limbic system connections in detail mechanism of memory approach to amnesia

1. Limbic System network
& approach to amnesia
Dr.Abhinav Kumar
Medicine Resident
M.S Ramaiah medical college

2.  Border is between the neocortex and the subcortical
structures (diencephalon).
 Concept of limbic system as an emotional system is the
legacy of McLean (1950’s)
 proposed by Papez (1930’s)
 anatomical name “limbic” introduced by Broca (1870’s).
 The limbic system has evolved to the point that it is not
longer anatomically correct or relevant. It should be
abandoned and replaced by “brain emotional system” or
“emotional brain”.

10. Limbic System
 Limbic Lobe and Papez Circuit together
 Distinguishes human emotions and responses to
situations from the stereotypical response of animals
due to reflexive systems involving brainstem

15. Hippocampus
 Hippocampus means seahorse in Greek.
 Hippocampus aka cornu ammonis.
 The term hippocampal formation typically refers to the
dentate gyrus
hippocampus proper (i.e., cornu ammonis)
subicular cortex.
 Location temporal lobe of each cerebral cortex, medial to the
inferior horn of the lateral ventricle.
 Ammon was an Egyptian god, near whose temple ammonia or the
salt of Ammon was prepared.
 Ammon’s Horn because the two hippocampi bend around in the
form of the horns of a ram.

17. Fornix
 fornix is a “C” shaped tract (in sagittal section).
 The fornix begins as the bundle of fibers called the alveus.
 The alveus is white matter consisting of mylinated afferents
and efferents.
 fibers of the alveus travel posteriorly, they aggregate medially
to form the fimbria of the fornix.

18.  Fimbria means fringe and in this case it is the fringe of the
hippocampus.
 The fimbria looks like a thick rubber band.
 The fimbria of each hippocampus thickens as it moves
posteriorly and eventually splits off from the hippocampus
forming the crua or “legs” (singular—crus) of each
hippocampus.
 The two crua come together and form the hippocampal
commissure. The hippocampal commissure provides one of
two major paths whereby the hippocampi communicate with
each other

20.  After the hippocampal commissure the single fiber bundle
isfornix. The fornix continues in an arc to the anterior
commissure.
 The anterior commissure landmark fornix splits into three
parts and goes to different structures:
 1) Split just before the anterior commissure 
precommissural fornixseptal nuclei, the ventral striatum, and
the cingulate cortex.
 2) Some fibers from the fornixanterior commissure to the
contralateral hippocampus.
 3) Split after the anterior commissurepostcommissural
fornixmammillary bodies of the hypothalamus and the
anterior nuclei of the thalamus.

21. Output Pathways of the
Hippocampus

22.  afferents and efferents of the hippocampus are bundled
together in the same paths.
 Two major pathways into and out of the hippocampus are
the fornix and entorhinal cortex (via the cingulate cortex).
 The precommissuralconnects to the septal nuclei, preoptic
nuclei, ventral striatum, orbital cortex and anterior
cingulate cortex.
 The postcommissuralanterior nucleus of the thalamus and
the mammillary bodies of the hypothalamus.
 The mammillary bodies are destroyed in Korsakoff’s syndrome
as profound difficulty forming new memories
mammillothalamic tract also goes to the anterior thalamic
nucleus, the hippocampus can affect the thalamus indirectly as
well as directly.

23.  The anterior thalamic nuclei in turn connect to the cingulate
cortex.
 The cingulate cortex projects back to the entorhinal cortex of
parahippocampal gyrus, completing a “great” loop called the
Papez circuit.
 The Papez circuit like many other areas of the limbic system is
involved in learning and memory, emotion, and social behavior.
 The amygdala, along with neocortical areas, are now known to
be centrally involved in emotional experience.

24. The Medial Temporal Lobe
and Hippocampus

25. Posterior section: Hippocampus,
Fornix
(Fig. 16-15)
Divisions or nuclei of
hippocampal formation

27.  The hippocampus has direct connections to the entorhinal
cortex (via the subiculum) and the amygdala
 The entorhinal cortex projects to the cingulate cortex.
 hippocampus can affect the cingulate cortex through the
anterior thalamic nucleus or the entorhinal cortex.
 The cingulate cortex, in turn, projects to the temporal lobe
cortex, orbital cortex, and olfactory bulb.
 Thus, all of these areas can be influenced by the
hippocampus.

