Chapter 18 – Limbic System:
Homeostasis, Olfaction, Memory, and Emotion
Summarized by Kira Armstrong – 6/02; shortened by Dean Beebe – 9/04
Anatomical and Clinical Review
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Limbic system includes cortical and subcortical structures which are located mainly in medial and ventral
regions of the cerebral hemispheres
Simplification of Limbic Functions and Corresponding Key Structures:
Limbic Function
Key Structure
1. Homeostasis, autonomic
Hypothalamus
& neuroendocrine control
2. Olfaction
Olfactory Cortex
3. Memory
Hippocampal Formation
4. Emotions and drives
Amygdala
mnemonic: HOME (Homeostasis, Olfaction, Memory, Emotion)
Main Components of the Limbic System:
 Limbic Cortex
 Parahippocampal gyrus
 Cingulate gyrus
 Medial orbitofrontal cortex
 Temporal pole
 Anterior insula
 Hippocampal Formation
 Dentate Gyrus
 Hippocampus
 Subiculum
 Amygdala
 Diencephalon
 Hypothalamus
 Thalamus
 Habenula
 Basal Ganglia
 Basal forebrain
 Septal nuclei (includes nucleus accumbens)
 Brainstem
 Olfactory Cortex
Overview of Limbic Structures
Limbic cortex
 forms a ring like limbic lobe around the edge of the cortical mantle, which surrounds the corpus callosum and
upper brainstem-diencephalic junction
 The limbic cortices share immunological markers. The herpes simplex virus has a tropism for limbic cortex and
can cause severe encephalitis involving predominately limbic cortex or limbic association cortex
Amygdala
 serves important functions in emotional, autonomic, and neuroendocrine circuits of limbic system
Diencephalic structures
 participate in all functions of the limbic system
Basal Ganglia
 ventral portions process limbic information
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Limbic System ~ 2 ~
Basal Forebrain and Septal Region
 contains cholinergic neurons that project to the hippocampus and cortex
 nucleus basalis of Meynert (inside the substantia innominata) contains cholinergic neurons and is a major site
of degeneration in Alzheimer’s Dementia
Hippocampal Formation
 the medial and dorsal continuation of the parahippocampal gyrus
 forms the floor of the temporal horn of the lateral ventricle
 one of several C-shaped structures in the limbic system
 unlike the 6-layered neocortex, the hippocampal formation has only 3 layers and is called archicortex
 about 95% of the cortex in humans is 6 layered neocortex (also called isocortex meaning “same cortex)
 more phylogenetically ancient forms of cortex, which do not have 6 distinct layers, are referred to as
allocortex (i.e., “other cortex”)
Olfactory System
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bipolar olfactory receptor neurons in the olfactory mucosa are activated by odor and send unmeylinated axons
in the olfactory nerves to the olfactory bulb
without any relay in the thalamus, stimuli are sent directly to the ipsilateral and contralateral olfactory bulbs
Information then relayed in part to the orbital cortex, anterior entorhinal cortex (involved in memory) and
amygdala, but not directly to the hippocampus
The Rhinencephalon – “nose brain” – term formally used from many limbic structures, but which is now more
appropriately used only for the structures involved directly in olfaction
Hippocampal Formation and Other Memory Related Structures
Critical regions involved in memory formation, consolidation and retrieval:
 Medial temporal lobe memory areas – including hippocampal formation and adjacent cortex of the
parahippocampal gyrus
 Hippocampal formation – has an elaborate curving S shape on coronal sections, which inspired the term
hippocampus (meaning sea horse). Consists of 3 components (although sometimes “hippocampus” is used
to refer to all 3 components): Dentate gyrus, Hippocampus, Subiculum
 Parahippocampal gyrus – includes several cortical areas with connections to the hippocampal formation,
the most important of which is the entorhinal cortex (Brodman’s area 28), which is the major input and
output relay between association cortex and the hippocampal formation
 Medial diencephalic memory areas – including the thalamic mediodorsal nucleus, anterior nucleus of the
thalamus, internal medullary lamina, mammillary bodies, and other diencephalic nuclei lining the 3rd ventricle
 White matter network connections – are also essential for normal memory function as these 2 regions are
interconnected with one another and with widespread regions of cortex
 Basal forebrain - may also play a role in memory through its widespread cholinergic projections but effects of
lesions may be explained by damage to nearby white matter fibers….
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Limbic System ~ 3 ~
Long-Term Potentiation
 Long-term potentiation – a form of synaptic plasticity found in the hippocampal formation in which high
frequency activity causes a long-lasting increase in synaptic strength between the involved neurons
 It is believed that this property allows these synapse to perform an associative function, similar to the
learning rule proposed by the psychologist Donald Hebb
 Hebb Rule – “when an axon of cell A excites cell B and repeatedly or persistently takes part in firing it,
some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of
the cells firing B is increased”—i.e., neurons that fire together wire together.
