Memory Disorders

Abstract

Memory disorders are a type of neurobehavioral manifestations: disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. This article covers the amnesic syndrome that follows damage to the hippocampus and related structures, the dissociation between episodic and semantic memory, spatial memory deficits, Korsakoff syndrome, age-related memory decline, mild cognitive impairment and subjective cognitive decline, the debate over memory consolidation and retrograde amnesia, and the rehabilitation of memory-impaired patients.

Keywords: memory disorders, amnesia, hippocampus

The hippocampus, together with anatomically related structures, is essential for a specific kind of memory, termed declarative memory, whereas a heterogeneous collection of nondeclarative memory abilities, such as skills and habits, simple conditioning and priming, does not require it (Squire, 1992). Work with the patient H.M., whose severe memory impairment resulted from experimental neurosurgery to control seizures, established fundamental principles about how memory functions are organized in the brain (Squire, 2009).

What Memory Disorders Are

MeSH defines Memory Disorders as disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression, notes that memory impairments are associated with dementia, craniocerebral trauma, encephalitis, alcoholism and schizophrenia, and lists entry terms including Memory Loss, Memory Deficits, Cognitive Retention Disorders, Age-Related Memory Disorders, Semantic Memory Disorders and Spatial Memory Disorders. MeSH files the descriptor under neurobehavioral manifestations, under nervous system diseases and under behavior and behavior mechanisms.

A general review of the field surveys the clinical varieties of the amnesic syndrome, transient and persistent, and asks what is impaired and what is spared in anterograde amnesia, whether temporal lobe, diencephalic and frontal amnesias differ, what determines the pattern and extent of retrograde memory loss, and whether psychogenic amnesia involves the same mechanisms as organic amnesia (Kopelman, 2002).

Types of Memory Disorders

MeSH lists two narrower descriptors beneath memory disorders. MeSH is an indexing classification, not a theory of the mind: its subtypes record how the literature is indexed, they need not be mutually exclusive, and the entry terms above (semantic, spatial and age-related memory disorders among them) are indexed under the parent rather than as separate descriptors.

The Korsakoff syndrome is a preventable memory disorder that usually emerges, although not always, in the aftermath of an episode of Wernicke's encephalopathy; it is most commonly associated with chronic alcohol misuse, episodic memory is severely affected, the learning of new semantic memories is variably affected, and implicit aspects of memory are preserved (Kopelman et al., 2009). The lesions linked to its memory disorder are diencephalic: lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus (Kopelman et al., 2009), and a later review of its neuropathology focuses on abnormalities in the diencephalon, including the mammillary bodies and thalamic nuclei (Arts et al., 2017). The same review concluded that thiamine deficiency is a crucial factor in its etiology and that, although alcohol abuse is by far the most important context in which thiamine deficiency occurs, there is no convincing evidence for an essential contribution of ethanol neurotoxicity (Arts et al., 2017).

The Amnesic Syndrome

Scoville and Milner reported the loss of recent memory that followed bilateral hippocampal lesions (Scoville & Milner, 1957). The patient, H.M., was the subject of study for five decades until his death in December 2008 (Squire, 2009). A synthesis of work with rats, monkeys and humans proposed multiple memory systems with different functions and distinct anatomical organizations, with the hippocampus needed temporarily to bind together distributed sites in neocortex that together represent a whole memory (Squire, 1992). That division by consciousness is contested: a processing-based model argues that the hippocampus mediates rapid associative learning with and without consciousness, that consciousness seems to be a poor criterion for differentiating declarative from nondeclarative memory, and that memory systems should instead be distinguished by the processing operations involved (Henke, 2010).

Figure 1

Declarative and Nondeclarative Memory

Figure 1 summarises the division.

Episodic and semantic memory can come apart. Global anterograde amnesia was described in three patients whose brain injuries occurred at birth, by age 4 and at age 9, with bilateral hippocampal pathology in all three; despite pronounced amnesia for the episodes of everyday life, all three attended mainstream schools and attained levels of speech and language competence, literacy and factual knowledge within the low average to average range, which the authors took to support the view that the episodic and semantic components of cognitive memory are partly dissociable (Vargha-Khadem et al., 1997). That reading is disputed: in patients with adult-onset bilateral damage thought to be restricted primarily to the hippocampal region, the patients acquired less factual knowledge than controls since the onset of their memory impairment, and the authors concluded that the hippocampal region supports semantic memory as well as episodic memory and that its role in the acquisition and storage of semantic knowledge is time limited (Manns et al., 2003). A later review concluded that current behavioral, neuropsychological and neuroimaging data are compatible with the idea that episodic and semantic memory are inextricably intertwined, yet retain a measure of distinctiveness, despite the fact that their neural correlates demonstrate considerable overlap (Renoult et al., 2019). The reverse pattern appears in semantic dementia: five patients showed a radically impoverished knowledge about a range of living and man-made items, while autobiographical and day-to-day episodic memory were relatively retained, and imaging showed marked focal temporal atrophy in all five (Hodges et al., 1992).

