Clinically Relevant Functional Neuroanatomy IV: Neuroanatomy of Memory Russell M. Bauer, Ph.D....

Clinically Relevant Functional Neuroanatomy

IV: Neuroanatomy of Memory

Russell M. Bauer, Ph.D.University of Florida

AACN 5th Annual ConferenceJune 8, 2007

Anatomy of Memory

Russell M. Bauer, Ph.D. (DON’T BELIEVE HIS LIES)

Multiple Forms of MemoryMultiple Forms of Memory

“Core” Features of Amnesia

1. anterograde amnesia: defect in new learning

2. retrograde amnesia/remote memory disturbance: defect in retrieving old memories

3. spared memory abilities: attention span, psychometric intelligence, and ‘nondeclarative’ forms of memory are generally spared

The Human Amnesic Syndrome

• Impaired new learning (anterograde amnesia), exacerbated by increasing retention delay

• Impaired recollection of events learned prior to onset of amnesia (retrograde amnesia), often in temporally graded fashion

• Not limited to one sensory modality or type of material

• Normal IQ, attention span, “nondeclarative” forms of memory

Clinically Relevant Dimensions of Human Memory Performance

Immediate-recent-remoteEncoding-storage-retrieval

Material, modality specificityTests vs. processes

Encoding

• Definition: process of transforming to-be remembered in formation into memorable and retrievable form– Encoding I: bringing information-processing

capacity to bear on stimuli– Encoding II: ability to use the results of E-1

mnemonically• Relevance: levels-of-processing accounts of

memory (memory as by-product of information processing)

• Clinical manifestation: poor immediate (superspan) recall

Consolidation/Storage

• definition: process of making new memories permanent

• basis: anatomic and physiological changes at cellular level; hippocampal system important

• when? during study-test interval• duration: hours? days? years?• clinical symptom: delayed memory

<< immediate memory (forgetting)

Performance on a test of memory for news stories. From Squire & Bayley, Curr Opin Neurobiol, 2007, 17, 185-196.

Retrieval• definition: process of locating,

selecting, and activating a memory representation

• basis: re-enactment of pattern of excitation occurring at encoding

• when? at point of test• clinical symptom: recall <<

recognition (also true of shallow encoding), inconsistent errors

Medial Temporal Syndromes

• Anoxic-hypoxic syndromes– cardiac arrest– CO poisoning

• Amnesia associated with ECT• CNS Infections (Herpes)• MTS and complex-partial epilepsy

(material-specific)• Early AD

Temporal Lobe Pathology Associated

with Herpes Simplex Encephalitis

FLAIR (Fluid Attenuated Inversion Recovery) in Medial Temporal Sclerosis

Hippocampus in ischemia

Hippocampus in Alzheimer’s Disease

The Case of Henry M (H.M.)

Bauer, Grande, & Valenstein, 2003

Integrated Circuitry Linking Temporal, Diencephalic, and Basal Forebrain Regions

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits

Medial (Papez) Lateral

Amygdalofugal pathways

DG

CA3

CA1

subic

Bauer, Grande, & Valenstein, 2003

Delayed Nonmatching to Sample

Delayed Nonmatching to Sample, multiple trials, trial-unique objects

6-8 weeks postsurgery 2 years postsurgery

Bauer, Grande, & Valenstein, 2003

Zola-Morgan & Squire, 1990

Zola-Morgan & Squire, 1990

Murray & Richmond, Curr Opin Neurobiol, 2001

-perirhinal cortex obviously important in memory, but also has many additional connections

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits and the Two-system theory of amnesia

Medial (Papez) Lateral

Amygdalofugal pathways

PRPH

Hippocampus is important in specific types of relational memory (e.g., transitive inference)

Morris Water Maze

Lesioned rats

Sham operated rats

Morris Water Maze

(Eichenbaum, et al, 1990)

(Gallagher, et al, 1993)

Time to Target

Aged rats

Young rats

Leutgeb, et al., Curr Opin Neurobiol, 2005, 15, 738-746.

Galani, et al., Behav Brain Res, 1998, 96, 1-12.

Hippocampus v. Entorhinal Cortex Lesions and “Reference” vs. “Working” Memory MWM

“Reference Memory (H<ECo) “Working Memory (H=Eco=Sub<Sham)

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits and the Two-system theory of amnesia

Medial (Papez) Lateral

Amygdalofugal pathways

PRPH

Integrated Circuitry Linking Temporal, Diencephalic, and Basal Forebrain Regions

Diencephalic Syndromes

• Korsakoff Syndrome associated with ETOH abuse or malabsorption– prominent encoding deficits– role of frontal pathology

• Vascular disease• Thalamic trauma

Mamillary Body Lesions in a case

of Korsakoff’s Disease

MRI in paramedian thalamic stroke

Lövblad, et al (1997)

Neuroradiology, 39, 693-698.

Caolo, et al (2005). Brain, 128, 1584-98.

Mammillary body (a), medial thalamic (arrows in B,C) and fornix (arrowheads in B) damage in a case of Alcholic Korsakoff syndrome. D shows resolution of signal changes after 5 months of abstinence.

