Memory and Learning I

Learning and Memory

Learning and memory are not interchangeable terms; instead, they are complementary concepts. Memory is the behavioral change caused by an experience, and “learning” is how this happens. Learning is the process by which new information is acquired; memory is the process by which that knowledge is retained.

Learning

Learning can be divided into different processes that involve different modalities using different neuropsychological systems or neuroanatomical substrates: 1) Explicit learning and memory is the conscious acquisition of knowledge about people, places and things. It occurs in largely in diencephalic structures. 2) Implicit learning is the non conscious learning involving stimulus-response associations, such as classical and instrumental conditioning, motor learning and habit formation. It does not depend on the temporal lobe, but mainly engages brain circuits involving the basal ganglia, prefrontal cortex and amygdale.

Some basic forms of learning

• Perceptual learning accomplished by changes in the sensory association cortex.
• Stimulus-response learning involves establishing connections between circuits involved in perception and those involved in movement.
• Motor learning a component of stimulus-response learning. Cannot happen without sensory assistance.
  • Perceptual learning is the establishment of changes within the sensory systems,
  • stimulus-response learning is the establishment of connections between sensory and motor systems,
  • motor learning is the establishment of changes within the motor systems.
• Relational learning involves learning the relations among individual stimuli. Episodic and observational learning are forms of relational learning.

Learning and Synaptic Plasticity

The Hebb Rule (1949): if a synapse repeatedly becomes active at about the same time the post-synaptic neuron fires, changes will take place in the structure or chemistry of the synapse that will strengthen it.

Hebb’s Theory

• Short-term memory (STM) is an active process of limited duration, while long-term memory (LTM) involves an actual structural change in the nervous system
• Each psychologically important event is the flow of activity in a given neuronal loop
• The synapses in a particular path become functionally connected to form a cell assembly (a system that is initially organized by a particular sensory event but is capable of continuing its activity after the stimulus has ceased)
• Cell assembly must be repeatedly activated – after initial sensory input, assembly reverberates
• Structural changes: STM is reverberation, LTM is lasting structural change
• Consolidation: 15 min-1 hour in which assembly is undisturbed and undergoes structural changes
• Any assembly can be excited by others

Lomo (1966) discovered that intense electrical stimulation of axons leading from the entorhinal cortex to the dentate gyrus caused a long-term increase in the magnitude of excitatory post-synaptic potential in the post-synaptic cells (long-term potentiation; LTP). LTP occurs when the postsynaptic cell is depolarized at the same time it is being stimulated – NMDA receptors only open when glutamate is in the cleft an the postsynaptic membrane is depolarized simultaneously

Additionally, when weak and strong synapses to a single neuron are stimulated at approximately the same time, the weak synapses become strengthened (associative long-term potentiation; ALTP).

LTP and ALTP require two things:

• Activation of synapses
• Depolarization of the post-synaptic neurons
• Many experiments have demonstrated that LTP in hippocampal slices follows the Hebb rule. Additionally, LTP has been demonstrated in numerous other brain regions, including the prefrontal cortex, piriform cortex, entorhinal cortex, motor cortex, visual cortex, thalamus, and amygdala. NMDA (a specialized glutamic receptor that controls a calcium channel), is involved in LTP in most cortices.

• Post-synaptic and pre-synaptic changes are two of several mechanisms that account for the increases in synaptic strength during LTP.

• Several studies have shown that NMDA-mediated LTP increases the number of post-synaptic AMPA receptors (specialized glutamic receptor that controls a sodium channel).
  • This increase makes the post-synaptic membrane of the dendritic spine more sensitive to the release of glutamate by the pre-synaptic terminal button, thereby strengthening the synapse.
  • The LTP produced by the activation of NMDA receptors is initiated post-synaptically by the entry of calcium ions, but the entry of calcium activates special calcium-dependent enzymes known as protein kinases.
• Pre-synaptic changes also occur by means of nitric oxide (NO) synthase, which is theorized to be a retrograde messenger involved in long-term potentiation.

Summary: entry of calcium ions through channels controlled by NMDA receptors activates at least two calcium-dependent protein kinases. These enzymes may activate processes that produce post-synaptic changes that cause the insertion of AMPA receptors into the post-synaptic membrane. Additionally, the entry of calcium activates a calcium-dependent NO synthase, and the newly produced NO then presumably diffuses out of the dendritic spine, back to the terminal button, where it induces pre-synaptic changes.