 LTP has also been demonstrated at synapses in other areas of the nervous system. Also, many other forms
of excitatory and inhibitory, short-term and long-term synaptic modulation have been described
Input and Output Connections of the Medial Temporal Lobe Memory System
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History note: James Papez first described a circuit involving several of the following input and output structures
(the Papez circuit) which led to the development of the concept of the limbic system in the 1950’s
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Main input to hippocampal formation: entorhinal cortex
 Information travels from the association cortex in the 4 lobes to the entorhinal cortex in order to provide
input to hippocampal formation
 These inputs are thought to contain higher order information from multiple sensorimotor modalities which
are processed further by temporal structures for memory storage
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The memory storage process – is believed to occur NOT in the medial temporal structures, but in the
association and primary cortices that allow a particular memory to be reactivated
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Main output pathways occur via the subiculum:
 projection from the subiculum entorhinal cortex  back to the multimodal association cortex
 subiculum  fornix (“arch”—follows curve of corpus callosum & lateral ventricles) mammillary nuclei,
diencephalon (directly from fornix and via mammilothalamic tract) & septal nuclei
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Hippocampal commissure – allows inputs to reach the hippocampus from the contralateral hippocampus
Memory Disorders
Patient HM
 27 y.o. male in 1953 underwent a bilateral resection of the medial temporal lobes including the hippocampal
formation and parahippocampal gyri to control his medically refractory seizures
 seizures improved, but he had severe anterograde memory problems
 unable to learn new facts or recall new experiences
 could recite 3-4 words back immediately, but no recall after 5 minutes even with cues – did not even
remember the list had been given to him in the first place
 Personality and IQ testing were normal
 memory of remote events from childhood up to several years prior to the surgery was intact – no recollections
from that point on (reflecting some degree of retrograde amnesia—see below)
 procedural memories intact (e.g., mirror writing)
 In part because of H.M., bilateral medial temporal lobe resection has been replaced with unilateral resection
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Limbic System ~ 4 ~
Lessons Learned from H.M. – Classification of Memory and Memory Disorders
 Declarative vs. nondeclarative memory
 Declarative or explicit memory involves conscious recollection of facts and events
 Nondeclarative or implicit memory involves nonconscious learning of skills, habits, and other acquired
behaviors (e.g., priming, classical conditioning)
 HM lost declarative memory but his nondeclarative memory remained intact
 Amnesia – typically refers to loss of declarative memory which is related to bilateral medial temporal lobe or
bilateral medial diencephalic lesions. Unilateral lesions do not usually produce severe memory loss, although
unilateral lesions of the dominant hemisphere can cause deficits in verbal memory
 Specific/localized lesions rarely cause selective loss of nondeclarative memory
 Learning of skills involves plasticity in several areas, incl. basal ganglia, cerebellum, and motor cortex.
 Caudate nucleus appears important in habit learning – note that caudate pathology also linked to OCD.
 Cerebellum appears to be involved in classical conditioning; amygdala involved in conditioned fear.