Lesion Profile in a Case of Thalamic Amnesia

Graff-Radford, et al (1990). Brain, 113, 1-25.

Anterior thalamic lesions affecting the MTT and VAF pathways produce persistent amnesia, posterior lesions do not

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits and theTwo-system theory of amnesia

Medial (Papez) Lateral

Amygdalofugal pathways

Integrated Circuitry Linking Temporal, Diencephalic, and Basal Forebrain Regions

Basal Forebrain Syndromes

• Anterior Communicating Artery (ACoA) infarctions– prominent anterograde, variable retrograde

amnesia– prominent confabulation– frontal extension of lesions

• Basal forebrain and cholinergic projections to hippocampus

Myers, et al. (2006)

Myers, DeLuca, Hopkins, & Gluck (2006), Neuropsychologia, 44, 130-139.

Myers, et al. (2006)

Reversal

H<AcoA

Learning

AcoA<H

Myers, et al. (2006)Myers, et al. (2006)

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits

Medial (Papez) Lateral

Amygdalofugal pathways

Hippocampus

Mammilary Bodies

Anterior Thalamus

Cingulate Gyrus

Fornix

Mamillothalamic Tract

Amygdala

Dorsomedial Thalamus

Orbitofrontal

Uncus

Two Limbic Circuits

Medial (Papez) Lateral

Amygdalofugal pathways

Bauer, Grande, & Valenstein, 2003

Frontal Contributions to Memory

• Working Memory

• Selective Engagement

• Cognitive contributions– Strategy development– Retrieval support/intention– Metamemory

Miller, G. A., Galanter, E. & Pribram, K. H. (1960). Plans and the structure of behavior. New York: Holt, Rinehart & Winston.

G.A. Miller

E. Galanter

K.H. Pribram

Alan Baddeley

EpisodicBuffer

Working memory and associative memory may be distinguished using the delayed response task

When PFC-lesioned monkey must remember which well is baited from trial to trial, performance is poor

When PFC-lesioned monkey must remember which symbol is baited from trial to trial, performance is good

Patricia Goldman-Rakic (1937-2003)

Smith & Jonides, 1999

A question to think about: why would you have spatially-sensitive neurons in pre-MOTOR cortex?

Two views about specificity in WM

• Domain-specificity (Goldman-Rakic, Ungerleider, Courtney)– Ventral prefrontal: object working memory– Dorsal prefrontal: spatial working memory

• Process-specificity (Petrides, D’Esposito)– Ventral prefrontal: sequential organization and

storage– Dorsal prefrontal: executive control and

monitoring

Smith & Jonides 1999

Storage Exec

+

Storage

D’Esposito, Postle, and Rypma, 2000

Curtis & D’Esposito, 2003 (from Rowe et al, 2000)

D’Esposito, M., Zarahn, E., Balard, D., Shin, R.K., and Lease, J. (1998) Functional MRI studies of spatial and nonspatial working memory. Cogn. Brain Res. 7:1-13

Curtis & D’Esposito, 2003

Selective Engagement

• “Activation” or “bringing online” of a cortical processor needed to perform a cognitive task

• Dependent on complex reciprocal connections among regions in frontal lobe, basal ganglia, thalamus, and ascending activation centers

• Important for memory retrieval

General Organization of Frontal General Organization of Frontal cortical-striatal-pallidal-thalamic-cortical-striatal-pallidal-thalamic-

cortical loopscortical loops

Motor Activation/Preparation

Heilman, Watson, & Valenstein, 2003

Cortex

Thalamus

Nucleus Reticularis

Selective Engagement and Disengagement of Cortex

Excitatory cortical projections to the thalamus (A) course through the nucleus reticularis (NR) synapsing on inhibitory thalamicinterneurons (B), reticulo-thalamic neurons (C), and providing arborizing collaterals (D). The direct cortical projection to the thalamicinterneuron (B) results in the inhibition of thalamo-cortical projection (E). This inhibition of thalamo-cortical projections results in thedisengagement (inhibition) of select cortical areas. The reticulo-thalamic neuron (C) synapses on, and inhibits, a thalamic interneuron(F), resulting in excitation of the thalamo-cortical neuron (G). This excitation of the thalamo-cortical projection results in the engagementof select cortical areas. The collateral (D) synapses on, and inhibits, a reticulo-thalamic neuron (H) which synapses on a thalamicinterneuron (I). The thalamic interneuron (I) inhibits the thalamo-cortical neuron (J) resulting in the disengagement of select corticalareas.

= Glutamatergic (excitatory) = GABA-ergic (inhibitory)

Dashed lines represent inhibited neuron (neuron unable to exert it’s influence on downstream neuron).

A

J

C

B

G F

E

HI

D

Key Points• Extended memory system including hippocampus,

amygdala, and basal forebrain (and their connections)• We (basically) understand anatomy, now we need to

understand computation• Notion of distinct subtypes of amnesia generally less

favorable now than 10 years ago• Certain structures are ‘wired’ for associational processing

through intrinsic and corticocortical connections; these structures appear important in establishing distributed network connections supporting memory

• Cortical-subcortical interactions appear critical for selectively activating and engaging specific cortical processors needed for performance of specific tasks