Memory Dysfunction in Neurological Practice Andrew E Budson, Bruce H Price

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HOW TO UNDERSTAND IT Pract Neurol 2007; 7: 42–47 Memory dysfunction in neurological practice Andrew E Budson, Bruce H Price

A E Budson Geriatric Research Educational Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA; Boston University Alzheimer’s Disease Center, Boston University, Boston, MA; Division of Cognitive and Behavioral Neurology, Department of Neurology, Brigham and Women’s Hospital, Boston, MA; Harvard Medical School, Boston, MA, USA

B H Price Department of Neurology, McLean Hospital, Belmont, MA and Harvard Medical School, Boston, MA, USA

Correspondence to: Dr A E Budson Building 62, Room B30, Edith Nourse Rogers Memorial Veterans Hospital, 200 Springs Road, Bedford, MA 01730, USA; [email protected] Downloaded from pn.bmj.com on 5 February 2007

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omplaints of impaired memory are Episodic memory is the explicit and declarative among the most common symptoms reported to neurologists. Moreover, memory system that we all use to recall our C impairment of memory is one of the personal experience most disabling aspects of many neurological disorders, including neurodegenerative diseases, strokes, tumours, head trauma, collection of mental abilities that use hypoxia, cardiac surgery, malnutrition, atten- different systems within the brain. A memory tion deficit disorder, depression, anxiety, system is a way that the brain processes medication adverse effects, and just normal information in order to make it available for aging. This memory loss often impairs the use at a later time. Some systems are patient’s daily activities, profoundly affecting associated with conscious awareness (explicit) not just them but also their families. and can be consciously recalled (declarative), Memory research that began with neuro- whereas others are typically unconscious psychological studies of patients with focal (non-declarative) and are instead expressed brain lesions now includes new methods such by a change in behaviour (implicit). as positron emission tomography, functional Here we will describe the four systems that MRI, and event-related potentials which have are of clinical relevance: episodic memory, all provided a more refined and improved semantic memory, procedural memory, and classification system. Instead of conceptualis- working memory (table 1). Additional details ing memory as ‘‘short-term’’ versus ‘‘long- may be found in Budson and Price1 and the term’’, we now think of memory as a other references listed below.2–6

TABLE 1 Selected memory systems

Length of Main anatomical Memory System Examples Awareness storage structures Episodic memory Remembering a short story, Explicit Minutes to Medial temporal lobes, what you had for dinner years anterior thalamic nucleus, last night, and what you mamillary body, fornix, did on your last birthday prefrontal cortex

Semantic memory Knowing who was the first Declarative Minutes to Inferior lateral temporal President of the US, the Explicit years lobes colour of a lion, and how a fork and comb are different

Procedural memory Driving a standard Declarative Minutes to Basal ganglia, cerebellum, transmission car (explicit), Implicit years supplementary motor area and learning the sequence of numbers on a touch-tone phone without trying (implicit)

Working memory Phonological: keeping a phone Non-declarative Seconds to Phonological: prefrontal number ‘‘in your head’’ before Explicit minutes; cortex, Broca’s area, dialing information Wernike’s area Spatial: mentally following a Declarative actively Spatial: prefrontal cortex, route, or rotating an object in rehearsed or visual association areas your mind manipulated