Location of Synaptic Change

If morphological change in neurons is the basis of memory, which neurons are modified by experience? Three issues address this question…

1. A sensory experience cannot change every neuron in the relevant system. It is logical to assume that experiences will more likely affect higher level sensory areas than lower level sensory areas.
2. Sensory experiences change sensory systems, allowing us to remember ideas or thoughts. However, the mechanism by which we remember is probably located elsewhere.
3. Experiences result in widespread changes in synapses, but how we “find” a specific memory is probably related to the cortical and subcortical storing of memories and to the notion that memory is a multiple component system.

MEMORY

Memory is a process that results in a relatively permanent change in behavior. Events are not stored in toto; only certain critical elements are stored from which the event is reconstructed. The more cues or elements provided contextually, the more exactly the event can be reconstructed and “remembered.”

History

NP study of memory dates back to about 1915, when Lashley looked to identify the neural locations for learned habits. After years of study, dissection and neurosurgical experiments, he concluded: “it is not possible to demonstrate the localization of a memory trace anywhere in the nervous system. Limited regions may be essential for learning or retention of a particular activity, but … the engram is represented throughout the region.”

In 1953, a neurosurgeon, William Scoville (and his colleague Brenda Milner) made one of the most influential discoveries when he removed H.M.’s bilateral hippocampi (medial temporal lobes), rendering him unable to remember any events following the surgery. This surgery did not remove previous memories but interfered with the formation or retrieval of new memory. Subsequently, the study of memory shifted from trying to find its location in the brain to looking at how memory is formed and stored.

DEFINITIONS (simplified)

Sensory Memory – lasts only seconds

• Echoic memory – auditory immediate memory
• Iconic/eidetic imagery – visual immediate memory

Short-Term Memory – refers to the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. In some theories of memory, thought to be a separate system from long-term memory.

Long-Term Memory – corresponds best to the layperson’s conception of memory.

Consolidation – The process by which “new memories” (which are initially ‘labile’ and sensitive to disruption) undergo a series of processes (e.g., glutamate release, protein synthesis, neural growth and rearrangement) that render the memory representations progressively more stable.

Encoding – active organization or manipulation of incoming stimuli, such as visual imagery, mnemonics, rehearsal and repetition.

Retrieval – ability to access previously stored information; “tip of the tongue phenomenon,” state-dependent learning and memory

Forgetting – passive decay and interference;

• Proactive interference – previously learned information interferes with current learning
• Retroactive interference – recently learned information interferes with ability to remember previously learned information.

Amnesia – partial or total loss of memory abilities.

Retrograde amnesia (RA) – difficulty recalling events prior to amnesia onset; seen with diencephalic lesions (i.e., mammillary bodies, thalamic nuclei, and interconnecting pathways)

Anterograde amnesia (AA) – inability to recall events subsequent to amnesia onset; seen with hippocampal damage (bilateral + amygdala). Immediate recall does not require temporal lobe.

Ribot’s Law – oldest memories are the most resistant to amnesia

Priming – unconscious facilitation of performance due to prior exposure to stimuli. Works in normals and amnesics. Involved in error-free learning.

Metamemory – frontal process; “feeling of knowing”

Recent Memory – memory stored within last hours-months

Remote Memory (aka tertiary memory) – memory from earliest years of one’s life

Episodic memory – autobiographical form of memory for contextually specific events tied to time and place

Semantic memory – generalized world knowledge not tied to time or circumstance, linguistic skill, and vocabulary

MAJOR TYPES OF MEMORY

• Explicit (declarative) memory – available to awareness; conscious/intentional recollection process; information that can be stated explicitly (or declared), that can be brought to mind as an image or proposition in the absence of ongoing perceptual support, and/or of which one is consciously aware. Comprises both episodic & semantic material. This is what patients complain about, and it is not very amenable to treatment. Involves hippocampus and surrounding structures, and amygdala.

• Aspects of Declarative Memory

1. Retrieval – “remembering”
   1. Recall – active, complex, search process
   2. Recognition – always easier; stimulus triggers
2. Material-specific – may forget only verbal or nonverbal, etc.
3. Episodic (event) – one’s own experiences; unique and localizable in time and space. vs. Semantic – what is learned as knowledge; “timeless/spaceless”
4. Automatic – passive learning (e.g., digits forward) vs. Effortful – learning with active, effortful processing (e.g. digits backwards)
5. Source (contextual) – knowledge of where or when something was learned; may be a form of incidental memory
6. Prospective – involves the “what” knowledge of declarative, and executive function; ability to remember to do something at a particular time

• Implicit (Nondeclarative/Procedural) memory – reflects a constellation of abilities, such as the acquisition of motor or cognitive skills, classical conditioning, habituation, and priming. “Habit” memory. Learning without conscious awareness (see Squire, 1986, 1987). Relatively spared even in severe amnesics, except in PD and basal ganglia pathology. Can use this to chain habits.

