LIMBIC SYSTEM“visceral, vital, or emotional brain.”

DR PRAVEEN K TRIPATHI

Scheme of presentation

HistoryAnatomy and organisationConnections and circuitsFunctionsDiseases and abnormalities

History Concept of Limbic SystemBroca (1877) - ‘La Grand Lobe Limbique’

Papez (1937) - ‘Limbic Circuit’ - emotion

MacLean (1952) - ‘Limbic System’ - visceral brain

Nauta (1972) - ‘Septo-hypothalamo-mesencephalic continuum’

PAUL BROCA (1824-1880)

JAMES PAPEZ (1883-1958)

Paul D. MacLean (1913- )

Limbic System- term of Paul MacLean (1952)- Visceral Brain

HypothalamusNucleus accumbensamygdaloid nuclear complexorbitofrontal cortex

Some psychiatric implications onphysiological studies on fronto-temporal portions of limbic system(visceral brain). ElectroencephalogrClin Neurophysiol 4: 407-418, 1952

Septo-(Preoptico)-Hypothalamo- Mesencephalic Continuum

Main Components of Limbic System

Septal Region Hypothalamus

LimbicMidbrain

Area Hippocampal

Formation

Limbic cortex

AmygdaloidNuclearComplex

SpinalCord

&BrainStem

Limbic System

Scoville and Milner memory loss following bilateral ATL Bilateral hippocampal ablation loss of

recent memory and anterograde amnesia

The amygdala German physician Burdach in the early 19th century.

Heinrich Klüver Paul Clancy Bucy (1897-1979) (1904-1992)

Klüver and Bucy in 1939 hypersexuality in monkeys after bilateral temporal lobectomy

The human counterpart was

described by Terzian and Dalle Ore in 1955 and by Marlowe in 1975.

limbic lobe

structures that form a limbus (ring or border) around the brain stem.

The limbic lobe is a synthetic lobe whose component parts are derived from different lobes of the brain (frontal, parietal, temporal)subcallosal gyrus cingulate gyrus isthmus parahippocampal gyrus uncus

The term limbic system refers to the limbic lobe and the structures connected to it.

Limbic lobe crescent of tissue

that caps the lateral end of the fissure, bulges into the medial wall and floor of the temporal horn and then curves medially above the dentate gyrus

The Limbic System

Components

Archicortex hippocampal formation and dentate gyrus

Paleocortex rostral parahippocampal gyrus and uncus

Juxtallocortex / mesocortex cingulate gyrus

Originally, the limbic lobe was assigned a purely olfactory function. only a minor part of the limbic lobe

has olfactory function

Rest of the limbic lobe plays a role in emotional behavior and memory

Limbic system limbic lobe and all the cortical and subcortical

structures related to itSeptal nucleiAmygdalaHypothalamus (particularly the mamillary body)Thalamus (anterior and medial thalamic nuclei)Brain stem reticular formationEpithalamusNeocortical areas in the basal fronto-temporal regionOlfactory cortexVentral parts of the striatum

Subcortical Structures Reticular Formation of the Brain Stem

and Spinal Cord limbic nuclear groupings

(1) mesencephalic reticular formation hypothalamus, thalamus, and septum

(2) the locus ceruleus of the upper pons and the raphe of the midbrain ascending serotoninergic and adrenergic systems onto the diencephalon and telencephalon.

Interpeduncular Nucleus

habenulopeduncular tract hypothalamus and the midbrain limbic region

Amygdaloidal information via the stria terminalis to the septum and then from the septum to the interpeduncular nucleus.

Hypothalamus highest subcortical center

body temperature Appetite water balance pituitary functions emotional content

most potent control of the autonomic nervous system

Thalamusnociceptive pathwayshypothalamus reticular system cingulate, frontal association

cortex

Epithalamus habenular nuclei habenulopeduncular tract midbrain tegmentum and interpeduncular

nucleus.

