Multiple Sclerosis’ Effects on Cognitive Dysfunction with an Emphasis on Memory

By Bryan Hansen

Memory allows individuals to learn from experiences in the past, to study complex information, and to communicate with others. However, not everyone possesses this gift to its full capacity. Cognitive dysfunction in multiple sclerosis (MS) stems from a breakdown in the interdependent relationships between aspects of cognition. It is useful to visualize this relationship in terms of the vast network of communication that encompasses the central nervous system (CNS). As the myelin surrounding the axons deteriorates, it severs the line of communication. This breakdown leaves neurons cut off from the CNS, unable to send or receive vital neural messages. Individuals who suffer from MS endure cognitive dysfunctions associated with the domain of memory. In addition to memory, individuals with MS often suffer from subjective complaints, strategy application deficits, and impaired speeded information processing. A comprehensive understanding of MS and the relationship between cognitive and memory dysfunction is essential in defining memory as the area of cognition most severely affected by MS.

The Disease

Severe demyelinization of the CNS, which consists of the brain and spinal cord, characterizes MS. Myelin, white-matter, is a fatty substance that acts as an insulator and covers the outer surface of axons. Myelin’s role in the CNS is vital to the communication that occurs between neurons, for it facilitates smooth communication by accelerating conduction along the axon (Mathews, 1985).

The etiology of MS is currently unknown, but doctors and neuroscientists offer theories to account for its characteristic demyelization. One prominent theory of MS is the presence of a virus that specifically targets the CNS by destroying the myelin. The widely accepted cause is that MS is an autoimmune disease characterized by the body’s own destruction of myelin (Flagg, 2003; Munschauer & Greenstein, 2001).

During demyelinization, lymphocytes envelop the axon where the myelin sheath has been damaged or removed. Oligodendrocytes have also been thought as a cause of demyelinization given their close relationship with myelin formation and maintenance (Keegan & Noseworthy, 2002; Mathews, 1985). However, it is the astrocytes’ removal of cellular waste, consisting of myelin, which causes the most damage to the CNS. The astrocytes inflict multiple scars on the surface of the axons; over time, scarring may lead to severe plaque formation. The term sclerosis, or hardening, describes astrocytes and their role in plaque formation. Thus, MS is a disease of the CNS that produces multiple hardenings on the surface of axons (Mathews, 1985).

MS can be further categorized by the following four types: Relapsing-Remitting (RRMS), Secondary-Progressive (SPMS), Progressive-Relapsing (PRMS), and Primary Progressive (PPMS) (Flagg, 2003). As the name implies, RRMS is defined by the oscillation between relapses (periods when symptoms are present) and remissions (when symptoms may lie dormant). It is important to note that during remission the inflammatory progression of the disease may or may not stop, and can lead to more severe periods of relapse than before. SPMS begins as a severe form of the RRMS, but also occurs through a gradual decrease in symptom improvement or the appearance of new symptoms. The transition from RRMS to SPMS is an indication of disease progression, which may lead to an increase in symptom severity. PRMS appears as a deterioration of nerve function resulting from a sudden and often severe onset of symptoms. Relapses in PRMS are unpredictable and often much worse than expected. PPMS often mimics PRMS with initial symptoms causing severe nerve deterioration. However, a complete lack of relapse, causing a quick and ravaging deterioration of nerve function, also characterizes PPMS (Flagg, 2003).

Since MS is a disease of the CNS, it encompasses a wide range of symptoms extending throughout the body’s systems. The most common symptoms are weakness, vertigo, visual loss, bowel and bladder dysfunction, fatigue, parasthesias (the “pins and needles” sensation), and a host of varying cognitive dysfunctions (Flagg, 2003). These specific cognitive dysfunctions in MS yield a valuable amount of research that offers varying opinions on the causes and relationships between cognitive domains.

Cognitive dysfunction in MS

Causes

Rao et al. (1989; as cited in Arnett, 2001) observes that many of the cognitive dysfunctions associated with MS originate in the localization of lesions in the CNS; the severity is consistent with the extent of myelin damage and location. Moreover, Arnett et al. (1994; as cited in Arnett, 2001) finds a strong correlation between frontal lobe lesion and decreased performance on the Wisconsin Card Sorting Test, a test of conceptual reasoning.

