2. Nothing is ever really lost to us
as long as we remember it.
-L. M. MONTGOMERY
3. Introduction
Definition of Memory: The process by which, what is experienced or learned is established as a
record in the CNS, where it persists with a variable degree of permanence, and can be recalled
or recollected from storage at will. [CTP]
Memory provides the essential substrate for cognitive activities that define experience;
development of personality and the possibility of growth and change. Without it life would
perpetually be spent in ‘here’ and ‘now’.
Studying Memory is important to us as disorders of memory and complaints about memory are
common in association with neurological and psychiatric illnesses (anxieties, phobia, and
maladaptive behaviors) and some medical treatments too.
4. Types of memory
On basis of Temporality, memory was classified by Atkinson and Shiffrin in 1986 into:
◦ Sensory Memory (Haptic, echoic, iconic): sub-second to seconds to hours, as when we can recover what
was said when we weren’t paying attention.
◦ Short term memory (Secondary/Working): Seconds to minutes, as with retaining a phone number
◦ Long term memory: Longer – Days, weeks, up to years or even lifetime.
Stimulus
Sensory
Memory
Short term
Memory
Long term
Memory
Attention Encoding
Retrieval
Fig: Information Processing model
(Atkinson and Shiffrin; 1986)
6. Neurobiology of memory
Neurobiology of memory can be studied under these broad headings:
1. Neuroanatomy
2. Neurophysiology
3. Neuroimaging
4. Neuropathology and clinical implications
8. Neuroanatomy Cont.
Hippocampus: It is part of the limbic system,
and lies next to the medial temporal lobe. It is
made up of two structures, the Ammon's Horn,
and the Dentate gyrus, each containing different
types of cells:
Hippocampal formation: Dentate Gyrus,
Hippocampus and Subicular complex: This plays
a role in Consolidation of STMs into LTMs
Limbic Association Cortex: Surrounding
diencephalon, Medial + inferior (orbital) surface
– Cingulate gyrus, parahippocampal gyrus,
orbital gyrus, temporal pole: Links emotion with
many sensory inputs. Important in learning and
memory.
Amygdala: Located above the hippocampus in
the medial temporal lobes: associated with both
emotional learning and memory
9. Neuroanatomy Cont.
Basal ganglia: a group of nuclei which are located in the medial temporal lobe, above the
thalamus and connected to the cerebral cortex.: associated with learning, memory, and
unconscious memory processes, such as motor skills and implicit memory.
Cerebellum: located at the rear of the brain, near the spinal cord: plays a role in the learning of
procedural memory, and motor learning, such as skills requiring co-ordination and fine motor
control.
Prefrontal cortex: covers the front part of the frontal lobe of the cerebral cortex: involved in
Short term memory/ Working memory.
Cerebral Cortex: aka the Neocortex is involved in Priming
11. Neuroanatomy cont.
The figure shows input and output
pathways to and from the hippocampal
formation, that give rise to the circuitry
famously known as Papez circuit that is
involved in Spatial and episodic memory.
14. Neurophysiology: Cellular and molecular
mechanisms
NEUROTRANSMITTERS AND RECEPTORS:
Glutamate: Two types of glutamate receptors
a) Linked to ion channel (NMDA, AMPA, and kainite): Induction of Long Term Potentiation(LTP) is
mediated post-synaptically and by activation of NMDA receptor leading to influx of calcium into the
postsynaptic cell; increases the pre-synaptic release of neurotransmitter and increase in the number
of postsynaptic receptors
b) Linked to G- protein (metebotropic receptors): mediate LTP
Glutamate antagonists are beneficial in Alzheimer’s and vascular dementia (prevents glutamate
excitotoxicity related neurodegeneration) e.g. memantine
Norepinephrine: Postsynaptic α2 adrenoceptors has role in prefrontal cognitive functions.
Infusion of α2 agonist Guaifencine into the prefrontal cortex of monkey improves working memory
performance and infusion of α2 antagonist Yohimbine into monkey prefrontal cortex impaired the
working memory performance.
15. Neurophysiology Cont.
Acteylcholine: Deficiency in cholinergic functioning, due to degeneration in cholinergic
projections from the nucleus basalis of meynert in Alzheimer’s dementia. Beneficial effect of
acetyl cholineesterase which increases the ACh level e.g Donepezil, Rivastigmine and
Galantamine in Alzheimer’s disease.