• Septal area

▪ septum pellucidum glia ,lined by ependyma

▪ septum verumvental to s. pellucidum

▪ Poorly developed in humans

The hippocampal-septal relationship is topographically organized

specific areas of the hippocampus project on specific regions of the septum

CA1 medial septal region CA3 and CA4 lateral septal region medial septal region to CA3 and CA4

Septal connectionsAmygdala stria terminalis ,ventral amygdalofugal

pathway

Hypothalamus medial forebrain bundl Midbrain (PAG and VTA )medial forebrain bundle Habenular nuclei stria medullaris thalami

Interpeduncular nucleus of the midbrain habenulointerpeduncular tract

Thalamic nuclei septothalamic tract

Functions

ACTIVITY high initial state of activity in response

to a novel situation which rapidly declines almost to immobility.

LEARNING tend to learn tasks quickly and perform

them effectively once they have been learned.

REWARD Stimulation pleasure or rewarding

effects.

AUTONOMIC EFFECTS Stimulation inhibitory effect

Cardiac deceleration reversible with atropine septal effects are mediated via the

cholinergic fibers of the vagus nerve.

SEPTAL SYNDROME

Destruction of the septal nuclei behavioral overreaction to most environmental stimuli. changes occur in sexual and reproductive

behavior, feeding, drinking, and the rage reaction

ACh euphoria and sexual orgasm

Septal recording during sexual intercourse spike and wave activity

septal damage increased sexual activity in humans.

Nucleus Accumbens

below the caudate

amygdala ventral amygdalofugal pathway basal ganglia major link between the

limbic and basal nuclei

high content of acetylcholine

Alzheimer’s disease significant loss of cholinergic neurons in this nucleus.

crescent of tissue that caps the lateral end of the fissure, bulges into the medial wall and floor of the temporal horn and then curves medially above the dentate gyrus

THE HIPPOCAMPUS

The hippocampus (Ammon's horn)

Ammon the Egyptian Ram God Seahorse

Ammon’s horn(Cornu Ammonis)

Hippocampus Proper CA1 CA2 CA3 CA4 - Area Dentata Dentate Gyrus Subiculum Prosubiculum Subiculum Presubiculum Parasubiculum

Hippocampal Formation

Hippocampus

Hippocampus of humans contains 1.2 million principal neurons on each side, a figure close to the number of pyramidal tract fibers

Archicortex - 3 layers

Hippocampus Proper Molecular Layer Pyramidal Layer Polymorphic Layer Dentate Gyrus Molecular Layer Granular Layer Polymorphic Layer Subiculum Transitional type between hippocampal archicortex and entorhinal paleocortex

Hippocampal Formation - Archicortex

The HippocampusCA fields

A) Lateral Ventricle, B) ependymal glia (ventricular surface), C) Alvear Layer, (pyramidal axons) 3 layers of hippocampus (archicortex):

1. Polymorph Layer (pyramidal axons & basket cells (-))2. Hippocampal pyramidal layer (pyramidal cell bodies)

3. Molecular Layer (pyramidal dendrites)

A) Lateral ventricleB) Ependymal glia

C) Alvear layer

1. Polymorph Layer

2. Pyramidal Layer

3. Molecular Layer(pyramidal dendrite)

(pyramidal axon)

(pyramidal cell body)

Hippocampus is divided in three parts   Based on relation to brain stem Head : anterior edge of brain stemBody : adjacent to brain stemTail : ascending , curving behind brain stem

Hippocampal Head  

The hippocampal head is the voluminous anteror part of the arc of the hippocapus.

It includes an intraventricular part and an extraventricular part.