Spatial memory is affected too. A meta-analysis of 27 studies of patients with hippocampal damage found impairments on all spatial-memory tasks, with clear differences in effect size between positional memory and maze learning, object-location memory and working memory, and its authors took the results to support the notion that the hippocampus is important in processing metric positional information, probably in the form of an allocentric cognitive map (Kessels et al., 2001).

Consolidation and Retrograde Amnesia

Retrograde amnesia is where the theories divide. On the standard consolidation theory, systems consolidation is the process by which the hippocampus guides the reorganization of information stored in the neocortex until it becomes independent of the hippocampus, and early evidence came from retrograde amnesia that impaired memories formed in the recent past but typically spared memories formed in the more remote past; its proponents report that systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues (Squire et al., 2015). The rival multiple trace theory drew on findings that retrograde amnesia after damage to the hippocampal complex can be extensive and encompass much of a subject's lifetime, depending on the type of memory assessed, and proposed that the hippocampal formation is involved in autobiographical episodic and spatial memory for as long as they exist (Nadel & Moscovitch, 1997). Retrograde loss of this kind can be measured with a structured interview for autobiographical and personal semantic memory, which reported an age-related temporal gradient in amnesic patients and a consistent pattern of impairment across the two kinds of memory once the age of the memories was controlled (Kopelman et al., 1989).

Its proposers have since revised multiple trace theory. Building on its ideas, a transformation account holds that some autobiographical and spatial memories are transformed with time and experience from highly detailed, context-specific memories to less detailed, schematic memories that retain the gist of an experience and do not depend on the hippocampus, whereas memories that remain detailed and retain their contextual specificity continue to depend on representations encoded in the hippocampus, regardless of their age (Moscovitch et al., 2016). A later account argues that, contrary to a unidirectional view of memory reorganization, information about events may be retained in multiple forms, from event-specific episodic memory to gist, schematic and abstract semantic memory, which can coexist for long durations and whose relative strength changes with time, experience and task demands; on this view there are only variations of synaptic consolidation and memory dynamics without assuming a distinct systems consolidation process (Gilboa & Moscovitch, 2021).

Age-Related Memory Disorders

Memory complaints in later life have been framed in several ways. A National Institute of Mental Health work group proposed diagnostic criteria and measures of clinical change for age-associated memory impairment (Crook et al., 1986). In an early clinical characterization, subjects with mild cognitive impairment had a memory impairment beyond that expected for age and education yet were not demented; in a community cohort of 76 subjects with mild cognitive impairment, 234 healthy controls and 106 patients with mild Alzheimer disease, the primary distinction between controls and subjects with mild cognitive impairment was in memory, and subjects with mild cognitive impairment declined faster than controls but less rapidly than patients with mild Alzheimer disease (Petersen et al., 1999). An international working group later recommended general criteria under which the person is neither normal nor demented, there is evidence of cognitive deterioration shown by objectively measured decline over time or by subjective report of decline in conjunction with objective cognitive deficits, and activities of daily living are preserved (Winblad et al., 2004).

Later estimates put the prevalence of mild cognitive impairment at between 15% and 20% in persons 60 years and older and its annual rate of progression to dementia at between 8% and 15%, while noting that not all mild cognitive impairment is due to Alzheimer disease and that if treatable causes are identified the person might improve (Petersen, 2016). Subjective cognitive decline, in individuals with unimpaired performance on cognitive tests, may represent the first symptomatic manifestation of Alzheimer disease, and a working group proposed research criteria for it (Jessen et al., 2014). Epidemiological data show an increased risk for mild cognitive impairment and dementia in individuals with subjective cognitive decline, but the majority of them will not show progressive cognitive decline (Jessen et al., 2020).

Rehabilitation

Memory-impaired patients can learn new material under the right conditions. With the method of vanishing cues, the systematic reduction of letter fragments of to-be-learned words across trials, four memory-impaired patients acquired a substantial amount of computer-related vocabulary, produced the target words without fragment cues and retained the vocabulary over a 6-week interval, although learning was slow and strongly dependent on first-letter cues (Glisky et al., 1986). On a stem completion task, errorless learning was beneficial, with the effect particularly marked for the amnesic group, which its authors interpreted in terms of an implicit learning that is particularly vulnerable to interference (Baddeley & Wilson, 1994). A later study tested that account and found no evidence that the benefits of errorless learning rely upon implicit memory, proposing instead that they stem from the effects of error prevention on residual explicit memory (Hunkin et al., 1998). A later systematic review rated errorless learning only a Practice Option for people with severe memory impairments after traumatic brain injury: such techniques may be effective for learning specific skills or knowledge, with limited transfer to novel tasks or reduction in overall functional memory problems (Cicerone et al., 2019).