• Aspects of Procedural Memory
  • Falls under Implicit Memory – knowledge that is expressed in performance without subject’s awareness they possess it
  • Corpus striatum is key component; implicit memory usually unimpaired even in dense amnesia; not available to conscious awareness;
  • “Habit system” (e.g., walk, talk, dress, eat, etc.)
  • 3 categories: learning of these skills/procedures does not take conscious effort
    • Skill Memory – motor and cognitive skill learning and perceptual; “how to” learning
    • Priming – form of cued recall; prior exposure facilitates response without awareness
    • Classical Conditioning

THEORIES OF MEMORY FUNCTIONING

Cermak (1984) – suggested that the episodic/semantic distinction helped explain temporally graded RA, whereby biographical material becomes progressively more semantic as it ages because it is retold and elaborated. This resembles the consolidation theory of memory, but implies that cognitive not automatic physiological processes result in the storage of memories.

• Notably, recent evidence (Cermak; Butters; Zola-Morgan) suggests that many amnesic patients suffer impairments of semantic and episodic memory; thus, amnesia is probably not accurately described as an exclusively episodic deficit. Also, episodic and semantic memories are neither easily dissociable nor universally agreed upon.

• Information-Processing Model Information processing model has several stages.

1. Attention – alertness/arousal [brainstem, subcortical], focusing (preparedness), sustained (vigilance); more or less vulnerable to interference (distractibility) [thalamus or frontal], divided (allocate resources)
   1. working memory – hold info. in temporary storage and manipulate
2. Encoding – In this process, information is received or registered through one or more of the senses and modified for entry into the memory system. The level of analysis/modification affects the likelihood of recall (e.g., deep –> semantic; shallow –> phonological) [language or visual processing systems; frontal; diencephalic structures – dorsomedial nucleus]
3. Storage – transfer of transient memory to form or location for permanent storage/access [hippocampus/mesial temporal lobe]; facilitated by:
4. Consolidation – construct; integrate new memories into cognitive/linguistic schema
5. Retrieval – search/activate memory traces; monitor for accuracy and appropriateness

• Baddeley’s (2000) Working Memory Model (Model of Short Term Memory)
  • Composed of three main components—the central executive which acts as supervisory system and controls the flow of information from and to its slave systems: the phonological loop and the visuo-spatial sketchpad. The slave systems are short-term storage systems dedicated to a content domain (verbal and visuo-spatial, respectively). In 2000 Baddeley added a third slave system to his model; the episodic buffer.
    • All are considered Fluid Systems that link to long-term memory, entailed in Visual Semantics, Episodic Long-Term Memory, and Language, which are considered crystallized systems.

• Atkinson and Shiffrin’s 3-Stage Model of Declarative Memory

1. Registration/Sensory Memory (milliseconds)
   1. Holds info for 1-2 seconds (in sensory store); not just memory or perception
   2. First traces: visual image (iconic memory) or auditory replay (echoic memory)
   3. Further processing depends on affect, set, & attention-focusing components
2. Stage 2 — Short Term Memory
   1. Immediate Memory (1st stage of STM; 30 sec. to several minutes)
      1. Limited capacity store (+/- 7 bits of information)
      2. Then transfer to more permanent storage
      3. Info is maintained in reverberating neural circuits (two outcomes: more stable biochemical organization = LTM; dissipates = no memory)
   2. Rehearsal (hours) (Repetitive mental process that serves to lengthen duration of a memory trace that increases likelihood of permanent storage
   3. Longer Impermanent Memories (1 hour – 1or 2 day) This may just be brand-new LTM, and therefore vulnerable to interference
3. Long-Term Memory (LTM, aka secondary memory)

• General concepts in this model
  • LTM is the ability to store information
  • Concept of amnesia – intact STM capacity, impaired LTM
  • consolidation – process of storing information as LTM; what is “learned” is consolidated
  • incidental learning – requires no directed effort
  • LTM is organized based on meaning, STM is organized based on sensory properties
  • LTM occurs at a cellular level – alterations in neuron, synapse, elaboration of dendrite, pruning with disuse (i.e., no single storage site)