Intrinsic ConnectionsClassic Trisynaptic Pathway1. Entorhinal cortex (perforant path) dentate gyrus granular cell

2. Granular cell axon

(mossy fiber) CA3 pyramidal cell

3. Pyramidal cell (Schaffer

collateral) CA1 pyramidal cell subiculum entorhinal cortex

The Hippocampus Dentate Complex(HC-DG)

Afferent Pathways

Pyramidal cell(CA1,2)

PHG (ERC, Sub)

1. Perforant Pathway: PHG (ERC) --> DG Also ….2. Alvear Pathway: PHG --> CA1 3. Septo-hippocampal path (via fornix): Septal nuclei --> DG4. Hippocampal commissure (connects bilateral hippocampi)

Dentate gyrus (granule cells)

(mossy fibers)

Pyramidal cell(CA3)

(schaffer collaterals)

1. (perforant path)

(Also note: this efferent path closes the HC circuit loop!)

2. (alvear path)

Septal nuclei3. (septo-hippocampal path - thru fornix)

Afferent Connections

From Entorhinal Cortex Alveolar Path from medial part of EC to CA1 and Subiculum

Perforant Path from lateral part of EC to CA1, CA2, CA3 and Dentate Gyrus

Entorhinal Cortex

.1 entorhinal cortex2. uncus 3. fornix4. dentate gyrus 5. hippocampal sulcus 6. collateral sulcus  

Afferent Connections

EC & Hippocampal Afferents Surrounding

Neocortex from association areas - temporal, frontal lobe

Limbic System from hypothalamus, amygdala, septal area, anterior thalamic nuclei, and midbrain limbic area

Efferent Connections

FORNIX 1. Alveus 2. Fimbriae 3. Crus4.

Commissure5. Corpus 6. Column

Efferent Connections

Fornix - from pyramidal neurons of hippocampus & subiculum

Postcommissural Fornix – main bundle toMammillary Body Anterior Thalamus Lateral Septal Nuclei

Hypothalamus Midbrain Tegmentum

Hippocampal Formation:Circuitry.A.Components and structure – a banana-shaped structure with its components (dentate, hipp,subiculum) folded upon one another like a “jelly roll”.Inputs are from entorhinalcortex, which collects infofrom other association areasdentate gyrus hipp formation + subculumoutput to fornix andalso back to entorhinal cortex

Summary of Hippocampal ConnectionsAfferent Connections

Entorhinal Cortex Alveolar Path from medial part of EC to CA1 and Subiculum Perforant Path from lateral part of EC to CA1, CA2, CA3 and Dentate Gyrus Dentate Gyrus Mossy fiber - CA3 Schaefer fiber (CA3-CA1) Others Hypothalamus, Septal Nuclei, Substantia Innominata Midbrain Limbic Area

Efferent Connections

fornix from Pyramidal Neurons of hippocampus &

subiculum Precommissural Fornix

Nucleus Accumbens Septi Anterior Hypothalamic Area Medial Surface of Frontal Lobe Anterior Olfactory Nucleus

Postcommissural Fornix to Mammillary Body Anterior Thalamus Hypothalamus Bed Nucleus of Stria Terminalis

Functions

attention and alertness Stimulation of the hippocampus in

animals glancing and searching movements bewilderment and anxiety

Unilateral ablation of the hippocampus in humans does not affect memory to a significant degree

declarative (explicit) memoryfacts, words, and data that can be brought to mind and consciously inspected

plays a time-limited role (being needed only for recently acquired information)

Episodic memory more severely disrupted than semantic memory

left hippocampus verbal memory right hippocampus nonverbal memory

low threshold for epileptic activity spread of such epileptic activity to the

nonspecific thalamic system, and hence all over the cortex, is not usual

Why Selective Vulnerability?

CA1 NMDA receptors. dentate hilus ,CA3 sector kainate

receptors

Activation by glutamate entry of calcium ions into the pyramidal neurons

The pyramidal neurons of these sectors contain very little calcium-buffering protein repeated activation of these pyramidal

neurons could result in cell death.