 Temporal aspects of memory and memory loss
 Different anatomical regions of the brain are important for storing memories at different times
 Memories stored for <1 sec. (“attention” or “registration”) – involve the brainstem-diencephalic
activating systems; frontal-parietal association networks and heteromodal cortices
 Seconds – Minutes (working memory) – dorsolateral PFC; specific unimodal and heteromodal cortices
 Minutes to years (“consolidation”) – medial temporal & diencephalic structures; specific unimodal and
heteromodal cortices
 Years – specific unimodal and heteromodal cortices
 Immediate recall, attention, working memory do not depend on medial temporal or diencephalic systems
 Medial temporal and diencephalic structures appear to mediate the process by which declarative memories are
consolidated in the neocortex. Ultimately, declarative memories can be recalled through activity of the specific
regions of neocortex without requiring medial temporal/diencephalic involvement
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Anterograde amnesia – deficit in forming new memories
Retrograde amnesia – loss of memories from a period of time before the brain injury
 The phenomenon of retrograde amnesia suggests that recent memories for a period of up to several years
are dependent upon normal functioning of the medial temporal and diencephalic structures while more
remote memories are not
 Ribot’s law – vulnerability of memory loss is inversely related to age of memory
HM’s pattern of combined retrograde and anterograde amnesia is typical of lesions of the medial temporal lobe
or diencephalic memory systems (although it can also be seen in concussion or other diffuse disorders)
Differential Diagnosis of Memory Loss
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Memory loss caused by cerebral contusions – often involve the anteromedial temporal lobes and basal
orbitofrontal cortex, thereby resulting in permanent deficits in memory
Concussion – associated with reversible memory loss, except for the hours around the time of the injury
Infarcts/ischemia – can cause memory loss, especially when bilateral medial temporal or diencephalic
structures are affected (medial temporal lobes are supplied by distal branches of the PCA – thus arterial lesions
at the top of the basilar artery are well positioned to cause bilateral medial temporal or diencephalic infarcts)
Anoxia – hippocampus is particularly vulnerable to anoxic injury
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Limbic System ~ 5 ~
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Rupture of ACA aneurysm – can damage basal forebrain - causing memory loss and other deficits seen in
frontal lobes. Unclear in these patients if memory loss is due to damage to basal forebrain, medial
diencephalon, frontal lobes, or a combination of these
Wernicke-Korsakoff Syndrome – caused by thiamin deficiency; bilateral necrosis of mammillary bodies and a
variety of medial diencephalic and other periventricular nuclei
 Acutely, will present with a triad of : ataxia, eye movement abnormalities (horizontal gaze paresis,
nystagmus, opthalmoplegia) and confusional state (mnemonic: “ace”)
 Severe cases can result in coma or death
 Survivors left with anterograde and retrograde amnesia thought to be due to bilateral diencephalic lesions
 Usually have other neuropsych deficits suggestive of frontal lobe dysfunction such as impaired judgment,
initiative, impulse control and sequencing
 In contrast to patients with pure medial diencephalic/temporal lesions these patients often lack awareness
of memory deficits and tend to confabulate (presumed to be related to additional frontal dysfunction)
Complex partial and generalized tonic-clonic seizures – often associated with loss of memory for events
during seizure and post ictal period; memory between seizures may be normal unless seizures are severe or
there is some hippocampal sclerosis
ECT – during treatment period patients develop retrograde and anterograde amnesia similar to that seen in
patients with bilateral temporal/diencephalic lesions. Amnesia gradually resolves after treatment; but residual
memory loss around treatment period generally remains (both anterograde and retrograde)
Transient Global Amnesia - abrupt development of retrograde and anterograde amnesia with no obvious cause
and no other deficits.
 Episodes often occur with physical exertion or emotional stress. Amnesia typically lasts about 4 - 12 hours
after which patient fully recovers except for permanent memory loss for a few hour before and after onset.
 In about 85%, no recurrence.
 Cause unknown.
 EEG does not show epileptic activity during episode.
 History of migraine is common, thus, a migraine-like mechanism has been proposed
 Functional imaging studies show decreased blood flow or decreased glucose metabolism in medial
temporal lobes and other areas during episodes.
 Kaufman proposes that transient global amnesia due to TIAs in posterior circulatory system
Alzheimer’s - memory loss for recent events prominent, which may occur due to preferential affect on bilateral
hippocampal, temporal, and forebrain structures.
psychogenic amnesia - can occur in dissociation, repression, conversion, malingering
 Typically have memory loss for events of emotional significance rather than a pattern of retrograde and
anterograde amnesia surrounding incident
Infantile amnesia – inability for adults to recall events from the first 1-3 years of life; actual cause unknown,
but believed to be due to result of ongoing central nervous system maturational processes like myelination
Benign senescent forgetfulness – “normal” decline in memory function that occurs gradually with age
The Amygdala:
Emotions, Drives, and Other Functions
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As discussed above, plays a pivotal role in the emotions and drives. However, also is an active participant in all
four major limbic functions due to its connections to other structures in the limbic system
Amygdala is important for attaching emotional significance to stimuli perceived by the association cortex
