Neurobiology of Memory

Historical Foundations of Memory Research

• Theodore Ribot (1881):

  • In his work Diseases of Memory, Ribot was one of the first to call attention to the nature and specific course of amnesia accompanying dementia (a decline in cognitive and mental faculties).
  • He observed a specific pattern of memory loss: patients lost their most recent memories first, while memories from the remote past remained relatively preserved.
  • Ribot\'s Law: This refers to the time gradient observed in retrograde amnesia, stating that the most recent memories are the most vulnerable to loss, while older memories are more highly preserved.

• Sergei Korsakoff (late 1890s):

  • A Russian psychiatrist who described alcoholic patients suffering from a neuropsychiatric syndrome characterized by heavy memory loss.
  • Like Ribot, he noted a disturbance for recent and new materials while older memories remained intact.
  • He documented confabulation, where individuals make up for missing gaps in their memory by creating stories, and a tendency for patients to repeat themselves in conversation.

• Karl Wernicke:

  • Famous for identifying language-related brain areas, Wernicke also described clinical syndromes involving confusion, ataxia (motor impairment), and chronic amnesia.
  • He investigated brain pathology and noted differences in areas surrounding the third ventricle of the brain.
  • He identified specific structures potentially involved in memory: the thalamus, the dorsal medial nucleus, and the mammillary bodies.
  • Wernicke observed that the brains of individuals with amnesia often weighed less than normal brains, leading to the early hypothesis that the cortex must be involved in memory storage and retrieval.

• Arnold Pick (early 1900s):

  • Characterized Pick's Disease, a memory disorder affecting adults in their late $30s$ and early $40s$.
  • Pathology revealed profound changes in the frontal lobe.
  • Pick suggested that memory material might be localized in this region, though he could not make conclusive causal statements at the time.

• Vladimir Bekhterev (early 20th century):

  • Reported that individuals with profound amnesia often exhibited a "softening" (a change in texture and composition) of specific brain areas.
  • His research, along with others of the era, linked memory to the mammillary bodies, dorsal medial thalamus, frontal lobe, and the medial temporal lobe.

The Case of Patient HM (Henry Molaison)

• Background and Surgical Procedure (1954):

  • At age $7$, Henry was hit by a bicycle and suffered a head injury. By age $10$, he developed minor seizures that grew in severity. By age $27$, he was incapacitated and unable to work.
  • Neurosurgeon William Scoville performed an experimental procedure previously used on psychotic patients called the McGill procedure (associated with Wilder Penfield) to identify and ablate seizure focal points.
  • The surgery involved a bilateral resection (removal) of the rostral medial temporal lobes.
  • Anatomical Terms: Rostral means towards the front; Medial means towards the midline.

• Anatomy of the Medial Temporal Lobe:

  • The medial temporal lobe contains a spiral-like organization of structures forming the hippocampal formation.
  • Key regions include:
    • CA1, CA2, CA3, CA4 fields.
    • The dentate gyrus.
    • The parahippocampal gyrus (located on the very bottom/central side).

• Post-Surgical Outcome:

  • The seizures stopped, but HM developed a profound and specific memory deficit.
  • Anterograde Amnesia: The inability to form new memories following the event/surgery. HM remained "suspended in time" in the $1950s$, losing his "future."
  • Retrograde Amnesia: In HM's case, most of his old memories (prior to surgery) remained intact.

Contributions of Brenda Milner

• Pioneering Memory Psychology:

  • A Canadian psychologist mentored by Donald Hebb (known for synaptic learning theory) and Wilder Penfield.
  • She worked with HM for over $30$ years (though he never learned her name) and bridged cognitive psychology (Ebbinghaus, James) with neurobiology (Pick, Wernicke).

• Short-term vs. Long-term Memory:

  • Milner discovered HM's short-term memory was normal.
  • Memory Span/Digit Span: Defined as the longest list of items a person can repeat back in order immediately after presentation on at least $50\%$ of trials. Most people can recall $6$ or $7$ digits; HM excelled at this.
  • However, if HM was distracted for even a few moments, he could not recall the list—or even that there was a list.

• The Mirror Drawing Test:

  • HM was asked to trace a star-shaped target while watching his hand in a mirror (a difficult motor task).
  • He performed $10$ trials on $3$ consecutive days.
  • Results: On Day $1$, his errors dropped from approximately $30$ to less than $10$. On Day $2$ and Day $3$, despite having no conscious memory of ever doing the task, his performance began at a much better level than Day $1$ and reached nearly flawless levels.
  • Conclusion: This proved HM could form long-term memories, but only of a specific type (non-declarative/procedural).

Categorizing Memory: Declarative vs. Non-declarative

• Declarative Memory (Explicit):

  • Definition: Conscious memories; things you know that you can tell others/verbalize.
  • Episodic Memory: Personal memories of specific events.
  • Semantic Memory: General knowledge of facts (e.g., knowing Ottawa is the capital of Canada without remembering the specific moment you learned it).
  • Hippocampus Role: Used for the consolidation of declarative memories, but not their permanent storage.

• Non-declarative Memory (Implicit):

  • Definition: Memories you show by doing; improved task performance without conscious awareness.
  • Skill Learning: Learning motor, cognitive, or perceptual tasks (e.g., riding a bike, mirror drawing).
  • Priming (Repetition Priming): A change in stimulus processing due to prior exposure.
    • Perceptual Priming: Based on visual forms; linked to the bilateral occipital temporal cortex.
    • Conceptual Priming: Based on word meaning; linked to the left frontal cortex (Wernicke\’s area).
  • Conditioning: Associative learning between stimuli (e.g., Pavlov\’s dog). Linked to the cerebellum.

Animal Models and Further Research

• Delayed Non-Matching to Sample Task:

  • A test of object recognition/declarative memory used in monkeys.
  • A monkey finds a reward under a distinctive object (e.g., a key). After a delay, it is presented with the original object and a novel one (e.g., a blue cup). The monkey must choose the novel object to get the reward.
  • This requires the monkey to "declare" what it has seen before. Research showed the rhinal cortex, amygdala, and hippocampus are key to this task.

• Spatial Memory and the Hippocampus:

  • Eight-arm Radial Maze: Tests spatial location memory in rats. Animals must remember which arms they already entered. Hippocampal damage profoundly affects performance; damage to the basal ganglia or extra-striate visual cortex does not.
  • Place Cells: Specialized neurons in the hippocampus that become active when an animal is in or moving toward a specific location.
  • Species Comparisons:
    • Marsh Tits: Birds that cache (hide) food have a larger hippocampal volume than non-caching cousins.
    • London Taxi Drivers: To become a driver, one must pass a complex spatial navigation test. Study results showed taxi drivers have a larger posterior hippocampus compared to controls. Volume was positively correlated with the number of months spent driving ($r > 0$).

• Skill Learning and the Basal Ganglia:

  • In tasks where animals must remember a movement (e.g., turning the same way they did previously), lesions to the basal ganglia significantly impair performance, while other lesions do not.

Summary Conclusions

• Memory is not a single, unique construct but a collection of distinct workflows.
• Multiple brain regions are involved in learning and memory.
• Different forms of memory rely on different mechanisms and brain regions.
• The same brain structure can be part of the circuitry for several different forms of learning.