29. Papez circuit

30. Afferents to the
hippocampus.

32. Structures and Processes
within the Hippocampus

33.  The hippocampus proper and the dentate gyrus processes
information that passes through the hippocampus.
 These two structuresform two interlocking “Cs.”
 The term dentate gyrus beaded or toothed small blood
vessels from subarachnoid space that penetrate the dentate
gyrus.
 The hippocampus and dentate gyrus arecortex3-layered
cortex rather than 6-layered cortex as in the neocortex.

34.  Because of the smaller number of layers and their location
between the neocortex and diencephalon, these cortices have
been called paleocortex/old cortex/archicortexancient cortex.
 Misleadingfalse impression that these cortices are
antiquated remnants left over as the brain evolved and
became more complex.
 Actually continued to develop structurally and functionally
throughout phylogeny.

35.  The hippocampus and dentate gyrus, like the neocortex,
have a superficial molecular layer and a deep polymorphic
layer.
 Structures are "inside-out" cortex, the molecular layer is on
the inside and the polymorphic layer is on the outside.
 Middle layer of the hippocampus properpyramidal cell
layer.
 Middle layer of the dentate gyrusgranular layer.
 Molecular layer of the hippocampus proper faces the
dentate gyrus.
 The area of the hippocampus proper that is capped by the
dentate gyrus is referred to as CA3 (CA for cornu ammonis).

36.  The polymorphic layer  alveus and is equivalent to the
white matter of the neocortex.
 The subiculum is the transition layer from the hippocampus
to the parahippocampal gyrus and changes gradually from
three to six layers.
 A major flow of information through the hippocampus is a
one-way circuit.

38. 3-cell circuit of the hippocampal
formation

39. Frontal Lobes of Cortex
 Provides Rationale Control of emotional disposition & involved
in personality
 Injury to frontal lobes causes change in personality
 Control of emotions and impulse control
 Example of Phineas Gage

43. Pathologies
 Tumors and injury to areas of the brain lead to
emotional changes.
 Damage to cingulate cortex lead to emotional
disturbances: fear, depression, irritability

44. Fear, Agression &
Anxiety
Learned Fear, Anxiety & Temporal Lobes and
AMYGDALA

46. Amygdala
 Neurons at the pole of the temporal lobe below the cortex on
the medial side
 Greek name for almond shape
 Has 3 nuclei, basolateral, corticomedial and central
 Afferents from all lobes of neocortex & hippocampus and
cingulate gyrus

49. Input to Amygdala
 Basolateral nuclei receive sensory input (visual, gustatory,
auditory and tactile); also projects to cortex for perception of
emotion
 Corticomedial nuclei receive olfactory inputs
 Central nuclei contain output neurons to hypothalamus and
periaqueductal grey in brainstem for physiological responses

50. Inputs or afferents to the amygdala

52. Major Output Pathways
of the Amygdala
 Ventral amygdalofugal pathway
 Stria terminalis
 Directly to the hippocampus
 Directly to the entorhinal cortex
 Directly to the dorsomedial nucleus of the thalamus

53. Outputs or efferents from the amygdala

54. Ventral Amygdalofugal Pathway
 "fugal" comes from the word fuge—to drive away—as in
fugitive.
 Pathway continues 
anterior olfactory nucleus,
anterior perforated substance,
piriform cortex,
orbitofrontal cortex,
anterior cingulate cortex,
ventral striatum.

55.  The ventral striatum includes
part of the caudate, putamen, and the
nucleus accumbens septi (nucleus that reclines on the
septum).
 Projections from the ventral striatum are links in a basal
ganglia circuit that are important in stimulus-response
associative learning.
 The ventral amygdalofugal pathway also connects to the
hypothalamus and septal nucleus, but the amygdala's major
connection to the hypothalamus and septal nucleus is through
the stria terminalis.

56. Important
 Link motivation and drives, through the limbic
system
 Link responses are learned.
 Link associative learning takes place  rewards
and punishers.