TYPES OF AMNESIA

Note: Chapter 21 on Amnesic Syndromes in Clinical Neuropsychology: A Pocket Handbook for Assessment provides several nice tables that address neuroanatomic distinctions in, neurological illnesses associated with, and evaluation of amnesia. Also, Chapter 15 on Amnesic Disorders in Clinical Neuropsychology and Chapters 35 and 36 in Behavioral Neurology and Neuropsychology are excellent…

• Disorders may be transient (e.g., EtOH, toxic, TIA, seizure, ECT), in which memory disturbance is temporary but memories never regained, or permanent (e.g., TBI, attention deficit, Korsakoff’s, hypoxia, bilateral t-lobe damage)

Functional Amnesia

• AA does not usually occur
• RA is extensive and frequently includes loss of personal identity and can be limited to autobiographical memory.

Organic Amnesia

• AA is severe without loss of personal identity (just the opposite in functional amnesia)
• RA (plus public event and autobiographical memory) is usually temporally graded
• Causes include temporal lobe surgery, chronic alcohol abuse, brain injuries, anoxia or ischemia, encephalitis, epilepsy, tumor, or cerebrovascular accident (stroke). Significant problems with new learning occur after bilateral temporal damage.

Transient Global Amnesia

• Profound AA problems and variable profiles of RA, perhaps because of retrieval problems
• Associated with decreased perfusion to the medial temporal or diencephalic regions
• No clear etiology, but believed to be transient disturbance in the medial temporal lobe and/or diencephalon
• Does correlate with migranes, but migraine and transient global amnesia do not share the same etiology
• Onset is often abrupt, and may follow emotional or physical strains
• Occurs after ECT; AA can be quite severe (esp. bilateral ECT). Recovery of new learning capacity occurs within several months after ECT, but some patients demonstrate residual deficits
• People whose transient global amnesia is not secondary to ECT generally regain ability to form new memories, although they will not recall events that occur during the amnestic period

Medial Temporal Lobe Amnesia

• Historically, described as having preserved insight, increased rates of forgetting, limited RA, and lack of confabulation.
• Recent studies have underscored an association between severity of RA and extent of hippocampal (and adjacent cortices) pathology.
• Causes include anoxia, limbic encephalitis, stroke, and probable Alzheimer’s disease. H. M. is the primary example.

Diencephalic Amnesia

• Deficits in the initial processing stages of memory
• Confabulation
• Sensitivity to proactive interference
• Lack of insight into the memory disturbance
• Rate of forgetting may be normal. Remote memory is variably affected (some – minimal; others – severe problems in retrieval for events immediately predating the onset of amnesia.
• Causes – infarctions of thalamic arteries, trauma, diencephalic tumors, and Korsakoff’s syndrome. Patients with thalamic amnesias demonstrate frontal pathology, which may also contribute to confabulation and lack of insight.

Frontally-related Amnesia

• Attentional deficits adversely affect encoding and retrieval (therefore, some demonstrate RA).
• Retrieval may be normal, suggesting that consolidation is relatively intact.
• Unawareness of memory problems and tendency to confabulate are common.
• Also includes proactive interference, poor contextual memory, and poor semantic categorization. [see Baddeley’s (2000) working memory model]

CONDITIONS THAT MAY CAUSE AMNESTIC SYNDROMES

Memory problems can occur in a number of neurological (and psychiatric) conditions. Such conditions include:

• Anoxic/hypoxic encephalopathy
• Anterior communicating artery aneurysm/stroke
• Herpes simplex encephalopathy
• Posterior cerebral artery stroke
• Surgical intervention
• Wernicke-Korsakoff Syndrome

Anoxic / Hypoxic encephalopathy

This condition may occur following any disruption in oxygen satruation to the brain. Typically, five minutes or more without oxygen can permanently damage the brain. The medial temporal lobes are particularly sensitive to oxygen depletion. New learning is often impaired, while remote memory remains intact.

• Frontal watershed cortex and basal ganglia structures often involved.
  • May result in perceptual, motor and executive deficits
• Deficit in memory often one of retrieval rather than encoding.
  • These folks benefit from cues and recognition formats.