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visual scenes. Distortions of memories, and false memories, may occur due to frontal lobe dysfunction, such as when information Prefrontal Thalamocingulate Cingulate gyrus becomes associated with the wrong context, cortex tract or specific details are incorrect. One way to think about how the frontal and medial temporal lobes work together is by Anterior thalamic an oversimplified but useful analogy: nucleus Fornix N the frontal lobes are the ‘‘file clerks’’ of Thalamus the episodic memory system Mammillothalamic tract N the medial temporal lobes are the ‘‘recent Mammillary body memory file cabinet’’ N other cortical regions are the ‘‘remote memory file cabinet’’. Parahippocampal Amygdala gyrus So if the frontal lobes are impaired, it is Hippocampal difficult, though not impossible, to get formation information in and out of storage. And the information may be distorted due to ‘‘impro- per filing’’ leading to inaccurate context or Figure 1 EPISODIC MEMORY sequence. If the medial temporal lobes are Episodic memory. The medial temporal Episodic memory is the explicit and declara- damaged, it will be difficult or impossible for lobes, including the hippocampus and parahippocampus, form the core of the tive memory system that we all use to recall recent information to be retained. Older episodic memory system. Other brain our personal experience, framed in our own information that has been ‘‘consolidated’’ regions are also necessary for episodic context, such as remembering a short story or over months to years is thought to be stored memory to function correctly. (From Budson AE, Price BH. Memory what we had for dinner last night. Episodic in other cortical regions, and will therefore be dysfunction. N Engl J Med memory loss follows a predictable pattern available even when the medial temporal 2005;352:692–9. Copyright known as Ribot’s law: recently acquired lobes are damaged. Massachusetts Medical Society. All memories are more vulnerable to loss than Alzheimer’s disease is the most common rights reserved.) longer established ones. This memory system disorder that disrupts episodic memory. Recent depends on the medial temporal lobes research suggests that these patients suffer (including the hippocampus, entorhinal and from memory distortions and false memories in perirhinal cortex). Other critical structures addition to their failure to remember informa- (some of which are associated with a circuit tion. Other common disorders that disrupt described by Papez in 1937) include the basal episodic memory are listed in table 2. forebrain with the medial septum and the If a patient presents with an inability to diagonal band of Broca’s area, the retro- remember recent information and experi- splenial cortex, the mammillothalamic tract, ences, a disorder of episodic memory should and the anterior nucleus of the thalamus. A be suspected. The evaluation should include a lesion in any one of these structures may detailed history, with emphasis on the time cause the impairment that is characteristic of course of the memory disorder. For example: dysfunction of the episodic memory system N degenerative diseases such as Alzheimer’s (fig 1). start insidiously and progressively worsen The frontal lobes are also important for N vascular dementia and other multifocal certain aspects of episodic memory, including disorders such as multiple sclerosis tend the registration, acquisition, or encoding to start suddenly and progress in a (learning) of information, retrieval of infor- stepwise manner mation without contextual and other cues, N staticdisorderssuchasstrokesand recalling the source of information, and traumatic brain injuries are typically assessing the temporal sequence and recency maximal at onset, improve, and are then of events. The left medial temporal and stable frontal lobes are most involved when learning N transient disorders of episodic memory words, whereas the right medial temporal and include those attributable to a concussion, frontal lobes are most involved when learning a seizure, and transient global amnesia. Downloaded from pn.bmj.com on 5 February 2007

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Interviewing a family member or other informant is usually necessary because the TABLE 2 Four memory systems and the common clinical disorders patient will invariably not remember impor- which disrupt them tant aspects of their history. Any history of other cognitive deficits should also be elicited, Episodic Semantic Procedural Working such as attention, language, and visuospatial Disease memory memory memory memory skills. Medical and neurological examination Alzheimer’s disease +++ ++ – ++ should be performed to look for signs of Frontotemporal dementia ++ ++ – +++ neurodegenerative disorders, focal neurologi- Semantic dementia + +++ ?– cal injury, and systemic illness. Lewy body dementia ++ ?? ++ There are many cognitive tests that can be Stroke and vascular +++ ++ used to assess a patient’s episodic memory dementia Parkinson’s disease + + +++ ++ function. But the relationships between a Huntington’s disease + + +++ +++ patient’s cognitive functions, test perfor- Progressive supranuclear + + ++ +++ mance, and their ‘‘real life’’ activities are palsy often complex. Test performance is rarely Korsakoff syndrome +++ –– ¡ pathognomonic of a specific disorder. And no Multiple sclerosis + ¡ ? ++ single test is capable of evaluating all aspects Transient global amnesia +++ ¡ –– of memory. Factors confounding test inter- Hypoxic–ischaemic injury ++ –– ¡ pretation include aphasia, dyslexia, low intel- Head trauma ++¡ ++ ¡¡¡ ¡ lectual function, alterations in mood and Tumours ¡ ¡ motivation, confusion or delirium, psychosis, Depression + ++ Anxiety + –– ¡ and medication adverse effects. Cognitive Obsessive-compulsive + – ++ ++ testing can be performed in the office by disorder asking the patient to remember a short story Attention deficit ––? + or several words, or by using tests such as the hyperactivity disorder Mini-Mental State Examination, Blessed 1 +++, Early and severe impairment; ++, moderate impairment; +, mild Dementia Scale, and others. The accompanying impairment; ¡, occasional impairment or impairment in some studies but not supplementary appendix available at http:// others; –, no significant impairment; ?, unknown. www.nejm.org or http://www.thebrainlab.org Tumours, strokes and other focal disease processes may affect any of these provides additional guidance about how to memory systems depending on the neuroanatomical structures affected. use such tests in clinical practice. Formal neuropsychological testing is necessary in complex cases. Depending on the differential is usually measured, suggests that it depends diagnosis, appropriate laboratory and imaging on the inferolateral temporal lobes (fig 2). studies are then carried out. Alzheimer’s disease is the most common disorder affecting semantic memory, as it is for episodic memory. This disruption may be SEMANTIC MEMORY attributable to pathology in the inferolateral Semantic memory is the explicit and declara- temporal lobes or to pathology in frontal tive memory system that underpins our cortex, leading to poor activation and retrieval general store of conceptual and factual of semantic information. Supporting the idea knowledge such as the colour of a lion, or that two separate memory systems are the first President of the United States. It is impaired in this disorder, episodic and not related to any ‘‘specific’’ memory. Indeed, semantic memory decline independently in in its broadest sense, semantic memory Alzheimer’s disease; one system may be includes all our knowledge that is not related affected first and decline faster than the to a specific episodic memory, and thus can be kept in many cortical areas. Visual images, for example, are stored in or nearby visual Semantic memory is the explicit and declarative association areas. A more restrictive view of semantic memory, justified in the light of the memory system that underpins our general store of naming and categorisation tasks by which it conceptual and factual knowledge www.practical-neurology.com Downloaded from pn.bmj.com on 5 February 2007

