Integrative systems: The Limbic System
What is included within declarative or explicitly memory?
*conscious memory of facts or events/experiences (the latter also being referred to as episodic memory)
Nondeclarative or implicit memory includes what?
*unconscious skills, habits and acquired behaviors
What are the subcortical areas of the Limbic system?
1. Amygdala 2. Ventral striatal structures
Many different conditions can be associated with memory loss; those involving MTLS and/or MDS include what?
1. Contusion and concussion 2. Infarcts or ischemic events 3. Global cerebral anoxia 4. Seizures 5. Hippocampal sclerosis 6. Transient global amnesia 7. Wernicke's encephalopathy/Wernicke's Korsakoff syndrome 8. Alzheimer's disease 9. Psychiatric disorders 10. Electroconvulsive therapy (ECT)
What are the cortical areas of the Limbic system?
1. Hippocampal formation - hippocampus, subiculum, dentate gyrus 2. Entorhinal cortex (Area 28) 3. Prefrontal association cortex 4. Orbito-frontal cortex 5. Insula 6. Cingulate gyrus
Do you remember the clinical triad that present which is present in Wernicke's encephalopathy?
Cognitive dysfunction (mental confusion) Occulomotor abnormalities Ataxia
Mental status changes in Wernicke's Korsakoff include confusion as well as profound loss of memory, or ability to form new memories; the memory impairment is accompanied by ____________, where answers to questions include information which is made up. The individual is not consciously lying, the brain is actually "filling in" the missing information.
Confabulation
HPA axis: ________ binding to hippocampal neurons has been shown to interfere with both memory formation and retrieval
Cortisol
_________ memory can also be viewed as a process which occurs over time (this is why scientists generally refer to the process of "learning and memory" as a unit); events which occur at various times involved different cellular mechanisms as well as different brain structures.
Declarative or explicit
There are two main Limbic System subsystems important for _________ memory; they are interconnected with each other; both of these systems appear to mediate a process by which memories of facts and events are gradually consolidated in the neocortex. What are the two subsystems?
Declarative or explicit memory 1. Medial temporal lobe structures (MTLS) 2. Medial diencephalic structures
BILATERAL damage to either the MTLS or MDS (which are interconnected) causes a loss of ____________; it is this type of memory loss that is usually referred to as _________
Declarative or explicitly memory It is declarative or explicit memory loss that is generally referred to as amnesia
Chronic activation of the HPA axis also causes a ________ _______ in the dentate gyrus (which may interfere with the ability to form new memories)
Decreased neurogenesis
The ______ _______ is one of the few areas in the adult brain in which significant neuro genesis can continue throughout life.
Dentate gyrus
There are many nuclei and pathways that are part of the Limbic system; Limbic system structures may be cortical, subcortical or involved nuclei/areas of the __________ and ________; here only a few of the most important of the Limbic system structures will be highlighted.
Diencephalon and brainstem
The projection from the ventral tegmental area (VTA) to the nucleus accumbens septi is __________
Dopaminergic
___________; used to treat refractory or treatment resistant depression, causes retrograde and anterograde amnesia which gradually resolves —although not completely for the period immediately surrounding the time of treatment
Electroconvulsive therapy
Current research suggests that the cingulate gyrus is actually composed of a number of functional subdivisions; the hippocampus and cingulate gyrus are part of a major circuit integrating _________ and __________ in the brain (________ circuit)
Emotion and memory Papez Circuit
The amygdala plays an important role in our _______ response to stimuli (especially _________stimuli) and in ________memory.
Emotional responses Fearful stimuli Emotional memory
The anterior cingulate and the anterior portions of the insula are implicated in the ability to experience __________
Empathy
Which area of the brain is the first area to show degenerative changes in Alzheimer's disease?
Entorhinal Cortes (Area 28)
________ memory is largely the type of memory that the Brian will use to create an autobiography or sense of "self"!
Episodic
Prefrontal association cortex; this neocortical area (which has a large number of subdivisions) plays a critical role in _______ ______, and in the ability to plan, prioritize, and inhibit behavior. Is also plays a role in "________" memory, or the ability to hold something in mind for a short period of time; from clinical studies we know that "_______" play a critical role in the ability to make rational judgements/decisions (I think this is why we now inlcude this area as part of the Limbic system)
Executive function Working memory Emotions
T or F: cortical Limbic areas only contain neocortical areas
FALSE! Cortical Limbic areas include Allo- and neo-cortical areas (what does this mean in terms of how these areas are organized at a neuronal level? - neocortical has 6 layers in the cortex: Allo-cortical can have anywhere from 3 to 5 layers)
T or F: damage to the areas of the medial temporal lobe structures or medial diencpehalic structures can cause implicit memory loss
FALSE! Damage to these areas does NOT disrupt non-declarative or implicit memory
T or F: memories are very accurate and cannot be changed
False **"memory". Can be very inaccurate — it is not a "snapshot" of some event, but an electrochemically encoded event; "memories" change with time — there is evidence that there are changes in memory content with each retrieval**
In 2013, it was reported that deep brain stimulation of the ________ which is a major connecting fiber pathway in the Papez circuits - can improve memory in patients in the early stages of Alzheimer's disease! Know this circuit!
