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Limbic system & approach to amnesia

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Limbic system & approach to amnesia

  1. 1. Limbic System network & approach to amnesia Dr.Abhinav Kumar Medicine Resident M.S Ramaiah medical college
  2. 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”.
  3. 3. 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
  4. 4. 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.
  5. 5. 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.
  6. 6.  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
  7. 7.  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.
  8. 8. Output Pathways of the Hippocampus
  9. 9.  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.
  10. 10.  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.
  11. 11. The Medial Temporal Lobe and Hippocampus
  12. 12. Posterior section: Hippocampus, Fornix (Fig. 16-15) Divisions or nuclei of hippocampal formation
  13. 13.  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.
  14. 14. Papez circuit
  15. 15. Afferents to the hippocampus.
  16. 16. Structures and Processes within the Hippocampus
  17. 17.  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.
  18. 18.  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.
  19. 19.  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).
  20. 20.  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.
  21. 21. 3-cell circuit of the hippocampal formation
  22. 22. 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
  23. 23. Pathologies  Tumors and injury to areas of the brain lead to emotional changes.  Damage to cingulate cortex lead to emotional disturbances: fear, depression, irritability
  24. 24. Fear, Agression & Anxiety Learned Fear, Anxiety & Temporal Lobes and AMYGDALA
  25. 25. 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
  26. 26. 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
  27. 27. Inputs or afferents to the amygdala
  28. 28. 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
  29. 29. Outputs or efferents from the amygdala
  30. 30. 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.
  31. 31.  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.
  32. 32. Important  Link motivation and drives, through the limbic system  Link responses are learned.  Link associative learning takes place  rewards and punishers.
  33. 33. 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.
  34. 34. 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
  35. 35.  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.
  36. 36.  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
  37. 37. 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
  38. 38. 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
  39. 39.  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.
  40. 40. fMRI results showing amygdala activity in normal viewing facial expressions from happy to fearful.
  41. 41.  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.
  42. 42.  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.
  43. 43. 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
  44. 44. Pathways of fear conditioning and emotional information.
  45. 45. Expression of different emotional responses by the amygdala.
  46. 46. Electrical Stimulation of Amygdala  Cause affective rage when basalateral nuclei is stimulated  Corticomedial stimulation reduces aggression
  47. 47. 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
  48. 48. Hypothalamus-brainstem  Autonomic nuclei in the brainstem receive synaptic input from hypothalamus via  Medial forebrain bundle  Dorsal longitudinal fasciculus
  49. 49. Memory Systems Hippocampus
  50. 50. Multi-store orAtkinson-Shiffrin model, after Richard Atkinson and Richard Shiffrin
  51. 51. Memory Processes  Encoding  Consolidation  Storage  Recall
  52. 52. 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.
  53. 53. 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.
  54. 54.  “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.
  55. 55. 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.
  56. 56. 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.
  57. 57.  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.
  58. 58. 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.
  59. 59.  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
  60. 60. 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.
  61. 61.  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.
  62. 62. Taxonomy of Long-term Memory Systems Squire L, Zola S PNAS 1996;93:13515-13522 Adapted from Squire, Knowlton 1994
  63. 63. 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
  64. 64.  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.
  65. 65.  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.
  66. 66. 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
  67. 67. Patients & Syndromes  HM-mediotemporal lobe  NA--thalamus  Korsakoffs-thalamus & hypothalamus
  68. 68. 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
  69. 69. 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
  70. 70. 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?
  71. 71. Diencephalon & Memory Processing  Anterior thalamic nucleus  Dorsal Medial Thalamic nucleus  Mammillary bodies in hypothalamus
  72. 72. Dorsal medial thalamic nucleus  Receives input from temporal lobe structures including amygdala & inferiortemporal cortex  Projects to all frontal cortex areas
  73. 73. 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
  74. 74. Lashley  Lashley: 1920s studied rats in maze after cortical lesions  Found that all cortical areas are involved in memory
  75. 75. 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
  76. 76. 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
  77. 77. 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
  78. 78. 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
  79. 79. LIMBIC CLINICAL SYNDROMES Hypolimbic Hyperlimbic Mania Depression OCD Apathy Utilization Behaviour Amnesia (Hippocampus) Social disdecorum Kluver-Bucy Syndrome (Amygdala) Anxiety/Panic Psychosis
  80. 80. 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
  81. 81. 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.
  82. 82. 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.
  83. 83. 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
  84. 84. 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)
  85. 85. 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
  86. 86. THANK YOU

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