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semantic information. For example, patients with mild dysfunction of semantic memory Supplementary may only show reduced generation of words motor area to semantic categories, such as the number of names of animals that can be generated in Basal ganglia one minute. With severe impairment of (putamen) semantic memory, however, patients have a Prefrontal ‘‘two-way’’ naming deficit: they are unable to cortex name an item when it is described, and they are also unable to describe an item when given its name. Inferolateral temporal lobe PROCEDURAL MEMORY Procedural memory is the ability to learn Cerebellum behavioural and cognitive skills and algo- Semantic memory rithms that operate at an automatic, uncon- Procedural memory scious level. Procedural memory is non- Working memory declarative and generally implicit, such as learning to ride a bike or the sequence of numbers on a touch-tone phone without trying. Brain regions involved in procedural other. Patients with the temporal variant of Figure 2 memory include the supplementary motor Semantic, procedural, and working frontotemporal dementia (known as semantic area, basal ganglia and cerebellum (fig 2). memories. The inferolateral temporal dementia) have deficits in all aspects of lobes are important in the naming and Parkinson’s disease is the most common semantic memory. Although articulation, categorisation tasks by which semantic disorder affecting procedural memory memory is typically assessed. However, non-verbal problem-solving skills, and episo- (table 2). Other neurological disorders that in the broadest sense, semantic dic memory are relatively preserved, most memory may reside in multiple and affect basal ganglia or cerebellar function also aspects of language are impaired: semantic diverse cortical areas that are related to disrupt procedural memory, such as various types of knowledge. The basal dementia patients have extreme difficulty Huntington’s disease and olivopontocerebellar ganglia, cerebellum, and supplementary naming, comprehending single words, and motor area are critical for procedural atrophy, in addition to strokes and tumours their general knowledge is impaired. Other memory. The prefrontal cortex is active affecting these brain structures. Patients with common disorders that disrupt semantic in virtually all working memory tasks. major depression also have impairment in Other cortical and subcortical brain memory include almost any pathology that procedural memory, perhaps because depres- regions will also be active, depending affects the inferolateral temporal lobes, such on the type and complexity of the sion involves dysfunction of the basal ganglia. as traumatic brain injury, stroke, surgical working memory task. (From Budson By contrast, because the disease process in AE, Price BH. Memory dysfunction. lesions, encephalitis, and tumours (table 2). early Alzheimer’s disease affects cortical and N Engl J Med 2005;352:692–9. Although difficulty recalling people’s Copyright Massachusetts Medical limbic structures while sparing the basal Society. All rights reserved.) names and other proper nouns is common ganglia and cerebellum, these patients show (particularly for older people), impairment of normal learning and maintenance of proce- semantic memory should be suspected when dural skills. a patient also has difficulty recalling the Disruption of procedural memory should be names of common items. An evaluation for suspected when there is either loss of semantic memory impairment should include previously learned skills or significant diffi- the same components as the evaluation of culty in learning new skills. Skills that are episodic memory disorders, as above. It is commonly affected include writing, playing a important to distinguish whether the problem musical instrument, and swinging a tennis is solely attributable to naming difficulties racket. Although these skills may be relearned, (anomia), or is attributable to a true loss of effortful explicit thinking is often required, such that patients with damage to the Procedural memory is the ability to learn procedural memory system may never behavioural and cognitive skills and algorithms achieve the automatic effortlessness of simple motor tasks that healthy individuals that operate at an automatic, unconscious level take for granted. Evaluation is similar to that Downloaded from pn.bmj.com on 5 February 2007