Seizure Activity

75% of the complex partial seizures arise in the temporal lobe; the remainder arise in the frontal lobe

Seizures might arise in the temporal neocortex, majority arise in

the mesial temporal structures, particularly the hippocampus

The hippocampus has a low threshold for seizure discharge; consequently, stimulation of any region that supplies hippocampal afferents or stimulation of the hippocampus itself might produce seizures

Hippocampal stimulation respiratory and cardiovascular changes, as well as automatisms (stereotyped movements) involving the face, limb, and trunk

 

Why Not All Pathological Processes Produce Seizures?

critical age during infancy and early childhood for the acquisition of the pathology

There might be an age-related remodeling of intrinsic hippocampal connections

Cingulate Cortex

anterior thalamic nuclei contralateral and ipsilateral cingulate

cortex temporal lobe via the cingulum bundle corpus striatum and most of the

subcortical limbic nuclei.

The cingulate cortex is continuous with the parahippocampal gyrus at the isthmus behind the splenium of the corpus callosum.

Cingulate Cortex

Stimulation respiratory, vascular, and visceral changes, but changes less than hypothalamic stimulation.

Interruption of the cingulum bundle, which lies deep to the cingulate cortex and the parahippocampal gyrus, has been proposed as a less devastating way to produce the effects of prefrontal lobotomy without a major reduction in intellectual capacity

Amygdala

K. F. Burdach’s term

The amygdalar nuclei (Gk :“almonds”)

tip of the temporal lobe beneath the cortex of the uncus and rostral to the hippocampus and the inferior horn of the lateral ventricle.

Nuclei

Corticomedial - central : small ,phylogenetically older connections with the phylogenetically older

regions -olfactory bulb, hypothalamus, and brain stem

Basolateral : larger , phylogenetically recent connections with the cerebral cortex intimately and reciprocally connected with

the prefrontal cortex via the uncinate fasciculus

Amygdala ConnectionsCerebral cortex

Olfactory systemThalamus

Brainstem reticular formationHypothalamus

AMYGDALA

Striaterminalis

Ventral Amygdalofugalfibers

Amygdala Inputs

AMYGDALACorticomedial Nuclear

GroupBasolateral Nuclear

GroupCentral Nucleus

OlfactorySystem

Temporal Lobe(associated with visual,auditory, tactile senses)

Brainstem (viscerosensory relayNuclei: solitary nucleus

and parbrachial nucleus)

VentralAmygdalofugal

Fibers

Amygdala Outputs

AMYGDALACorticomedial Nuclear

GroupBasolateral Nuclear

GroupCentral Nucleus

VentralAmygdalofugal

Fibers

Septal NucleiHypothalamus

Dorsal Medial Thalamic NucleusNucleus Accumbens

Hypothalamus

Nuclei ofANS

VentralAmygdalofugal

Fibers

Stria Terminalis

Connections of the Amygdala

Extended Amygdala

ConnectionsAfferents from Intra-amygdaloid association fibers from basolateral amygdaloid nucleus, whic recieves wealth of modality-specific and multimodal sensory input from the cerebral cortex.Efferents to Hypothalamus and Brain Stem

Extended Amygdala

- bridging cell groups directly interconnects amygdaloid and bed nucleus of stria terminalis (BST) which refered to as Extended amygdala.

Neurotransmitters

Acetylcholine gamma-aminobutyric acid (GABA) noradrenaline serotonin dopamine substance P enkephalin.

Afferent Pathways

exteroceptive afferents :olfactory, somatosensory, auditory, and visual) for integration with interoceptive stimuli from a variety of autonomic areas

(1) prefrontal, temporal, occipital, and insular corticeshighly processed somatosensory, auditory, and visual sensory information from modality-specific and multimodal association areas as well as visceral information

(2) the thalamus (dorsomedial nucleus) (3) the olfactory cortex(4) cholinergic input from the nucleus basalis

of Meynert

Efferent Pathways

Mostly terminate in nuclei that regulate endocrine and autonomic function, and others are directed to the neocortex

The two amygdala communicate with each other through the stria terminalis and the anterior commissure

Nuclear groups within each amygdaloid

nuclear complex communicate with each other via short fiber systems

Functions AUTONOMIC EFFECTS

heart rate, respiration, BP, and gastric motility

Stimulation Both increase and decrease depending on the.