57. Three simplifications
 The stria terminalis is similar in form, function, and location as
the fornix for the hippocampal pathway. Thus by way of
analogy one can say that the stria terminalis is to the
amygdala as the fornix is to the hippocampus.
 The stria terminalis connects only to subcortical structures.
(Connection to cortical structures  ventral amygdalofugal
pathway.)
 The stria terminalis overlaps with the ventral amygdalofugal
pathway in that it also connects to the septal nuclei and
hypothalamus and thus forms a loop.

58. Similarities to the fornix
 Like the fornix, the stria terminalis has
 Precommissural  to the septal area exactly
what
the
fornix
does
 postcommissural branches  to the hypothalamus
 postcommissural branch of the fornix projects to mammillary
bodies of the hypothalamus
 postcommissural branch of the stria terminalis projects to the

59.  As with the fornix,
 some fibers enter anterior commissure cross to the
contralateral side.
 Two hippocampi anterior commissure
 two amygdala communicate anterior commissure.
 The stria terminalis also projects to the habenula, which is part
of the epithalamus.

61.  The central nucleus of the amygdala produces
 autonomic components of emotion  output pathways to
the lateral hypothalamus and brain stem.
 conscious perception of emotion primarilyventral
amygdalofugal output pathway
to the anterior cingulate cortex
orbitofrontal cortex & prefrontal cortex

62. More on Function of the
Amygdala
 Stimulationintense emotion, such as aggression or fear.
 Irritative lesions of temporal lobe epilepsy have the effect of
stimulating the amygdala.
 Extreme form irritative lesionspanic attack.
 Panic attacks are brief spontaneously recurrent episodes of
terror that generate a sense of impending disaster without a
clearly identifiable cause.
 PET scans increase in blood flow to the parahippocampal
gyri, beginning with the right parahippocampal gyrus.
 During anxiety attacks blood flow increases

63. Damage to Amygdala
 Decreases emotional response
 Kluver-Bucy Syndrome  reduced
emotionality
 Fearlessness
 Some human cannot recognize emotional
expressions on faces that are fearful, anxious
& angry but recognize happy & disgust
 Bilateral amygdala removal reduces memory

64.  Lesions of the amygdalaUrbach-Wiethe disease
 calcium is deposited in the amygdala.
 early in lifewith bilateral amygdala lesions cannot
discriminate emotion in facial expressions, but their ability to
identify faces remains.
 The anatomical area for face recognition and memory is in the
multimodal association area of the inferotemporal cortex.
 This is a good example of how emotion in one area
(amygdala) is linked with perception in another area
(inferotemporal cortex) to create an intense emotionally
charged memory.

65. fMRI results showing
amygdala activity in normal
viewing facial expressions
from happy to fearful.

66.  Flatness of affectKluver-Bucy syndrome
 Lesions of the amygdalaflatness of affect
 Led to the psychosurgical technique of prefrontal lobotomies.
Remember the movie with Jack Nicholson, “One Flew Over
the Cuckoo’s Nest.”
 The prefrontal cortex inputs into the amygdala.
 Input a flatness of affect is produceddesirable in
schizophrenic patients who were aggressively violent or
emotionally agitated.

67.  amygdala combines many different sensory inputs.
 Like the hippocampus it combines external and internal stimuli.
 Integrated with somatosensory and visceral inputs—this is
where you get your “gut reaction”.
 Link between prefrontal cortex, septal area, hypothalamus,
and amygdala likely gives us our gut feelings.
 It is also where memory and emotions are combined.
 Reward is particularly sweet  last a lifetime.
 Trauma and humiliation of punishmentremembered for a
long time too.