A systematic review of the cognitive rehabilitation literature for traumatic brain injury and stroke, by a task force that had by then evaluated 491 articles, supported a Practice Standard for compensatory strategies for mild memory deficits (Cicerone et al., 2019). Korsakoff patients are capable of new learning, particularly if they live in a calm and well-structured environment and if new information is cued (Kopelman et al., 2009).

Worked Example

The mild cognitive impairment estimates can be turned into counts. Taking prevalence at 15% to 20% of persons aged 60 and older and progression at 8% to 15% per year (Petersen, 2016), a community population of 1,000 people aged 60 and older would include 150 to 200 with mild cognitive impairment (1,000 × 0.15 = 150; 1,000 × 0.20 = 200), of whom 12 to 30 would be expected to progress to dementia in a year (150 × 0.08 = 12; 200 × 0.15 = 30). The same figures imply that in any one year most people with mild cognitive impairment do not progress.

Discussion

Three conclusions follow. First, memory disorders are dissociations rather than a single loss: on the multiple memory systems account, declarative memory depends on the hippocampus while skills, habits, conditioning and priming do not (Squire, 1992), a division by consciousness that a processing-based model contests (Henke, 2010), and episodic and semantic memory are partly dissociable on one reading of early hippocampal pathology (Vargha-Khadem et al., 1997), a reading disputed by evidence that the hippocampal region supports semantic memory as well (Manns et al., 2003), while semantic dementia impoverishes knowledge with episodic memory relatively retained (Hodges et al., 1992).

Second, the time course of retrograde amnesia remains contested. One account holds that the hippocampus guides a reorganization until memories become independent of it (Squire et al., 2015), and another holds that memories exist in multiple coexisting forms without a distinct systems consolidation process (Gilboa & Moscovitch, 2021).

Third, memory complaints in later life are not destiny: most individuals with subjective cognitive decline will not show progressive decline (Jessen et al., 2020), and if treatable causes of mild cognitive impairment are identified the person might improve (Petersen, 2016).

Current Directions

Three lines of work are active. Mechanisms of consolidation: work has begun to characterize the dialogue between hippocampus and neocortex, such as neural replay during sharp wave ripple activity, and variables such as preexisting knowledge that affect the rate of consolidation (Squire et al., 2015). Early detection: an increasing number of studies investigate the link between subjective cognitive decline and the very early stages of Alzheimer disease and other neurodegenerative diseases (Jessen et al., 2020). Diagnosis: a definition of Korsakoff syndrome and draft outlines for prospective diagnostic criteria have been proposed (Arts et al., 2017).

Common Misconceptions

“Amnesia erases all kinds of memory.”

Skills and habits, simple conditioning and priming do not require the hippocampus (Squire, 1992).

“Mild cognitive impairment is early dementia.”

Not all mild cognitive impairment is due to Alzheimer disease, and if treatable causes are identified the person might improve (Petersen, 2016).

“People with amnesia cannot learn anything new.”

With vanishing cues, memory-impaired patients acquired and retained computer-related vocabulary (Glisky et al., 1986).

Glossary

Age-associated memory impairment.

A proposed diagnostic category for memory decline in older adults, set out with criteria and measures of clinical change by a National Institute of Mental Health work group.

Anterograde amnesia.

Impaired memory for events after the onset of brain injury, as in global anterograde amnesia after hippocampal pathology.

Declarative memory.

The kind of memory for which the hippocampus and related structures are essential; similar terms include explicit and relational memory.

Developmental amnesia.

Amnesia for everyday episodes after hippocampal injury early in life; in the three patients described by Vargha-Khadem and colleagues, factual knowledge reached the low average to average range.

Episodic memory.

Memory for the episodes of everyday life, the component of cognitive memory fully dependent on the hippocampus on one view.

Errorless learning.

Training in which learners are given the correct response instead of being encouraged to guess.

Korsakoff syndrome.

A preventable memory disorder that usually emerges after Wernicke's encephalopathy and is most commonly associated with chronic alcohol misuse.

Mild cognitive impairment.

A state of cognitive function between that seen in normal aging and dementia; an early clinical characterization required a memory impairment beyond that expected for age and education in a person who is not demented.

Multiple trace theory.

The proposal that the hippocampal formation is involved in autobiographical episodic and spatial memory for as long as they exist, later built on by a transformation account in which memories that become less detailed and schematic with time no longer depend on the hippocampus.