ORIENTING RESPONSEStimulation enhances the orienting

response to novel events. Animals with amygdalar lesions manifest

reduced responsiveness to novel events in the visual environment

Their responsiveness, however, is improved if they are rewarded for the response.

EMOTIONAL BEHAVIOR AND FOOD INTAKE

corticomedial nuclear group Lesionaphagia, decreased emotional

tone, fear, sadness, and aggression Stimulation defensive and aggressive

reaction basolateral nuclear group

Lesionhyperphagia, happiness, and pleasure reactions.

Stimulation fear and flight.

attack behavior Amygdalar stimulation gradual buildup

and gradual subsidence upon the onset and cessation of stimulation.

Hypothalamic stimulation begins and subsides almost immediately after the onset and cessation of the stimulus.

prior septal stimulation prevents aggressive behavior of both amygdala and hypothalamus stimulation

FACIAL EXPRESSION

link the perception of the face to the retrieval of

knowledge about its emotional and social meaning.

Bilateral amygdalar lesions alteration in social behavior and social cognition, especially as related to the recognition of social cues from faces,impaired recognition of facial expressions

Functional imaging studies activation of the amygdala during presentation of emotional facial expressionsfor negatively valenced emotions (fear, anger, and

sadness).

AROUSAL RESPONSE

Stimulation of the basolateral nuclear

group of the amygdala arousal response that is similar to but independent of that of ARAS.

Stimulation of the corticomedial nuclear group of the amygdala, by contrast, produces the reverse effect (a decrease in arousal and sleep).

The net total effect of the amygdala, however, is facilitatory

SEXUAL ACTIVITY

contains the highest density of receptors

for sex hormones

Stimulation erection, ejaculation, copulatory movements, and ovulation

Bilateral lesions of the amygdala produce hypersexuality and perverted sexual behavior.

MOTOR ACTIVITY

Stimulation CMN group complex rhythmic

movements related to eating, such as chewing, smacking of the lips, licking, and swallowing

Electric stimulation of the amygdala elicits defensive or fear-related behavior

The amygdaloid projections to the hypothalamus via the ventral amygdalofugal pathway seem to be essential for fear-related behavior

CLINICAL ASPECT

low threshold for electrical discharges focus of seizures.

kindlingCPS : oral and licking movements

with a loss of conscious activity

Stimulation of the amygdala during brain surgery autonomic and emotional reactions ,feeling of fear and anxiety, déjà vu

Destruction of both amygdalas relieve intractable epilepsy and treat violent behavior. Such patients usually become

complacent and sedate and show significant changes in emotional behavior

Basal Forebrain Area

structures deep to the anterior perforating substance

Olfactory Tubercle Substantia Innominata Basal Nucleus of Meynert

Ventral Pallidum - non cholinergic portions of the substantia innominata - part of limbic basal ganglia

Limbic Basal Ganglia

Ventral Striatum Afferents hippocampal formation amygdaloid body cingulate gyrus ventral tegmental area dorsal raphe nuclei Efferents mediodorsal (MD) thalamus substantia nigra subthalamic nucleus amygdaloid nucleus lateral habenular nucleus 

Limbic System and Basal Nuclei

Medial and lateral temporal lobeHippocampus

AmygdalaEntorhinal cortex (24)

Ventral Striatum(nucleus accumbens)

Caudate Nucleus(head)

Anterior Cingulate GyrusOrbitofrontal Areas (10, 11)

Ventral PallidumMedial Globus Pallidus

Pars Reticularis(Substantia nigra)

Ventral Anterior NucleusDorsomedial Nucleus

Papez Circuit (Emotions)Mammillary bodies

Other hypothalamic nucleiSeptal nuclei

Substantia innominata(Basal nucleus of Meynert)

Hippocampal Formation(hippocampus

and dentate gyrus)Anterior Thalamic

nuclear group

Cortex of Cingulate GyrusParahippocampal Gyrus

Neocortex

Fornix Mammillothalamictract

Memory• Short-term memory

– The information is accessed via temporary links or associations formed in the hippocampus.