Fatigue and depression are described as two possible catalysts of cognitive dysfunction in MS (Arnett, 2001; Barget, Camplair, & Bourdette, 2002; Rao, 2001), yet correlations between fatigue and cognitive dysfunction are inconsistent and highly subjective. Studies have shown that MS patients tend to report cognitive decline during heightened fatigue, but these results are not universal. Additionally, depression has been debated as a possible factor contributing to cognitive dysfunction in MS. Arnett et al. (1999a; as cited in Bagert et al., 2002) hypothesizes that the cumulative effects of depression, which gradually approach a threshold, may adversely affect some but not all cognitive tasks. The symptoms contributing to the depression threshold (hypothesized by Arnett to be the cumulative effects of depression on cognitive dysfunction) and the cognitive tasks affected are not sound predictors across MS patients.

Subjective complaints

Furthermore, subjective complaints, nonspecific complaints made by MS patients regarding reduced cognitive efficiency, are observed in mild MS (Matotek, Saling, Gates, & Sedal, 2001). A person’s emotional state does not positively or negatively effect cognitive efficiency. On the other hand, the control group demonstrates that the major source of overall cognitive dysfunction is affective state. According to Matotek et al. (2001), the presence of a depressive or affective state does not influence cognitive impairment in MS patients. However, Arnett et al. (1999a) finds that the cumulative effects of depression do play a significant role in cognitive impairment in MS patients given data that supports the theory of a depression threshold.

Strategy application abilities

Birnboim and Miller (2004) ask the question “Do MS patients experience impaired strategy application abilities (SAA)?” The idea of SAA is whether or not the implementation of an appropriate working strategy enables patients with cognitive impairment to perform tasks more efficiently. Each patient was given the Strategy Application Test (SAT) as well as questionnaires to assess their level of depression and fatigue. As predicted, MS patients scored significantly lower on the SAT than the control. These findings are consistent with the notion that MS patients have difficulty facing new situations and dealing with new and complex information. SAA impairment occurs only in the initial stages of MS given inconsistent results distinguishing between RRMS and SPMS. Evidently, the impairment in SAA is not influenced by the patient’s level of depression, fatigue, or duration of disease (Birnboim & Miller, 2004).

Speeded information processing

Speeded information processing, or the transfer of information between hemispheres, largely depends on neural communication. As a result, a decrease in one’s ability to process information is profoundly affected by MS. The slowed central processing resonates to a decreased efficiency in sensory-motor processing at work and at home (Bagert et al., 2002).

Rao (2001) notes the efficiency of information processing associated with driving ability as tested in MS patients. No differences in accuracy between cognitively-impaired and cognitively-intact MS patients were reported. However, this study observes cognitively-impaired MS patients who require a longer reaction-time compared to controls. Thus, MS severely effects a person’s information processing speed.

Coping strategies

Arnett, Higginson, Voss, Randolph, & Grandey (2002) investigate the correlation between cognitive dysfunction and the two types of coping strategies often seen in MS patients: maladaptive3 (or avoidance) and adaptive4 (or active) coping. Avoidance coping and active coping are strong predictors of the effects of cognitive dysfunction and depression. MS patients with cognitive difficulties are more likely to exhibit depressive symptoms when they use high levels of avoidance coping or low levels of active coping. Conversely, MS patients with cognitive difficulties who use high levels of active coping or low levels of avoidance coping do not report depressive symptoms (Arnett et al., 2002). This evidence supports the hypothesis that depression in MS negatively affects cognitive function (Arnett et al., 1999a).  

Memory dysfunction in MS

Memory is the most common domain of cognition affected by MS with over 40%-60% of patients showing a decrease in memory performance tests. According to Rao et al. (1993), memory impairments in MS are generally seen in un-cued long-term memory tests, such as spontaneous free-recall. Additionally, performances on tests of short-term memory, such as digit span, were normal. Rao et al. also suggests a mechanistic perspective of memory failure in MS, citing the inefficiency in retrieval from long-term-memory. Memory dysfunction and MS extend through the following: metamemory, semantic encoding, implicit memory, implicit memory across types of MS, and working memory.

Metamemory

Metamemory is an individual’s own knowledge through self-report of his or her memory abilities (Randolph, Arnett, & Higginson, 2001). Metamemory analysis is accurately made through ‘feeling-of-knowing’ (FOK) tests in cognitively impaired MS patients. Beatty and Monson (1991; as cited in Randolph et al., 2001) observe a strong correlation between impaired FOK judgments and poor performance on tasks of recognition and executive function.