Nondeclarative memory.

A heterogeneous collection of memory abilities, including skills and habits, simple conditioning and priming, that do not require the hippocampus.

Retrograde amnesia.

Loss of memories formed before the onset of brain damage, which can be extensive and depend on the type of memory assessed.

Semantic dementia.

A syndrome of fluent dysphasia and impoverished knowledge about objects, with relatively retained day-to-day episodic memory and focal temporal atrophy.

Subjective cognitive decline.

Self-perceived cognitive decline in a person whose performance on cognitive tests is unimpaired.

Systems consolidation.

On the standard consolidation theory, the process by which the hippocampus guides the reorganization of information stored in the neocortex until it becomes independent of the hippocampus.

Vanishing cues.

A training method that systematically reduces the letter fragments of to-be-learned words across trials.

Key Researchers

Michael D. Kopelman

Neuropsychiatrist at King's College London; developed with colleagues the Autobiographical Memory Interview for assessing autobiographical and personal semantic memory in amnesic patients, and reviewed the disorders of memory and the Korsakoff syndrome. ORCID - Wikipedia - Wikidata - Faculty Page

Brenda Milner

(b. 1918). Neuropsychologist at the Montreal Neurological Institute, McGill University; reported with Scoville the loss of recent memory after bilateral hippocampal lesions. Wikipedia - Wikidata - Faculty Page

Morris Moscovitch

(b. 1945). Cognitive neuroscientist at the University of Toronto and the Rotman Research Institute, Baycrest; proposed with Nadel that the hippocampus stays involved in episodic memory for as long as it exists. ORCID - Wikipedia - Google Scholar - Faculty Page

Ronald C. Petersen

(b. 1946). Neurologist at the Mayo Clinic; characterized mild cognitive impairment as a clinical entity. Wikidata - Faculty Page

Larry R. Squire

(b. 1941). Neuroscientist at the University of California San Diego and the VA San Diego Healthcare System; synthesized the hippocampal basis of declarative memory. ORCID - Wikipedia - Wikidata - Google Scholar - Faculty Page

Faraneh Vargha-Khadem

Neuropsychologist at the UCL Great Ormond Street Institute of Child Health, University College London; described differential effects of early hippocampal pathology on episodic and semantic memory. ORCID - Wikipedia - Wikidata - Google Scholar

Frequently Asked Questions

What are memory disorders?

MeSH defines them as disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression; a general review surveys the clinical varieties of the amnesic syndrome, transient and persistent (Kopelman, 2002).

What part of the brain is damaged in amnesia?

The hippocampus, together with anatomically related structures, is essential for declarative memory (Squire, 1992), and bilateral hippocampal lesions were followed by loss of recent memory (Scoville & Milner, 1957); in the Korsakoff syndrome, lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus (Kopelman et al., 2009).

Can someone lose episodic memory but keep factual knowledge?

Three patients with early bilateral hippocampal pathology had pronounced amnesia for everyday episodes yet attained factual knowledge within the low average to average range (Vargha-Khadem et al., 1997).

What is Korsakoff syndrome?

A preventable memory disorder that usually emerges after Wernicke's encephalopathy and is most commonly associated with chronic alcohol misuse (Kopelman et al., 2009); thiamine deficiency is a crucial factor in its etiology (Arts et al., 2017).

What is mild cognitive impairment?

A state of cognitive function between that seen in normal aging and dementia (Petersen, 2016), characterized in an early clinical study as a memory impairment beyond that expected for age and education in a person who is not demented (Petersen et al., 1999), with an estimated prevalence of 15% to 20% in persons 60 years and older (Petersen, 2016).

Does worrying about memory mean dementia is coming?

Individuals with subjective cognitive decline have an increased risk for mild cognitive impairment and dementia, but the majority will not show progressive cognitive decline (Jessen et al., 2020).

Why are old memories sometimes spared in amnesia?

On the standard account, the hippocampus guides a reorganization of neocortical memory until it becomes independent of the hippocampus (Squire et al., 2015); a rival account held that the hippocampal formation stays involved in autobiographical episodic memory for as long as it exists (Nadel & Moscovitch, 1997), and a later transformation account building on it holds that memories transformed with time into less detailed, schematic form do not depend on the hippocampus, while memories that remain detailed and context-specific continue to depend on it regardless of their age (Moscovitch et al., 2016).

Can memory be rehabilitated?

A systematic review supported compensatory strategies for mild memory deficits as a Practice Standard (Cicerone et al., 2019), and errorless learning particularly benefited amnesic subjects on a stem completion task (Baddeley & Wilson, 1994), although for people with severe memory impairments after traumatic brain injury the review expects limited transfer of errorless learning to novel tasks (Cicerone et al., 2019).

References