• Long-term memory– The links in the hippocampus are replaced

by more permanent connections within the cerebral cortex itself.

• Both types of memories involve the storage of information in the cerebral cortex.

Taxonomy of Long-term Memory Systems

Memory

• Hippocampus– Essential for acquiring new long-tern

memories, but not for maintaining them.• Amygdala

– Formation and storage of memories associated with emotional events.

– Involved in the modulation of memory consolidation.

Overview of Limbic Motor Systems

TRANSIENT GLOBAL AMNESIA

sudden memory loss of recent events, transient inability to retain new information (anterograde amnesia), retrograde amnesia of variable extension.

Complete recovery within a few hours.

epilepsy, migraine headache, and tumor. bilateral transient ischemia of medial

temporal structures spreading cortical depression in medial

temporal structures

KLÜVER-BUCY SYNDROME

amygdala, hippocampal formation, and adjacent neural structures.Visual agnosia or psychic blindnessHyperoralityHypersexuality Lack of emotional response, blunted

affect, and apathy.Increased appetiteMemory deficit.

SCHIZOPHRENIA

disorganized thought processes, hallucinations, delusions, and cognitive deficits.

Vulnerability to schizophrenia is 60% genetic and 40% environmental.

Cytoarchitectural studies in schizophrenic brains point to abnormal laminar organization in limbic structures that are suggestive of abnormal neuronal migration during brain development

ALZHEIMER'S DISEASE

atrophic gyri and widened sulci most prominent in the limbic cortex

Association cortices are heavily affected, primary sensory cortices are minimally

affected and the motor cortex is least affected.

Limbic encephalitis

InfectiousNon infectious

Paraneoplastic Non PLE ; VGKC Ab LE

HERPES SIMPLEX ENCEPHALITIS severe focal necrotizing process with a

predilection for the limbic system

intranuclear viral inclusions (Cowdry type A inclusions) and inflammation within limbic structures

Wenicke’s –Korsakkof’s syndrome Thiamine deficiency mammilary body

Infarcts of the medial or anterior thalamic areas

mammillothalamic tract Tumors of the posterior hypothalamus. Lesions in the fornix . corpus callosum Lesions of the basal forebrain

AMYGDALO-HIPPOCAMPECTOMY

Two basic approaches:1. transcortical: image guidance is very helpful A. Niemeyer approach: 2-3 cm longitudinal

cortical incision through the middle temporal gyrus centered at a point ≈ 4 cm posterior to the temporal tip

B. approach through the anterior superior temporal gyrus

2. transsylvian: approach advocated by Yasargil. More restrictive and greater risk of injury to M1 portion of MCA within sylvian fissure

Complications: vascular injury is the most significant risk.

Cingulotomy for Intractable Psychiatric Illness

The major psychiatric diagnostic groups that might benefit from cingulotomy are

1. chronic anxiety states, including OCD, and

2. major affective disorder (i.e., major depression or bipolar disorder).

Oblique coronal MR images are obtained and typically, target coordinates are calculated for a point in the anterior cingulate gyrus 2 to 2.5 cm posterior to the tip of the frontal horn, 7 mm from the midline, and 2 to 3 mm above the corpus callosum bilaterally

References Stephen G. Waxman, MD, PhD;

ClinicalNeuroanatomy,Twenty-Sixth Edition

Snell, Richard S; Clinical Neuroanatomy, 7th Edition

T. Scarabino,U. Salvolini ;Atlas of Morphology and Functional Anatomy of the brain

Stanley Jacobson, Elliott M Marcus; Neuroanatomy for the Neuroscientist

Charles R. Noback, Norman L. Strominger; The Human Nervous System Structure and Function , sixth edition

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