Dopamine: Regulates excitability of cortical circuitry upon which the working memory function
of PFC depends. It also plays role in LTP (LTP can be blocked by dopamine receptor antagonist)
Other Peptides and Hormones:
Glucocorticoids: Activation of adrenal steroid receptors in the hippocampus play role in memory
storage, also via amygdala.
Opioids: Opioid agonists impair memory and opioid antagonists enhance memory
GABA: Antagonist enhances memory and agonists impair memory
16. Neurophysiology Cont.
PHYSIOLOGICAL PROCESSES:
Memory is a special case of general biological phenomenon of neuronal plasticity.
Neurons can show history-dependent behavior by responding differently as a function of prior
input, and this plasticity of nerve cell and synapse is the basis of memory (Kandel 1991)
Short lasting plasticity – increase in neurotransmitter release and specific synaptic events
Long lasting plasticity – New protein synthesis, physical growth of neural processes and increase
in number of synaptic connections
Implicit memory was famously studied by Eric Kandel through the gill- and siphon withdrawal
reflex of the marine invertebrate Aplysa californica (Sea snail) which is capable of associative
and non associative learning. Its implicit memories are stored in spinal reflex pathways
Explicit memory however can best (and perhaps only) be studied in mammals.
17. Neurophysiology Cont.
LONG TERM POTENTIATION (LTP):
LTP is observed when a postsynaptic neuron is persistently depolarized following a brief burst of
high frequency stimulation. The phenomenon of LTP is a candidate mechanism for mammalian
long-term memory.
LTP is associative, in that it depends on the co occurrence od presynaptic activity and post
synaptic depolarization.
It occurs prominently in Hippocampus, and has a number of properties that make it suitable as a
physiological substrate of memory.
The Induction of LTP is known to be mediated post synaptically and to involve activation of the
NMDA receptor, which permits the influx of calcium into post synaptic cell.
LTP is maintained by an increase in the number of AMPA(non- NMDA) receptors in the post
synaptic cell and also possibly by increased transmitter release.
18. Normal Synaptic
Transmission
• During normal synaptic
transmission, glutamate binds to
non-NMDA receptors allowing
cations to flow through the
channels and the cell membrane
to hypopolarise.
• Glutamate also binds to
metabotropic receptors(G
protein Coupled receptors),
activating Phospholipase C, and
to NMDA receptors.
• NMDA receptor channels bind
glutamate but no current flows
through the channels unless the
Magnesium ion that binds to the
channel lumen is displaced. The
latter event can be effected by
hypopolarising the cell.
19. Induction of LTP
• The High frequency stimulation
opens the non-NMDA channels
leading to hypopolarise.
• This dislodges the Magnesium
ion from NMDA glutamate
channels, and Calcium ions enter
the cells.
• The Calcium triggers the activity
of Ca- dependent kinases, PKC
and Ca- Calmodulin, and Tyrosin
kinase. Ca- Calmodulin kinase
phosphorylates the non- NMDA
channels, increasing their
sensitivity to Glutamate and a
messenger is sent retrogradely
to the presynaptic terminal to
increase the release of
transmitter substance.
20. Late phase of LTP
• In the late phase of LTP, calcium
enters the cell and triggers Ca-
Calmodulin, which in turn
activates the adenylyl cyclase
and cAMP kinase.
• The Latter translates to the
nucleus of the cell and starts
processes that lead to protein
synthesis and to structural
changes, i.e., the formation of
new synapses.
• Many scientists believe that it is
the substrate of long term
memory- The formation of new
synapses.
21. Neurophysiology Cont.
LONG TERM DEPRESSION (LTD):
If synapses would simply increase in strength due to LTP, eventually it would be difficult to
encode new information.
Thus it is necessary to selectively weaken specific sets of synapses.
Long Term Depression refers to use dependent long-lasting decreases in synaptic strength.
(Linden et al. 1995)
It works in parallel to LTP with respect to memory functioning. It may help to reset synapses that
have been potentiated by LTP, serve as a cellular mechanism of forgetting, form active inhibitory
system to attenuate signals from adjacent potentiated synapses. (Tsumoto 1993)
LTD occurs when Schaffer collaterals are stimulated at 1 Hz for long periods.
22. Neurophysiology Cont.
LTP induced by an experience, is inhibited by a novel experience administered soon (within 1 hour)
after the first one, whereas and LTP established for more than 1 hour is immune to this reversal
mechanism.
Critical event in determining the retention of information may consist in the stabilisation of the
potentiated Hippocampal synapses in order to resist to LTP reversal upon new information.
