However, recall of more remote memories was unaffected by hippocampal damage. • AA = anterograde amnesia (inability to form new memories) • H = Patients (hippocampal damage) • CON = controls Years Before Onset of Amnesia

22. Recall vs. recognition Recognition (Multiple Choice) Free Recall Recognition vs.recall semantic memory Anterograde memory affected in both recall and recognition The period when the hippocampus is important varies depending on the test. Overall recognition memory is not statistically different from controls (69.3 ± 5% vs. 74.5 ± 5%) Questions from year of damage to present

23. Part II conclusions • The hippocampus is crucial for normal anterograde semantic memory. • Different forms of semantic memory might be processed differently by the hippocampus

24. Discussion • Were patients matched to controls only on age and years of education? Two patients became amnesiac after a drug overdose and associated respiratory failures! • Differences between monkeys and humans? • What if the hippocampus is just part of the pathway for recall?

25. Recognition (Multiple Choice) Years before amnesia Discussion • Patients and monkeys with hippocampal damage retain some recognition memory skills Patients: 69.3 ± 5% Controls: 74.5 ± 5% Above chance Above chance

26. Summary Semantic memory and the hippocampus: • There is a period of time after the formation of long-term memory and before the storage of long-term memory that memories are directly associated with the hippocampus. • This period can vary depending on the specific test of semantic memory • It is difficult to account for these differences based solely on lesion studies.

27. Summary (a way to look at the information) Semantic Memory Test Amount of time in Hippocampus Memory is more affected in hippocampal lesion Recognition Short Recall Long X Recognition Task Amount of time in Frontal Lobe Memory is more affected by hippocampal lesion Delayed non-matching to sample Long Visual paired comparison task Short X

28. Summary (a way to look at the information) Sensory Input Lost Memory Frontal Lobe Visual paired Delayed non-matching to sample Higher Cortical Areas (Consciousness) Hippocampus Recognition Memory Cortex (long-term memory storage Lost Memory Recall Memory

29. Conclusion Hippo

30. Experiment B • Sample Questions: • Is Kurt Cobain famous? • If yes, is Kurt Cobain still alive? * In the experiment, all of the options who were famous were well known before 1970

31. Experiment B C B

33. Other Interesting Results/Discussion • The size of the lesion does not correlate with the severity of recognition memory • It is possible that above a certain threshold (>20%) of damage, the hippocampus can no longer support recognition memory • “(the) process of forming associations and the ability to retain relational information across time that many have supposed is at the heart of declarative memory and in turn is the function of the hippocampal region in both humans and animals” • Ibotenic acid, which creates a more localized lesion, caused the same amount of memory deficit as other lesioning methods (e.g. ischemia). • This suggests that there is no “hidden damage” or neuronal dysfunction of visually/histologically unaffected portions of the brain.

34. Recognition (Multiple Choice) Years before amnesia Discussion • Does the term “semantic memory” have biological relevance? Does the area we call the hippocampus have behavioral relavence? • Are other structure involved in recognition memory? Is recognition memory a unique form of semantic memory? Patients: 69.3 ± 5% Controls: 74.5 ± 5% chance Above chance

35. Other Interesting Results/Discussion • No specific area of the hippocampus is important for recognition memory • Caudate nucleus damage, in addition to hippocampal damage, does not further disrupt recognition memory.

36. Experiment B (recognition) It is generally accepted that the hippocampus is necessary for episodic memory. What if episodic memory is enhancing for semantic memory for controls? DECLARATIVE (EXPLICIT) EVENTS (Episodic) FACTS (Semantic)

37. Experiment B (recognition) • Is semantic memory augmented by episodic memory? • Controls were asked if they could remember the circumstances in which they heard of the individual’s death. • When data associated with episodic recall was removed, the patients were still impaired compared to the controls.

38. Ebbinghaus Working Model Sensory Input Sensory Information Working Memory/Short term Memory (Minutes) Frontal Lobe Short term Long- term Hippocampus Cortex (long-term memory storage Long Term Memory (Hours/Days/Years)

39. What is the Role of the Hippocampus Semantic Memory? Two tests for semantic memory commonly used under the lesion model: • Free Recall What are the four cortical lobes? • Recognition Tests Multiple choice Which person have you seen before?

40. Ebbinghaus Working Model Receptors (e.g photoreceptors) Sensory Information Working Memory/Short term Memory (Minutes) Frontal Lobe Short term Long- term Hippocampus Long Term Memory (Hours/Days/Years) Long Term Memory (Hours/Days/Years)