Human Brain Disorders and Memory Nicola J. Broadbent Ph.D Dept. Psychiatry UCSD School of Medicine

Case H.M. Severely incapacitated by seizures despite maximum dosages of anticonvulsant medications At age 27, underwent experimental surgery that bilaterally removed the uncus, amygdala, parts of the hippocampus, perirhinal and parahippocampal cortices

H.M’s Lesion

Characteristics of Medial Temporal Lobe Amnesia Intact cognitive and intellectual abilites Normal I.Q. No change in personality, social graces intact Normal reasoning, abstract thinking and problem solving Spared immediate and working memory i.e. normal digit span

Characteristics of Medial Temporal Lobe Amnesia Intact cognitive and intellectual abilites Spared immediate and working memory Anterograde Amnesia: “a persistant inability to remember new information and events which occur after the onset of amnesia”.

Semantic memory: memory for facts, world knowledge Episodic memory: memory for an event that is autobiographical, and occurs in a specific time and place/context. Declarative Memory

“Everyday is alone in itself, whatever enjoyment I’ve had, and whatever sorrow I’ve had. Right now, I’m wondering. Have I done or said anything amiss? You see, at this moment everything looks clear to me, but what happened just before? That’s what worries me. Its like waking from a dream, I just don’t remember ” (p. 217; Milner et al., 1968)

Characteristics of Medial Temporal Lobe Amnesia Intact cognitive and intellectual abilites Spared immediate and working memory Anterograde amnesia Retrograde amnesia for premorbid events: “information acquired just prior to the brain damage is abolished, but information acquired at remote time points is spared”.

Characteristics of Medial Temporal Lobe Amnesia Intact cognitive and intellectual abilites Spared Immediate and working memory Anterograde amnesia Retrograde amnesia for premorbid events Spared Implicit Memory

Damage to the medial temporal lobe does not impair mirror drawing (nondeclarative/implicit learning)

Why is H.M.’s case so important? 1.Provided first strong evidence for the role of the medial temporal lobe structures in long-term memory (LTM) 2.Showed that memory was dissociable from other cognitive abilities 3.Amnesia with intact performance on implicit memory tasks suggests that there are multiple memory systems in the brain Working memory vs. LTM implicit memory vs. episodic and semantic memory

LONG-TERM MEMORY DECLARATIVE (EXPLICIT) SEMANTIC (facts) EPISODIC (events) Hippocampus/ Medial Temporal Lobe NONDECLARATIVE (IMPLICIT) PROCEDURAL (SKILLS & HABITS) PRIMING & PERCEPTUAL LEARNING SIMPLE CLASSICAL CONDITIONING NONASSOCIATIVE LEARNING FEARSOMATIC AMYGDALA CEREBELLUM STRIATUM NEOCORTEX REFLEX PATHWAYS Squire 1992

Declarative Memory vs. Nondeclarative memory Declarative Memory Facts and events Flexible use of information Acquired knowledge is available to conscious recollection or awareness Supported by the medial temporal lobe (and diencephalic structures) Nondeclarative memory Collection of memory abilities that support skill and habit learning Expressed through performance rather than recollection Unaware inflexible Supported by a wide array of brain regions specific to each type of memory

Neural Substrate of Declarative Memory MTL

Case R.B. Became amnesic after complications following heart surgery (atrial tear and respiratory arrest). Extensive neuropsychological testing and postmortem neuropathological analysis First case to show that damage limited to the hippocampus (specifically the CA1) resulted in anterograde amnesia.

Rey-Osterrieth Complex Figure

Damage to the Hippocampus Impairs Recall of Rey- Osterrieth Complex Figure

Subjects with medial temporal lobe damage are severely impaired at recalling the Rey-O figure.

Case RB demonstrates that damage restricted to the hippocampus is sufficient to result in anterograde amnesia RB’s amnesia is milder than HM, suggesting that other medial temporal lobe regions also make significant contributions to memory.

Case N.A. Became amnesic following a penetrating brain injury with a miniature fencing foil (up the nose!) MRI showed that damage was to the thalamic nuclei, mamillothalamic tract and mammillary bodies Dense anterograde amnesia Little retrograde amnesia Confabulation, disorientation in space and time This case shows that in addition to the MTL, the diencephalon is also involved in the formation of declarative memories.

What can cases with MTL or hippocampal damage tell us about the characteristics of Declarative Memory? MTL damage results in impaired Recall and Recognition memory –Recognition memory = the ability to identify a previously encountered item as familiar MTL damage impairs recognition memory across a wide array of modalities (odor, vision, audition)

0.5 sec 2 min2 hr McKee RD, Squire LR (1993) PREFERENCE FOR NOVEL OBJECT (%) DELAY Subjects with damage to the MTL are impaired at recognition tasks (vision, sound, odor) NONSENSE SOUNDS VISUAL PAIRED COMPARISON ODOR

Declarative Memory: Retrograde Amnesia CASE E.P Developed amnesia after contracting viral encephalitis MTL severely damaged Severe anterograde amnesia Temporally limited retrograde amnesia

Like H.M, E.P has normal IQ, perception and other cognitive abilities

E.P’s working memory is normal

E.P has severe Anterograde Amnesia

Teng and Squire (1999)

EP can navigate around his childhood neighborhood demonstrating intact remote spatial memory

P e r c e n t C o r r e c t Current Neighborhood EP cannot navigate from his current home to a different location (anterograde amnesia) EP CON Teng and Squire (1999)

EP has intact remote spatial memory

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

NEOCORTICAL AREAS HIPPOCAMPUS

Significance of Retrograde Amnesia: The hippocampus is initially critical for memory, but over time memories eventually become independent of the hippocampus. Memories are eventually consolidated within the neocortex FORGETTING OLDNEW MEMORY CORRECT (%)

Squire 1992 NONDECLARATIVE (IMPLICIT) PROCEDURAL (SKILLS & HABITS) PRIMING & PERCEPTUAL LEARNING SIMPLE CLASSICAL CONDITIONING NONASSOCIATIVE LEARNING FEARSOMATIC AMYGDALA CEREBELLUM STRIATUM NEOCORTEX REFLEX PATHWAYS

Features of Habit Learning system Learning occurs slowly over time Stimulus-response In humans, learning does not require conscious awareness of the contingencies Supported by the neostriatum!

Neostriatum SUBSTANTIA NIGRA CAUDATE NUCLEUS PUTAMEN

The Weather Task: Probabilistic classification task Knowlton et al., (1996)

Do these cards predict sun or rain?

Parkinson’s disease patients are impaired at learning the weather task but amnesic patients are not

LONG-TERM MEMORY NONDECLARATIVE (IMPLICIT) DECLARATIVE (EXPLICIT) SEMANTIC (facts) EPISODIC (events) PROCEDURAL (SKILLS & HABITS) PRIMING & PERCEPTUAL LEARNING SIMPLE CLASSICAL CONDITIONING NONASSOCIATIVE LEARNING FEARSOMATIC Hippocampus/ Medial Temporal Lobe AMYGDALA CEREBELLUM STRIATUM NEOCORTEX REFLEX PATHWAYS Squire 1992