68. Fear Conditioning:Role of the
Amygdala in Learning
 Pavlovian conditioning.
 The crucial aspect of classical conditioning is that it is a
pairing between two stimuli.
 In fear conditioning, an organism hears a noise or sees a
visual stimulus. A few seconds, later it receives a mild shock.
 Reactions involve freezing, elevated blood pressure and heart
rate, and it gets twitchy—startles easily

70. Pathways of fear conditioning
and emotional information.

71. Expression of different emotional
responses by the amygdala.

72. Electrical Stimulation of
Amygdala
 Cause affective rage when basalateral nuclei is
stimulated
 Corticomedial stimulation reduces aggression

73. Learned Behaviors
 Require the amygdala and work through 2 pathways.
Integrate information from all sensory systems and orchestrate
the physiological and psychological response
 Ventral amygdofugal pathway
 Stria terminalis

75. Hypothalamus-brainstem
 Autonomic nuclei in the brainstem receive synaptic
input from hypothalamus via
 Medial forebrain bundle
 Dorsal longitudinal fasciculus

76. Memory Systems
Hippocampus

77. Multi-store orAtkinson-Shiffrin model,
after Richard Atkinson and Richard Shiffrin

78. Memory Processes
 Encoding
 Consolidation
 Storage
 Recall

79. MEMORY ENCODING
 process of laying down a memory begins
with attention (regulated by the thalamus and the frontal
lobe),
 Emotion tends to increase
attentionamygdalasensations derived from an event
processed
 The perceived sensationsdecoded in sensory areas of the
cortex combined in the brain’s hippocampus into one single
experience.
 Hippocampus  sorting centre where the new sensations
are compared and associated with previously recorded
oneslong-term memorydifferent parts of the brain
 It is also one of the few areas of the brain where completely
new neurons can grow.

80. MEMORY CONSOLIDATION
 stabilizing a memory
 synaptic consolidation (which occurs within the first few
hours after learning or encoding)
 system consolidation (where hippocampus-dependent
memories become independent of the hippocampus over a
period of weeks to years).
 Long-term potentiationallows a synapse to increase in
strength as increasing numbers of signals are transmitted
between the two neurons.
 Potentiationsynchronous firing of neurons makes
those neurons more inclined to fire together in the future.

81.  “re-wire” itself by re-routing connections and re-arranging its
organization.
 neural network, is traversed over and over again, an enduring
pattern is engraved and neural messages are more likely to
flow along such familiar paths of least resistance.
 The ability of the connection, or synapse, between
two neurons to change in strength, and for lasting changes to
occur in the efficiency of synaptic transmission, is known
as synaptic plasticity or neural plasticity.

82. MEMORY STORAGE
 long-term memories widely distributed throughout
the cortex.
 After consolidation, long-term memories are stored throughout
the brain as groups of neurons that are primed to fire together
in the same pattern that created the original experience.
 Actively reconstructed from elements scattered throughout
various areas of the brain by the encoding process. Memory
storage is therefore an ongoing process of reclassification
resulting from continuous changes in our neural pathways, and
parallel processing of information in our brains.

83. SENSORY MEMORY
 ultra-short-term memory (200 - 500 milliseconds)
 ability to retain impressions of sensory information after the
original stimuli have ended
 ability to look at something and remember what it looked like
with just a second of observation is an example of sensory
memory
 sensory memory for visual stimuli iconic memory,
 memory for aural stimuli echoic memory
 Touch haptic memory.

84.  Smell closely linked to memory olfactory bulb and
olfactory cortex are physically very close - separated by just 2
or 3 synapses - to the hippocampus and amygdala.
 Information is passed from the sensory memory into short-term
memory  process of attention effectively filters the stimuli
to only those which are of interest at any given time.

85. SHORT-TERM (WORKING) MEMORY
 “scratch-pad” for temporary recall of the information which is
being processed at any point in time, and has been referred to
as "the brain's Post-it note"
 typically from 10 to 15 seconds, or sometimes up to a minute).
 the beginning of the sentence needs to be held in mind while
the rest is read, a task, which is carried out by the short-term
memory
 Central executive part of the prefrontal cortexplay a
fundamental role in short-term/working memory.

86.  Central executive controls two neural loops,
 one for visual data (near the visual cortex of the brainvisual
scratch pad),
 one for language (the "phonological loop", which uses Broca's area
as a kind of "inner voice" that repeats word sounds to keep them in
mind).
 limited capacity-George Miller in 1956 Memory span is between
5 and 9 (7 ± 2“magical number”/Miller's Law).
 spontaneously decays10 - 15 seconds
 Displacement  New contentgradually pushes out older content

88. LONG-TERM MEMORY
 Short-term memories can become long-term memory through the
process of consolidation
 Physiologically, the establishment of long-term memory involves a
process of physical changes in the structure of neuronslong-
term potentiation
 Whenever something is learned, circuits of neurons in the brain,
known as neural networks synapses.
 short-term memory is supported by transient patterns of neuronal
communication in the regions of the frontal, prefrontal and parietal
lobes of the brain.