MS patients’ reports of memory difficulty are consistent with impairments on verbal recall, executive functioning, and speeded attentional processing (Randolph et al., 2001). Executive functioning and speeded attentional processing affect memory, which suggests that patients may attribute other cognitive dysfunctions as possible memory dysfunctions. This is a concern, given the fact that MS patients may also be experiencing problems in other cognitive domains. Rao et al. (1991) (as cited in Randolph et al., 2001) reports that patients with memory dysfunction due to speeded attentional processing may actually reflect cognitive impairment in other domains. It is important to note that report of a deficiency in metamemory may translate to an impartment of cognition other than memory (Randolph et al., 2001).

Semantic encoding and implicit memory

Rao et al. (1993) attempts to identify the presence of memory dysfunction across semantic encoding, implicit memory, and working memory. The most accurate test of semantic encoding involves the use of the proactive inhibition (PI) paradigm. Prior research of semantic encoding using PI has been successful on Huntington’s patients who show impairments in storage and retrieval. Thus, memory dysfunction in MS can be attributed to retrieval failure from long-term memory (Rao, et al., 1993). One study conducted by Beatty et al. (1989; as cited in Rao et al., 1993) attempts to examine the effects of semantic encoding using PI. MS patients display a normal build-up of PI as well as a successful release from PI. Rao et al. and Beatty et al. confirm that a patient’s semantic encoding ability is virtually unaffected by MS.

Rao et al. also examines performance on tests of implicit memory, priming, and skill learning in patients with MS. Prior research proves that the cortical region distributes priming effects while learning is located in the coritcostriatal region (Rao et al., 1993). The study is significant given that MS is a subcortical disease that does not interact with the cortical mantle. MS patients display normal priming effects on a test of implicit memory. Both this study and Beatty (1990b; as cited in Rao et al., 1993) conclude that MS patients maintain a normal susceptibility to priming effects (Rao et al., 1993). MS patients perform normally on tests of motor and skill learning, which offers the idea that white-matter dementias may have distinct neurobehavioral features when compared to other subcortical dementias that target gray matter. Although these studies did not discover further memory dysfunction in MS, they show that the integrity of memory, to some degree, is maintained in semantic encoding and implicit memory (Rao et al., 1993).

Implicit memory across different types of MS

Blum et al. (2002) thoroughly examines memory dysfunction in MS, emphasizing the effects on implicit and explicit memory. This experiment attempts to account for varying differences in memory function associated with the three most common types of MS: PPMS, RRMS, and SPMS. Explicit memory was measured by a free-recall test, implicit memory was measured by a word fragment completion test, and conceptual implicit memory was measured by an exemplar generation test (Blum et al., 2002). MS patients were also given MRI scans to observe possible correlations between lesions in different groups and to study the relationship between the amount of lesions and memory performance. RRMS and SPMS patients performed higher on implicit memory tests than PPMS patients.

This test is significant because the results of the explicit memory and the conceptual implicit memory tests are universal across MS types; each shows a deficit in explicit memory and normal performance on conceptual implicit memory (Blum et al., 2002). The dissociation between perceptual implicit and conceptual implicit memory may be due to an underlying functional or neuroanatomical difference. The MRI scans indicate that SPMS patients posses a greater lesion load than PPMS patients. In addition, explicit memory impairment is dependent on the amount of lesions. A high number of lesions indicates severe impairment (Blum et al., 2002).

Working memory

Working memory, as proposed by Baddley and Hitch (1974; as cited in Baddley, 1986), is a system of memory function which allows information to be held temporarily in thought while simultaneously undergoing manipulation during the performance of cognitive tasks. Tasks such as learning comprehension and reasoning require a sufficient amount of working memory resources. The model of working memory consists of three main components: the central executive, the articulatory loop, and the visuo-spatial sketchpad. The importance of the central executive is subject to interpretation; however, Baddley (1986) describes it as a supervisor overseeing the two slave components. As a supervisor, it must be capable of prioritizing, selecting strategies, and distributing multi-source information to the appropriate slave components. Most of the focus lies on the articulatory loop component as a possible cause for cognitive dysfunction in MS. But evidence also exists implicating the central executive as a possible source of cognitive dysfunction. In a continuation of the previous debate, Baddley shows that depression is also an important factor contributing to working memory impairment in MS.

