Limbic System

Limbic System: Homeostasis, Olfaction, Memory, and Emotion

Anatomical and Clinical Review

• 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 Functions	Key Structures
Homeostasis, autonomis and neuroendocrine control	Hypothalamus
Olfaction	Olfactory Cortex
Memory	Hippocamplal Formation
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 the 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

• 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
  • 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….

• 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

• 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.

• 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

• 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

• 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

• 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

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, including 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

• 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

• 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
• 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

• 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
• 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 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
    • Dorsolateral Convexity
      • Contralateral tonic or clonic activity
      • Strong version (turning) of eyes, head, and body away from side of seizure
      • Aphasia (if dominant hemisphere affected)
    • 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

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

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