Budson, Price 47 of episodic memory disorders. It is worth Working memory is the explicit and declarative noting that the preserved procedural memory system has been used to rehabilitate patients memory system that enables us to temporarily hold whose episodic memory has been devastated and manipulate information in our consciousness by disease such as encephalitis.

WORKING MEMORY problem with episodic memory when infor- Working memory is a combination of the mation cannot be learned because it cannot traditional fields of attention, concentration be ‘‘kept in mind’’ by working memory. and short-term memory. It is the explicit and Continuing the filing analogy mentioned declarative memory system that enables us to above, if poor working memory impairs the temporarily hold and manipulate information ability of the episodic memory file clerk to in our consciousness to assist in goal- obtain new information, then it will be oriented behaviour. Working memory is often difficult or impossible to get that information divided into a central executive system that into the episodic memory filing cabinet. allocates attentional resources, and separate Evaluation is similar to that for episodic components that process phonological (such memory disorders. as keeping a phone number in mind) and spatial (such as mentally following a route) CONCLUDING COMMENTS information. While the prefrontal cortex is the Although once considered a simple concept, most invariant brain region involved (fig 2), converging and complementary lines of working memory also uses a network of evidence suggest that memory is composed cortical and subcortical areas which differ of separate and distinct systems. A single depending upon the particular task. A typical disease process (such as Alzheimer’s disease) network includes posterior brain regions (such may impair more than one memory system. as visual association areas) that are linked Hopefully research leading to improved with prefrontal regions to form a circuit. Left- understanding of these memory systems will sided brain regions are more active during in turn lead to better treatments for memory phonological working memory tasks, whereas disorders. right-sided brain regions are more active during spatial working memory tasks. ACKNOWLEDGEMENT However, regardless of the type of material being manipulated, as the complexity of This article was reviewed by Adam Zeman, the task increases there is an increase in the Exeter, UK. number of brain regions activated in the prefrontal cortex of both hemispheres. REFERENCES Since working memory depends on a 1. Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352:692–9. network of activity that includes subcortical 2. Mesulam M-M. Principles of behavioral and structures as well as frontal and parietal cognitive neurology, Second edition. New York, NY: cortical regions, it may be disrupted by many Oxford University Press, Inc, 2000. 3. Schacter DL. The seven sins of memory: how the degenerative and other neurological disor- mind forgets and remembers. Boston, MA: ders, including Alzheimer’s disease, fronto- Houghton Mifflin, 2001. temporal dementia, vascular dementia, 4. Schacter DL, Wagner AD, Buckner RL. Memory Parkinson’s disease, multiple sclerosis, head systems of 1999. In: Tulving E, Craik FIM, eds. The Oxford handbook of memory. New York: Oxford injuries, tumours, and strokes (table 2). University Press, 2000:627–43. Impairment of working memory most 5. Simons JS, Spiers HJ. Prefrontal and medial commonly presents as an inability to con- temporal lobe interactions in long-term memory. Nat Rev Neurosci 2003;4:637–48. centrate or pay attention. Trouble with work- 6. Solomon PR, Budson AE. Alzheimer’s disease. Clin ing memory may also present as an apparent Symp 2003;54:1–40.