Anterior Communicating Artery Aneurysm

Persons with ACoA aneurysm may experience the following:

• Amnesia
  • most likely secondary to basal forebrain damage
  • disorientation
  • confabulation common due to frontal systems involvement
  • attentionally based memory problems, again due to frontsl systems involvement
• Apathy

Herpes Simplex Encephalitis

Herpes is most common cause of nonepidemic, sporadic viral encephalitis in the US.

• Diagnosed by ID of virus in CSF or brain tissue through biopsy
• Brain involvement diffuse
  • petechial hemorrhages and necrosis throughout medial temporal and inferior frontal lobes
    • may include hippocampus, parahippocampus,insula, basal forebrain, mammillary bodies, fornix.
• Persons with HSE initially show confusion, aphasia, agnosia and impaired memory
  • may resolve over time to memory and learning problem, dependent on location of lesions.
• Typical pattern of memory problems includes both verbal and nonverbal material, with severe retrograde amnesia

Posterior Cerebral Artery Stroke

Memory problems occur secondary to bilateral posterior cerebral artery stroke

• Posterior cerebral artery irrigates medial temporal lobes and posterior occipital lobe
• Material specific memory loss depending on laterality of lesion
  • Memory problems also noted on unilateral left PCA stroke but not well studied to this point
• Other cognitive deficits may also be seen, including visual deficits, hemianopic alexia, color agnosia and object agnosia
  • more likely if lesion extends to occipitotemporal cortices

Surgical intervention

After Scoville’s surgical removal of HM’s bilateral thalami, many, many studies evolved on the nature of the memory impairment that HM experienced. Following this knowledge, surgical intervention for intractable seizures continues, but is usually restricted to unilateral ablation.

• Surgery usually done after careful neuropsychological and neurological work-up
  • Typically includes intracarotid amobarbital studies to minimize or avoid new learning problems

Wernicke-Korsakoff’s Syndrome

Wernicke’s encephalopathy is an acute medical condition, often called Wernicke-Korsakoff’s Syndrome. It is usually the result of chronic alcohol abuse and thiamine deficiency. It is recognized by a classic triad of gait ataxia, oculomotor problems (nystagmus) and confusion, often exhibited in incoherent speech and disorientation. Treatment with thiamine usually leads to clearing of the ataxia and disorientation/acute confusion, but there may be persistent memory problems/amnesia, personality changes and other cognitive problems. There may be several mechanism of the memory problems, including nutritional deficits.

The residual memory problems are called Korsakoff’s syndrome. This is an example of diencephalic amnesia. Major symptoms include:

• Anterograde amnesia – will have no recollection of what happened even 1/2 hour ago; involves intentional, episodic, or declarative memory
• Retrograde amnesia – extensive impairment of remote memory which covers most of their adult life
• Confabulation – rather than admit memory loss; often based on past experiences and are therefore often plausible
• Meager content in conversation – little to say in spontaneous conversation
• Visual-spatial deficits
• Sensory processing deficits
• Lack of insight into their deficit
• Apathy – lose interest in things quickly and generally appear indifferent to change; tend to lack the impulse to initiate activity
• Intact: incidental, semantic, or procedural memory.
• In addition, people with Korsakoff’s syndrome may tend to be:
  • disoriented to time and space
  • often sit doing nothing even when they talk about wanting to do something
  • emotionally flat; if sad worrisome or even happy issues are brought to their attention they will display somewhat appropriate response but the arousal is only transitory

Neuropathology of Korsakoff’s

• Bilateral damage along the diencephalon midline, esp. dorsomedial thalamic nuclei and mammilary bodies
• Highlights importance of the medial thalamus for memory function, including the dorsomedial nucleus, anterior nucleus, and connections and structures within the internal medullary lamina.
• Generalized cerebral atrophy
• Believed to have a diencephalic lesion and frontal lobe deterioration (shown in CT scans and by test performance)

Differences b/t Temporal Lobe Amnesia and Korsakoff’s

1. TL amnesics show normal release from proactive interference; diencephalic amnesias do not
2. Korsakoff’s patients have extensive loss of remote memory; TL amnesics do not
3. Moscovitch has suggested that Korsakoff’s patients also have frontal lesions (based on CT scans showing frontal atrophy)

NEUROANATOMY OF MEMORY (General)

More information can be found on the page called Neuroanatomy of Memory

MISCELLANEOUS

ECT

• bilateral ECT usually induces memory changes and effect on memory can be cumulative
• effects seem to be reversible w/a return to pretreatment levels w/in 6 – 7 months
• subtle defects may persist, usually in autobiographical info