89.  long-term memoriesmore stable and permanent changes in
neural connections widely spread throughout the brain.
 The hippocampus temporary transit point for long-term
memories, and is not itself used to store information.
 Essential to the consolidationshort-term to long-term
memory, changing neural connections for a period of three
months or more after the initial learning.

90. Taxonomy of Long-term Memory Systems
Squire L, Zola S PNAS 1996;93:13515-13522
Adapted from Squire, Knowlton 1994

91. DECLARATIVE (EXPLICIT) &
PROCEDURAL (IMPLICIT) MEMORY
 Declarative memory (“knowing what”)facts and events,
consciously recalled (or "declared”)
 Declarative memoryepisodic memory and semantic memory.
 Procedural memory (“knowing how”) is the unconscious memory of
skills and how to do things
 Declarative memories are encoded by  hippocampus, entorhinal
cortex and perirhinal cortex (medial temporal lobe of the brain)
 consolidated and stored in the temporal cortex and elsewhere

92.  semantic memory mainly activates the frontal and temporal
cortexes,
 episodic memory activity is concentrated in the hippocampus,
at least initially.
 Once processed in the hippocampus, episodic memories are
then consolidated and stored in the neocortex.
 The memories of the different elements of a particular event
are distributed in the various visual, olfactory and auditory
areas of the brain, but they are all connected together by
the hippocampus to form an episode, rather than remaining a
collection of separate memories.

93.  Procedural memoriesdo not appear to involve the
hippocampus at all
 Encoded and stored by the cerebellum, putamen, caudate
nucleus and the motor cortex, all of which are involved in
motor control.
 Learned skills such as riding a bike are stored in the putamen;
 Instinctive actions such as grooming are stored in the caudate
nucleus;
 cerebellum is involved with timing and coordination of body
skills.
 Without the medial temporal lobeperson is still able to form
new procedural memories (such as playing the piano), but
cannot remember the events during which they happened or
were learned.

94. Hippocampus &
Relational Memory
 Highly processed information from association cortex
areas enter hippocampus
 Hippocampus integrates them—ties them together
and then output is stored in other cortical areas
 Allows you to retrieve all the information about an
event

95. Patients & Syndromes
 HM-mediotemporal lobe
 NA--thalamus
 Korsakoffs-thalamus & hypothalamus

96. Amnesia
 Anterograde
 Cannot form any new types of memories so always live
at time of injury
 Retrograde
 Cannot recall stored memories for a specific time
period

97. HM
 Had bilateral mediotemporal lobes removed due to
epilepsy
 Removed amygdala, anterior 2/3 of hippocampus,
temporal cortex
 Had anterograde amnesia
 Studied by Brenda Milner
 Could learn by procedural memory but had no
recollection of having learned task

99. Squire & Mishkin
 Neuroscientists create an animal model for
HM symptoms
 Lesioned amygdala, hippocampus and
perirhinal cortex in temporal lobe of monkeys
and found that they could no longer perform in
recognition memory tests
 Later showed that perirhinal cortex is most
important for new memory; temporary
storage? Memory consolidation?

101. Diencephalon & Memory
Processing
 Anterior thalamic nucleus
 Dorsal Medial Thalamic nucleus
 Mammillary bodies in hypothalamus

103. Dorsal medial thalamic
nucleus
 Receives input from temporal lobe structures including
amygdala & inferiortemporal cortex
 Projects to all frontal cortex areas

104. NA
 Air Force technician injured by fencing foil –penetrated
the dorsalmedial thalamus
 Developed retrograde amnesia of previous 2 years
and severe anterograde amnesia
 Supports role of thalamus in memory

106. Lashley
 Lashley: 1920s studied rats in maze after cortical
lesions
 Found that all cortical areas are involved in memory