Although hippocampus is fundamental to acquire new memories, it appears to be dispensable after
the memory has been consolidated.
Hippocampus is still necessary to bind together the components of recent memories, whereas more
remote explicit memories can be recalled independently of the hippocampus as the connection
between cortical representation strengthen.
Permanent memories are distributed among different cortical regions according to various
perceptual features and that these various aspects are linked so that, upon recall, the different
components of a memory are bound together to reproduce the memory in its integrity.
23. Neuroimaging: Evidences from imaging
studies
With advancements in imaging studies, it is now easier to study processes and localisations
within the brain.
fMRI detects brain activity by measuring the changes in both the amount of oxygen in the
blood and the amount of blood flow. This measurement is known as blood-oxygen-level-
dependent activity (BOLD activity).
Memory functional magnetic resonance imaging (fMRI) has been used to study the localization
and functional lateralization of critical structures involved in the specific memory task employed.
Memory fMRI is also useful in the prediction of post-operative memory performance.
24. Neuroimaging: Evidences from imaging
studies
Visual memory: 2 streams that are
activated on visual memory tasks:
◦ Ventral/occipito-temporal stream:
essential for identifying objects.
◦ Dorsal/occipito-parietal stream:
essential for appreciation of spatial
resolution among objects
There are specialized processing areas
within the processing streams such as
those for perception of color, shape and
faces
Prefrontal areas are also activated with
visual memory tasks.
25. Neuroimaging Cont.
Figure shows reactivation of visual cortex
during vivid remembering of visual images.
(A) Subjects were instructed either to view
images of houses, faces, and chairs (left) or to
imagine the objects in absence of stimulus
(right). (B) At left, bilateral regions of ventral
temporal cortex are specifically activated
during perception of houses (yellow), faces
(red), and chairs (blue). At right, when subjects
recall these objects, the same regions
preferentially activated during the perception
of each object class are reactivated. (After
Ishai et al., 2000.)
26. Neuroimaging Cont.
Some other localisations obtained from Neuroimaging studies:
Attribute/fragment memory: anterior and posterior regions of temporal lobe are related with
memory of intact objects or faces.
In LTM retrieval of declarative type, the PFC is activated (Left PFC: encoding; Right PFC: retrieval).
Ventro-lateral frontal activation: updating/maintenance of information
Dorso-lateral activation: selection, manipulation and monitoring of information
Anterior activation: selection of processes and subgoals.
27. Neuropathology: Disorders in memory
Infarctions: Posterior cerebral artery disease (hippocampus, limbic nucleus of thalamus, and mesial
temporal lobe) result in amnesia. Thalamic strokes can present with dense retrograde amnesia
Intracranial tumours: Hypothalamus and third ventricle tumours (e.g meningioma) cause dense
anterograde amnesia.
Infections: Herpes simplex infection involving hemorrhagic necrosis of temporal lobes produce
profound amnesia.
Alcohol and licit drugs: Classic alcoholic blackout— Inability to encode new memories during
intoxication and inability to retrieve memories encoded proximate to the blackout. Cocaine and
heroin are not associated with amnesia.
Schizophrenia: Both Long termand short term memory is affected. Working and semantic memory is
lost, but procedural and implicit memory is intact. Memory loss is associated with severity and
chronicity of illness, presence of negative symptoms and Fronto temporal Dementia.
28. Neuropathology Cont.
Anoxia or Hypoxia: Exposure to neurotoxins
(such as trimethyltin or carbon monoxide,
inadequate oxygenation through
respiratory, circulatory and hematological
or metabolic compromise) leads to bilateral
damage of hippocampus particularly CA1
regions results in chronic amnesia and and
necrosis of hippocampus.
29. Neuropathology Cont.
Medications: Benzodiazepines and Barbiturates (IV), propofol and sildenafil, cause twilight or
semiconscious states.
Vitamin deficiencies: Particularly thiamine deficiency results in memory impairment.
ECT: Diminished ability to form new memories during/immediately following the period of treatment.
Korsakoff’s syndrome (KS): Marked anterograde amnesia, some retrograde amnesia, confabulation,
and poor insight. Neuropathology: neuronal loss, microhemorrhages, gliosis in paraventricular and
periaqueductal grey matter. (Victor et al 1971)
Sub-cortical dementias and basal ganglia lesions show impaired habit learning (Parkinson’s and
Huntington’s disease)
Semantic dementia is a variant of fronto-temporal dementia and Herpes encephalitis patients have
profound loss of semantic knowledge, loss of meaning encompassing verbal and non-verbal material
resulting in severe impairments in naming and word comprehension, perceptual and reasoning
abilities. Episodic memory is relatively preserved.