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Limbic System ~ 6 ~
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When both amygdalas have been ablated, behavior tends to be placid
Kluver-Bucy syndrome – nonaggressive behavior, together with other “behavioral changes” (hyperorality,
hypersexuality) occur in monkeys with bilateral lesions of the amygdala and adjacent temporal structures
Seizures involving the amygdala cause powerful emotions of fear and panic
While amygdala is involved in states of fear, anxiety and aggression, activity in the septal area appears to be
important in pleasurable states
Reciprocal connections between the amygdala and hypothalamic and brain systems allow for autonomic
control of heart rate, sweating, and other changes commonly seen with strong emotions
Although the amygdala appears to play an important role in attaching emotional significant to memories, does
not appear to be related to development of other memory functions
Seizures and Epilepsy
General seizure information was consolidated into Lisa’s seizure notes, except for the following sections:
Clinical Manifestations of Partial Seizures in Different Brain Regions
Temporal Lobe:
 Medial Temporal Lobe:
 Indescribable sensation
 Rising epigastrium (“butterflies” in the stomach)
 Nausea
 Déjà vu
 Fear, panic
 Unpleasant odor
 Autonomic phenomena – tachycardia, pupillary dilation, piloerection, belching, palor, flushing
 Bland staring with unresponsiveness
 Lip-smacking, chewing, swallowing
 Gestural automatisms
 Lateral Temporal Lobe:
 Vertigo
 Inability to hear
 Simple auditory hallucinations (buzzing, roaring engines)
 Elaborate auditory hallucinations (voices, music)
 Receptive or expressive aphasia
Frontal Lobe:
Nocturnal exacerbation common
Elaborate motor automatisms w/o loss of consciousness or postictal deficits are often misdiagnosed as psychogenic
episodes
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Dorsolateral Convexity
 Contralateral tonic or clonic activity
 Strong version (turning) of eyes, head, and body away from side of seizure
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Limbic System ~ 7 ~
 Aphasia (if dominant hemisphere affected)
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Supplementary Motor Area
 Fencing posture with extension of contralateral upper extremity
 Other tonic postures
 Speech arrest
 Unusual sounds
Orbitofrontal & Cingulate
 Elaborate motor automatisms
 Unusual sounds
 Autonomic changes
 Olfactory hallucinations (orbitofrontal)
 Incontinence (cingulate)
Parietal Lobe
 Vertigo
 Contralateral numbness, tingling, burning sensations
 Sensations of movement or need to move
 Aphasia
 Contralateral hemineglect
 Eyes and head may deviate toward or away from side of seizure
Occipital Lobe
 Sparkles, flashes, pulsating colored lights
 Scotoma or hemianopia in contralateral visual field
 Visual hallucinations
 Eye blinking
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Interesting facts about the “Wada” test
As you already know…sodium amytal is injected directly into each common corotid artery, causing transient
inhibition of injected hemisphere for upto 10 minutes
Testing memory:
 In patients with normal bilateral medial temporal memory function, injection of one hemisphere will not
eliminate memory, since the other hemisphere can compensate
 When a medial temporal lobe is not functioning properly (e.g., due to sclerosis) injection of the
contralateral hemisphere causes severe memory difficulties. Preserved memory with injection of the
ipsilateral hemisphere is reassuring, as it suggests the contralateral hemisphere will be able to support
memory function after resection of ipsilateral medial temporal structures
 Interestingly, amytal is injected into the carotid artery, which (as you no doubt remember…) serves the
ACA and MCA. BUT the medial temporal lobes are perfused by the PCA. So….not entirely clear why the
Wada test should inhibit medial temporal function. It is believed that it may be because the large
ACA/MCA perfusion inhibits most of the hemispheric cortex, white matter, and corpus callosum, thereby
indirectly inhibit the medial temporal lobe – by cutting off its major sources of input
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Limbic System ~ 8 ~
Anatomical and Neuropharmacological Basis of Psychiatric Disorders
Schizophrenia
 Abnormalities of the limbic system, frontal lobes, and basal ganglia have been implicated
 Both pathologic studies and MRI’s have demonstrated bilateral decreases in volume of limbic system
 PET has shown decreased activation of dorsolateral prefrontal cortex
 Dopamine abnormalities have also been implicated
Obsessive-Compulsive Disorder
 The improvement of symptoms with serotonin-enhancing meds suggests a role for this transmitter
 Imaging studies have shown abnormally increased activity in the basal ganglia (especially the head of the
caudate) as well as the anterior cingulate gyrus and orbitofrontal cortex – these changes improve with
pharmacological or behavioral treatment
 Given the apparent involvement of the caudate, cingulate gyrus, and orbitofrontal cortex – some have compared
it to a hyperkinetic movement disorder, but with unwanted thoughts or compulsions instead of movements
 Indeed, there may be some overlap, since OCD is present in about 50% of Tourette’s syndrome, and can
also occur in Huntington’s disease, Sydenham’s chorea, and other basal ganglia disorders
Anxiety
 Anxiety disorders are thought to be associated with an increase in noradrenergic and sertonergic transmitter
systems
 GABA may also be implicated since symptoms can be controlled with benzodiazepines
 Amygdala may also be involved with panic disorders
Depression and Mania
 Structural and functional neuroimaging studies of depression have been contradictory, but there is some
evidence of a global decrease in cerebral cortex activity – with a more prominent decrease in the frontal lobes
 Neuroendocrine changes occur in depression as well – e.g., an increased release of cortisol in about 40% of
patients
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