Arnett et al. (1999a) embarked on a study to examine the effects of depression on capacity-demanding memory. In a review of past literature, Arnett et al. notes that past research neglected to account for depression in tests of cognitive function. In this study, depression is isolated from any possible MS symptom overlap. The results show that depressed MS patients perform worse on measures of attentional capacity-demanding tasks when compared with a control group. Arnett et al. suggests that these results and the effects of depression are highly speculative. Another possible explanation is that cognitive dysfunction manifests in isolation; as symptoms worsen, frustration with the cognitive impairments may lead to depression.

In a desire to further examine effects of depression on capacity-demanding memory, Arnett et al. (1999b) studied working memory. Engle and Oransky (1999; as cited in Arnett et al., 1999b) documented cognitive tests to accurately pinpoint the component of working memory used during cognition. It was found that reading span tests measure the central executive while word span tests measure the articulatory loop. Working memory capacity was impaired in MS patients on tests of reading span. However, performance was normal on tests of word span. Baddley and Hitch’s (1974) model of working memory observed in conjunction with Engle and Oransky’s (1999) suggests that depressed MS patients suffer from an impairment of the central executive component (Arnett et al., 1999b).

To account for the possible effects of depression on working memory, Smith and Jonides (1997; as cited in Arnett et al., 1999b) provide neuroimaging that depicts the left frontal region as the area of the brain most excited by verbal working memory. Additionally, Davidson (1992; as cited in Arnett et al., 1999b) shows that depressed patients experience hyperactivity of the left frontal region. Hyperactivity of the left frontal lobe may preclude normal performance on tests of verbal working memory in depressed MS patients.

The results obtained by Arnett et al. strongly implicate the central executive for the cognitive dysfunction in MS. However, Rao et al. (1993) offers another possible suspect, the articulatory loop. Rao et al., replicating a study by Baddely et al. (1984; as cited in Rao et al., 1993), measures the efficiency of the articulatory loop through serial recall of auditorily presented words varying in phonological length. The results are consistent with impairment of the control process concerning articulatory rehearsal. MS patients show a distinct word length effect, suggesting a heightened sensitivity for articulatory length. Deficiencies in articulatory rehearsal may be attributed to a more encompassing dysfunction of information-processing speed.

The most recent study to examine working memory dysfunction and MS was done by Landro, Celius, and Sletvold (2004). The goal of this study was to determine if depression specifically affects working memory. Goldstein and Shelly (1974; as cited in Landro et al., 2004) suggest that depression is the main reason for cognitive dysfunction in MS. On the other hand, Wishart and Sharpe (1997; as cited in Landro et al., 2004) claim that depression does not affect cognitive impairment in MS patients. Landro et al. finds that depression does affect cognitive dysfunction in MS. Additionally, Landro et al. observes no correlation between depression and working memory deficits. It is important to note that this study uses Honig’s (1978; as cited in Landro et al., 2004) model of working memory which makes the distinction between working memory and reference memory. The use of this model may account for these contrasting results. Landro et al. concludes that depression only affects tasks requiring information-processing speed. This notion supports the hypothesis that articulatory rehearsal depends on information-processing speed (Rao et al., 1993).

Treatment

Arnett (2001) proposes ways of treating depression to circumvent treating the overwhelming number of other cognitive dysfunctions in MS. A strict treatment emphasizing depressive symptoms may benefit the patient’s mood. This new sense of well-being will transfer to individuals’ willingness to adhere to their drug-regimen. Cognitive dysfunctions should decrease if the drug-regimen is maintained, thus leading to a less depressive state. Treating depression in MS patients came from a study by Mohr et al. (2000; as cited in Arnett, 2001) which showed telephone-based therapy to be effective.

Fisher et al. (2000; as cited in Arnett, 2001) offers another possible treatment for cognitive dysfunction in MS. In a study consisting of 166 RRMS patients given the interferon Avonex®, results indicate a positive correlation between the use of Avonex® and information processing speed and memory. After two years of use, a follow up study tested MS patients using a variety of neuropsychological tests. A significantly higher performance rate was recorded on tests of memory and information processing speed. Further research is needed to determine whether Avonex® treats cognitive dysfunctions directly or decreases the severity of the disease (Arnett, 2001). 