30. Neuropathology Cont.
Alzheimers Dementia: Degenration of cholinergic neurons due to deposition of amyloid plaque
may begin early within the nucleus basalis of the basal forebrain at the time of vague and
undiagnosed memory symptoms.
Spreading to projection areas such as hippocampus, amygdala, and entorrhinal cortex by the
time of early diagnosis
Then diffusely throughout neocortex by the time of loss of functional independence.
Eventually involving the loss of a great many neurons and neurotransmitter systems by the time
of death.
Episodic memory is impared first > Short term memory > Semantic memory > Finally procedural
memory.
However, as the diseases advances, parts of memory which were previously intact also become
impaired, and eventually all reasoning, attention and language abilities are disrupted.
31. Neuropathology Cont.
REGIONAL LESION ANALYSIS
Three major types of “regional amnesia” based on injury or lesion of a particular brain region.
1. Diencephalon type
2. Temporal lobe type
3. Frontal type
32. Neuropathology Cont.
1. Diencephalon type: e.g Korsakoff’ssyndrome
Case of NA:
◦ Fencing accident with damage to the left dorsal thalamus, B/L mammillary bodies and mammilo-
thalamic tract.
◦ Patient developed anterograde amnesia, particularly for Declarative memories, but less so for non
declarative memories. Most of his mental faculties remained intact, including his memories from the
distant past (no retrograde amnesia), his perception, and vigilance.
◦ Similar findings are also seen in patients with lesions of the diencephalon.
◦ Diencephalon lesions also show temporal order memory dysfunction. (Parkin et al 1990)
33. Neuropathology Cont.
2. Temporal lobe type: e.g Herpes encephalitis
Case of HM:
◦ Bilateral Medial Temporal Lobe removal (amygdala, uncus and hippocampus) for intractable epilepsy.
◦ Later the patient was not able to transfer new information into long term storage resulting in rapid forgetting,
could not recall information that occurred shortly before surgery; but had normal implicit memory.
Case of RB:
◦ Bilateral hippocampus atrophy secondary to vascular accident (CA 1 neuron involvement)
◦ Findings were similar to HM, but retrograde memory was better.
Bilateral or Unilateral temporal lobe (MTL that includes hippocampus, amygdala, perirhinal,
entorhinal, parahippocampal areas) damage causes symptoms similar to KS but, with more
involvement of the retrograde memories
34. Neuropathology Cont.
Right hippocampus lesions: spatial memory dysfunction.
Left inferolateral temporal lobe: semantic memory dysfunction.
Temporal lobe lesions: spatial memory is maximally affected.
Right temporal lobe damage: impairment in face recognition memory.
To sum up, explicit/declarative memory loss, episodic memory loss, and anterograde memory
loss happens more than retrograde memory loss; implicit memory is not affected.
Diencephalic and temporal amnesias are mostly similar but somewhat different from frontal
lobe amnesias.
35. Neuropathology Cont.
3. Frontal lobe type:
Patients with frontal lobe pathology especially when lesions penetrated the dorso-lateral frontal
cortical regions showed impaired temporal context memory
Working memory (planning, organization of material, monitoring of responses, inhibition of
inappropriate responses) deficits are reported.
Emotional memories: Humans form more vivid memories of emotionally arousing events rather
than neutral events. Lesion in the basolateral nucleus (BLA) of amygdala (a major out put
pathway, the stria terminalis), can prevent the facilitation of memory produced by emotional
arousal.
Recognition memory and familiarity judgments may be impaired in damage to perirhinal cortex.
36. Neuropathology Cont.
Psychogenic Amnesia:
Also known as Dissociative amnesia or functional amnesia
Characterised by abnormal memory functioning in the absence of structural brain damage or a
known neurobiological cause.
Results from the effects of severe stress or psychological trauma on the brain.
Psychogenic amnesia typically doesn’t affect new learning capacity
The main positive symptom in psychogenic amnesia is extensive and severe retrograde amnesia.
By contrast, patients with neurological amnesias usually have their remote memories preserved.
Some patients of psychogenic amnesia have circumscribed retrograde memory loss that covers a
particular time period or that covers only autobiographical memories.