Fornix
3. ______ ______ _______; memory loss may occur following cardiac arrest, for example, where there is a decreased perfusion of the brain
Global cerebral anoxia
With more minor damage from contusions and concussions, memory loss may be temporary; head injury on the side of the head (________ injury) can produce injury on the opposite side of the brain (____________); thus _________ damage to the hippocampus can occur —resulting in memory loss and ________(which can cause more memory loss) .
Head injury on the side of the head (coup injury) can produce injury on the opposite side of the brain (Contre coup); thus bilateral damage to the hippocampus can occur - resulting in memory loss and seizures (which can cause more memory loss)
Although there is some controversy regarding wether this is the cause or the effect, ______ ______, which involves both loss of hippocampal neurons and formation of dense astrocytic scars, occurs in ~65% of individuals who have a specific type of epilepsy called ___________.
Hippocampal sclerosis Temporal lobe epilepsy (She asks what specific glial cell is involved in producing the scarring? - but really she gives the answer in the text as astrocytes)
Chronic stress can actually produce significant decreases in overall _________ volume (for example, in individuals suffering from PTSD)
Hippocampal volume
The ________, in particular, is very sensitive to hypoxia occurring from stroke or global anoxia.
Hippocampus (She was saying something in class about this area being particularly sensitive becasue it is a highly plastic area of the brain)
The hippocampal formation consists of what? **she emphasized this multiple times
Hippocampus proper, the dentate gyrus, and an area referred to as the subiculum
__________ of the amygdala is seen in anxiety disorders.
Hyperactivation (for example, generalized anxiety disorder, panic attack and post-traumatic stress disorder)
Outflow of the Limbic system also influences the autonomic response via the ___________ and autonomic nervous system
Hypothalamus
The ______ is the cortex buried within the Sylvian fissure.
Insula
Memory impairment seen in individuals with schizophrenia is believed to be due to the absence of a specific type of __________ in the _________; loss of these cells significantly interferes with normal memory encoding and retrieval.
Interneuron in the hippocampus
Both the hippocampus and dentate gyrus have been studied extensively and are known to be critically involved in ________ and ________
Learning and memory
The Limbic system is a large interconnected system of nuclei playing critical roles in ___________________________________.
Learning and memory; and emoions and drives
The orbit-frontal association cortex: this neocortical area represents part of the _________ association cortex and is especially important in the integration of ________ and emotional behavior.
Limbic Personality
Which part of the brain plays a major role in declarative or explicit memory?
Limbic system
Later, it became clear that learning, memory, and emotion involved many more areas than just those medially located structure and the terminology was changed to ________ ______
Limbic system (comparable to other "systems" in the brain)
Many neurodegenerative disorders are associative day with profound memory loss; in Alzheimer's disease, there is significant neuronal loss in both the __________ and ________, resulting primarily in __________memory loss; loss of neurons in the ____________ and other cortical areas result in loss of ________ and ________memory.
Loss in both the entorhinal cortex and hippocampus, resulting in primarily short-term memory loss as well as the inability to learn new information. Loss of neurons in the prefrontal cortex and other cortical areas results in loss of working and long-term memory
Changes similar to those discussed above for PTSD, both in terms of the loss of _________ volume and ____ _____, have also been documented in adults who were physically, emotionally, or sexually abused as children.
Loss of hippocampal volume Memory impairment
Degeneration in Wernicke's Korsakoff is most prominent in __________ (especially _____ _____) and in _________(________); there is also a significant reduction in both the volume and metabolism of ________ areas, and these changes are believed to underlie poor judgement and psychosis seen in this disorder
MDS (especially mammillary nuclei) MTLS (hippocampus) Prefrontal areas
It should be noted that many other disorders may cause memory impairment if they involved either __________ or _______, including multiple sclerosis, brain tumors, hemorrhage, toxic or metabolic encephalopathies, CNS vasculitis etc.
MTLS or MDS
Originally, the terms "Limbic lobe' (to make it comparable to other cortical "lobes" was used to denote the ring of primarily cortical tissue on the _________ aspect of the hemispheres involved in learning, memory, and emotion
Medial aspect of the hemispheres (the "edge" or "limbus")
Hippocampal sclerosis may also occur from injury, prolonged fever, etc: whatever the cause, it can result in significant __________ impairment.