Conclusion

The interaction between cognitive domains and their relationship with the underlying neurobiology suggests that memory is severely affected by MS. Due to the intricacies of memory, only specific areas show deficiencies. Results from Rao et al. (1993) show that semantic encoding and implicit memory appear to be unaffected by MS. In addition, Randolph et al. (2001) suggests that complaints of memory dysfunction may be associated with cognitive domains other than memory. However, Arnett (2001, 1999a, 1999b) offers that capacity-demanding memory and working memory are considerably affected by MS, with depression furthering memory impairment. On the other hand, information-processing speed may be the primary source of cognitive dysfunction, in which memory impairment may originate (Landro et al., 2004; Rao et al., 1993; Bagert et al., 2002). As for the future of research on memory dysfunction in MS, Endel Tulving (1985) put it best when he predicted the future of implicit memory, “We can not [sic] solve puzzles that do not exist” (p. 396). Memory dysfunction in MS is a puzzle; every new scientific finding is an important piece. 

References

Arnett, P.A. (2001). Neuropsicología en esclerosis múltiple [Neuropsychology in multiple sclerosis]. Cuadernos de Esclerosis Múltiple, 9.

Arnett, P.A., Higginson, C.I., Voss, W.D., Bender, W.I., Wurst, J.M., & Tippin, J.M. (1999a). Depression mood in multiple sclerosis: Relationship to capacity-demanding memory and attentional functioning. Neuropsychology, 13, 434-446.

Arnett, P.A., Higginson, C.I., Voss, W.D., Bender, W.I., Wurst, J.M., & Tippin, J.M. (1999b). Depression in multiple sclerosis: Relationship to working memory capacity. Neuropsychology, 13, 546-556.

Arnett, P.A., Higginson, C.I., Voss, W.D., Randolph, J.J., & Grandey, A.A. (2002). Relationship between coping, cognitive dysfunction and depression in multiple sclerosis. The Clinical Neuropsychologist, 16, 341-355.

Baddeley, A. (1986). Working memory. New York: Oxford University Press.

Bagert, B., Camplair, P., & Bourdette, D. (2002). Cognitive dysfunction in multiple sclerosis. CNS Drugs, 16, 445-455.

Birnboim, S., & Miller, A. (2004). Cognitive strategies application of multiple sclerosis patients. Multiple Sclerosis, 10, 67-73.

Blum, D., Yonelinas, P.A., Luks, T., Newitt, D., Oh, J., Lu, Y., & et al. (2002). Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients. Brain and Cognition, 50, 51-61.

Flagg, M. (2003). Multiple Sclerosis. Retrieved March 13, 2004, from WebMD, Web Site: http://my.webmd.com/hw/multiple_sclerosis/hw190816.asp.

Keegan, M.B., & Noseworthy, J.H. (2002). Multiple sclerosis. Annual review of medicine, 53, 285-302.

Landro, N.I., Celius, E.G., & Sletvold, H. (2004). Depressive symptoms account for deficient information processing speed but not for impaired working memory in early phase multiple sclerosis (MS). Journal of the Neurological Sciences, 217, 211-216.

Matotek, K., Saling, M.M., Gates, P., & Sedal, L. (2001). Subjective complaints, verbal fluency, and working memory in mild multiple sclerosis. Journal of Applied Neuropsychology, 8, 204-210.

Matthews, B. (1985). Multiple sclerosis: The facts (2nd ed.). Oxford: Oxford University Press.

Munschauer, F., & Greenstein, J. (2001). Multiple sclerosis 101. Retrieved March, 13, 2004, from MSnet, Web Site: http://msnet.healthology.com/printer_friendly.asp?b=msnet&f=m_sclerosis&c=m_sclerosis_ms101.

Randolph, J.J., Arnett, P.A., & Higginson, C.I. (2001). Metamemory and tested cognitive function in multiple sclerosis. The Clinical Neuropsychologist, 15, 357-368.

Rao, S.M. (2001). Cognitive impairment in ms: The latest research. Retrieved March 20, 2004, from MSnet, Web Site: http://msnet.healthology.com/printer_friendly.asp?b=msnet&f=m_sclerosis&c=m_sclerosis_cogresearch.

Rao, S.M., Grafman, J., DiGiulio, D., Mittenberg, W., Bernardin, L., Leo, G.J., et al. (1993). Memory dysfunction in multiple sclerosis: Its relation to working memory, semantic encoding, and implicit learning. Neuropsychology, 7, 364-374.

Tulving, E. (1985). How many memory systems are there?. American Psychologist, 40, 385-398.