108. Hebb, Lashley student
 suggested CELL ASSEMBLY = all cells that respond
to an external stimulus & are reciprocally
interconnected
 Neurons that fire together, wire together
 1949 Organization of Behavior
 Sensory cortex also stores memory
 Led to neural networks computer modeling

110. Circuit using limbic
structures
 Hippocampal output axons travel as a bundle, the
fornix, to the mammillary bodies of the hypothalamus
 Mammillary body axons project to anterior thalamic
nucleus

111. Memory based on Vision
 Should be found in cortical area involved in vision
processing
 inferiortemporal cortex: higher order processing of
visual information—stores memory of previously seen
objects
 Allows recognition of visual objects
 Remember Kluver-Bucy pyschic blind monkeys

113. Penfield
 Neurosurgeon in the 1950’s removed epileptic foci
after stimulation
 Found that stimulation of temporal lobe in awake
patients caused halucinations or memory retrieval

117. LIMBIC CLINICAL SYNDROMES
Hypolimbic Hyperlimbic
Mania
Depression OCD
Apathy
Utilization Behaviour
Amnesia (Hippocampus)
Social disdecorum
Kluver-Bucy Syndrome (Amygdala)
Anxiety/Panic
Psychosis

118. LIMBIC SYSTEM - CLINICAL IMPLICATIONS
TEMPORAL LOBE EPILEPSY
Form of focal epilepsy, a chronic neurological condition, Characterized by
Recurrent epileptic seizures arising from one or both temporal lobes
Two main types
Mesial temporal lobe epilepsy (MTLE)
Lateral temporal lobe epilepsy (LTLE)
Mesial temporal sclerosis –
47-70% of all TLE
Severe neuronal loss in CA1, May spread to involve CA3 and CA4,
CA2 and dentate are only mildly involved

119. Pathological abnormalities:-
Specific pattern of hippocampal neuron cell loss
(m/c)
Associated with hippocampal atrophy and gliosis
Dispersion of granule cell layer in dentate gyrus
Pts classically describe fear, déjà vu, jamaisvu, elementary
and complex visual hallucinations, illusions, forced
thinking, emotional distress.

120. LIMBIC ENCEPHALITIS
 An inflammatory process involving the hippocampi, amygdala and less frequently
frontobasal and insular regions of the limbic system and other parts of the brain.
 Clinical features:-
severe impairment of short-term memory (cardinal sign),
confusion,
psychiatric symptoms (changes in behavior & mood –
seizures
 60%paraneoplastic in origin
 Paraneoplastic limbic encephalitismost commonly associated with small cell
lung carcinoma.

121. ALZHEIMERS’ DISEASE
 Neurodegenerative changes in limbic
system
 Amyloid proteins build up and form
amyloid plaques (outside cells)
 Neurofibrilllary tangles (inside cells),
leads to neuronal death
 Hippocampus is one of first areas to
degenerate, leads to anterograde
amnesia
 Cortex also degenerates early, leads
to retrograde amnesia and dementia

122. KLUVER-BUCY SYNDROME
Neurobehavioural syndrome associated with bilateral lesions in the
medial temporal lobe , particularly amygdala
Clinical features
 Facial Blunting (may not respond appropriately to stimuli)
 Hyperphagia (extreme weight gain without a strictly monitored diet)
 Hyperorality (marked tendency to examine all objects orally)
 Hypermetamorphosis (an irresistible impulse to attend& react to visual
stimuli)
 Inappropriate Sexual Behavior (Hyper sexuality) atypical sexual
behavior, mounting inanimate objects.
 Visual Agnosia/ "psychic blindness" (inability to visually recognize
objects)

123. KORSAKOFF’S SYNDROME
 Amnestic syndrome, caused by thiamine
deficiency
 Associated with poor nutritional habits of
people with chronic alcohol abuse, gastric
carcinoma, haemodialysis etc.
 Leads to damage to mammillary bodies and
dorsomedial nucleus of thalamus
 Symptoms
Amnesia, confabulation, attention deficit,
disorientation, and vision impairment, change in
personality like -lack of initiatives, spontaneity,
lack of interest or concern, Executive function
deficits
 Recent memory more affected than remote,
Immediate recall is usually preserved

124. THANK YOU