Memory
Profound and long-lasting ________ loss can occur from chronic activation of the HPA axis
Memory loss
The ventral tegmental area is located in the _____________ near the substantia nigra
Midbrain
The nucleus accumbens septi receives its major input from another Limbic system nucleus located in the ___________ (the ___________).
Midbrain (the ventral tegmental area (VTA))
A history of _______ is common in people with transient global amnesia; episodes most commonly occur during strenuous physical exercise or during times of great emotional stress.
Migraines
The medial temporal lobe structures system is primarily a circuit consisting of reciprocal connection between _________ and ______ and ________ structures.
Multimodal Association cortex <—> entorhinal cortex (area 28) <—> hippocampal formation
The ventral striatal structures are deep hemispheric nuclei; includes the _____ ____ _____which plays a role in "reward" in the brain.
Nucleus accumbens septi **can be seen on our Weigert sections - look at her power point from this lecture to see it labeled
There are actually a number of circuits which play a role in memory; the most famous of these "circuits" or pathways was also the first to be defined (in 1937) and is known as the _________ circuit (involving what structures?)
Papez Circuit Involving the hippocampus, mammillary bodies, anterior nuclei fo the thalamus and cingulate gyrus, and the connections between these areas.
The entorhinal cortex (Area 28)is also part of the ___________ gyrus (which type of cortex is it?)
Parahippocampal Neocortex
The hippocampus is part of the ___________ gyrus (_______ ________ lobe)
Parahippocampal gyrus (medial temporal lobe)
Our understanding of the importance of many of these areas to learning and memory arose primarily from a patient named _____________ (who died in 2008, he was followed continuously since the time of his surgery in 1953) who had ___________ removal of ___________in order to confront refractory epileptic seizures; the extend of the resection is shown in figure 14
Patient H.M. (Henry Molaison) Bilateral removal of medial temporal lobe areas (primarily the MTLS system) (He wasn't able to form any more new memories for the rest of his life; I think his implicit were still intact though, go back and listen to lecture)
2. Infarcts and ischemic events: both MDS and MTLS structures are supplied primarily by branches of the ____________, and memory loss can occur from strokes involving end arteries.
Posterior cerebral artery
The ________ cortex can inhibit the emotional reaction to stimuli. What is the clinical significance of this?
Prefrontal So talk, (particularly cognitive behavioral therapy) and desensitization therapies effectively increase activation of the prefrontal cortex which in turn decreases activation of the amygdala (Figure 10 shows a circuit in which prefrontal cortex projects to amygdala and amygdala projects to the mediodorsal nucleus of thalamus which has bidirectional connections with the prefrontal cortex)
The medial diencephalic structures (MDS) are primarily the _________ and ________nuclei of the _______, and the _______ of the ________
Primarily anterior nucleus and mediodorsal nucleus of the thalamus, and the mammillary bodies of the hypothalamus
Nondeclarative or implicit memory is also called _________ memory
Procedural
Many _________ disorders (for example, depression, anxiety disorders [including post-traumatic stress disorder], schizophrenia) are associated with memory impairment which can be significant.
Psychiatric
The entorhinal cortex receives information from ______________and relays this information to the ___________. Thus is it a critical player in _______ and _______ as well.
Receives information from the polymodal association cortex and relays it to the hippocampus Learning and memory
We will also learn shortly that Limbic system function is modulated by projection from the ______ ______
Reticular formation
Diencephalon: Limbic system structures What parts of the hypothalamus are considered part of the Limbic system?
The hypothalamus is the central control center of the ANS ; most Limbic system nuclei have connections with the hypothalamus which then mediate a "body response" (for example, blushing) to emotional stimuli; mammillary nuclei also play a role in memory circuits
The medial temporal lobe structures include the ______ _______ and adjacent areas of the __________ gyrus (such as Area ____)
The medial temporal lobe structures inlcude the hippocampal formation and adjacent areas of the parahippocampal gyrus (Area 28 - entorhinal cortex — in the anterior part of the parahippocampal gyrus adjacent to the subiculum)
The posterior cingulate gyrus plays a role in what?
The posterior cingulate plays a role in internal cognition (as part of the default mode network)
Normal maturation of the anterior cingulate and anterior portions of the insula implicated in the ability to experience empathy, is believed to underlie the normal development of a ____________. Abnormalities of this area are found in a number of neurological and psychiatric illnesses, most notably in ____________
Theory of mind (which involved, in part, the ability to appreciate how others feel and are motivated to act) Autism spectrum disorder
____________ is a sudden temporary loss of ability to form new memories in middle-aged and elderly patients, with no other signs/symptoms with apparent full recovery within ~4-12 hours or less. The cause is unknown
Transient global amnesia
_________ damage of the MTLS or MDS does not generally cause sever memory loss
Unilateral
what part of the brainstem is involved in the Limbic system structures?
Ventral tegmental area (VTA)
The ventral tegmental area provides the major __________ input to areas of the ________("________") and to the ______________("_______") which are part of a ________ system in the brain
Ventral tegmental area provides the major dopaminergic input to areas of the cortex (meso-cortical) and to the nucleus accumbens septi (meso-Limbic) which are part of the reward system in the brain Note: these projections are essentially "hijacked" by drugs of abuse, and over-indulgence of sugar and fat etc. (These are the final two of the major dopaminergic pathways in the brain, we covered the other two in earlier material)
However, unilateral damage to either the MTLS or MDS can cause deficits in _________memory (if in the dominant hemispheres, which is generally the left) or _________ memory (if in the non-dominant hemisphere, generally the right)
Verbal memory (dominant) Spatial memory (non-dominant)
Do you remember what causes Wernicke's encephalopathy and in what types of individuals it can be found?
Vitamin B1 (thiamine) deficiency Typically found in alcoholics but can be in any individual that is malnourished
Wernicke's encephalopathy is an acute disorder; it may progress to ______________ which is a chronic disorder involving permanent ______ _____ and _______.
Wernicke's Korsakoff (or Korsakoff's psychosis) which is a chronic disorder involving permanent memory loss and psychosis
Memory impairment in psychiatric disorders may also be secondary to the chronic activation of the _______________ which plays a critical role in our response to physical and emotional stress by (ultimately) causing the release of norepinephrine and epinephrine and cortisol from the adrenal glands, responses which prepare the body for "fight or flight"
hypothalamic-pituitary-adrenal axis (HPA axis)
In general, memory can be divided into what two general types?
1. Nondeclarative or implicit memory 2. Declarative or explicitly memory
A significant loss of memory can occur from infarcts that occur at what location?
A significant loss of memory can occur from infarcts of the superior portion of the basilar artery that gives rise to both posterior cerebral arteries (thus producing bilateral infarction)
Because most cases of Wernicke's Korsakoff's are seen in chronic _________, and because it is ultimately fatal, some beer and wine manufacturers are exprimenting with putting B1 into their products.
Alcoholics
Seizures results in memory loss except for the most brief, all _____________seizures result in some amnesia. More localized seizures involving the _______ lobe are also associated with amnesia; repeated seizures can result in the death of ________ neurons and permanent loss of memory
All generalized seizures (seizures involving both hemispheres) Temporal lobe Hippocampal neurons
Describe the connections and structures involved in Papez Circuit
Anterior nuclei of the thalamus project to the cingulate gyrus via the anterior limb of the internal capsule; the cingulum connects the cingulate gyrus with the hippocampus; the fornix connects the hippocampus with the mammillary bodies of the hypothalamus which then project to the anterior nuclei via the mammillo-thalamic tract
What is the Broadmann number for the entorhinal cortex?
Area 28
Do you remember what areas of the brain are primarily affected in Wernicke's encephalopathy?
Areas of the diencephalon (mammillary nuclei and thalamus), midbrain structures such as the periaqueductal gray and oculomotor nuclei, and the cerebellum
The nondeclarative or implicit memory includes many areas of the brain including ____ _____ nuclei like the ______, ____________;Limbic System structures like the __________also play a role in implicitly memory, particularly of fearful — or highly emotionally charged events.
Basal ganglia nuclei like the caudate ("habit") Cerebellum (learned, skilled motor movements) Amygdala
The ventral tegmental area of the midbrain and the nucleus accumbens septi of the ventral striatal structures and their connections play a critical role in motivating behavior that allows for satisfaction of ______ ________
Basic drives (for food water, sex, novelty, exploration)
What are the Broadmann areas for the cingulate gyrus?
Broadmann's areas 23-25, 33
The cingulate gyrus: the "girdle" of transitional cortical tissue (_______ layers in the cortex) immediately dorsal to and surrounding the ____ _____ on the ______ aspect of the hemisphere
5 layers in the cortex Dorsal and surrounding the corpus callosum Medial aspect of the hemisphere
A few Limbic system areas are within the diencephalon and brainstem Diencephalon: What are some of the thalamic nuclei that are involved in the Limbic system?
A number of thalamic nuclei are involved in the Limbic system; these include anterior nuclei and the mediodorsal (or sometimes called the dorsomedial - which gets it confused with a hypothalamic nucleus by the same name!) nucleus ** see lecture for labeled Weigert slides of these specific nuclei
