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A Randomized Controlled Pilot Trial: The Effects of EGb 761 on Information Processing and Executive Function in Multiple Sclerosis
RESEARCH LETTER
A RANDOMIZED CONTROLLED PILOT TRIAL: THE EFFECTS OF EGB 761 ON INFORMATION PROCESSING AND EXECUTIVE FUNCTION IN MULTIPLE SCLEROSIS Bruce J. Diamond, MEd, PhD,1# Susan K. Johnson, PhD,2 Michael Kaufman, MD,3 Samuel C. Shiflett, PhD,4 and Linda Graves, MD5 Multiple sclerosis (MS) is a chronic neurological disease primarily affecting young and middle-age adults and often accompanied by problems in motor and sensory function, affect, and fatigue with slower processing speed figuring prominently.1 EGb 761 (Dr Wilmar P. Schwabe Company, GmbH, Germany) is a ginkgo extract standardized to 24% Ginkgo-flavone glycosides, 6% terpenoids, and major constituents (ie, ⬎0.1%).2 Ginkgo biloba’s peripheral and central effects are thought to be mediated by a variety of mechanisms, including antioxidant and antiplatelet-activating factor properties, cerebrovascular modulating properties (ie, enhancing blood flow), neurotransmitter potentiating activity, and effects on glucose metabolism.3 Although rare, adverse side effects have included skin reactions, headache, and mild gastrointestinal upset.3 Ginkgo has shown some efficacy in improving neurologic and cognitive functions in patients with Alzheimer disease, multiinfarct dementia, aging, idiopathic cognitive impairment,4,5 and in the symptomatic treatment of impairments in memory, concentration, and depression.3,5 Although individuals taking EGb 761 have shown some improvement in mood and fatigue, few investigators have assessed its efficacy in ameliorating cognitive impairments in MS.4 In a recent study authors reported that the use of Ginkgo may positively impact susceptibility to interference and mental flexibility6 and some evidence points to improvements on the Paced Auditory Serial Addition Test and a Perceived Deficits scale of a Quality of Life Index compared to placebo-treated patients (240 mg/day for 90 days).7,8 In this pilot study we examined the effects of EGb 761 on cognitive performance in MS. The data are derived from a previous study4 in which we performed a randomized, placebocontrolled, double-blinded, parallel group design in accordance with appropriate institutional review and the ethical standards set forth in the Helsinki Declaration of 1975. The final analyses were performed with 12 participants in the Ginkgo intent-totreat group and nine participants in the placebo group. The goal was to determine the effect of ginkgo versus placebo on information processing and executive function and evaluate the relative contributions of fatigue and mood in mediating changes in cognition.
1 William Paterson University, Wayne, NJ 2 University of North Carolina–Charlotte, NC 3 Carolinas Healthcare System, MS Center, Charlotte, NC 4 Department of Psychology, University of Arizona, Tucson, AZ 5 Comprehensive Rehabilitation Center, PC, Paterson, NJ # Corresponding Author. Address: William Paterson University, 300 Pompton Rd, Wayne, NJ 07470 e-mail: [email protected]
106
© 2013 Elsevier Inc. All rights reserved ISSN 1550-8307/$36.00
There were no significant differences between the ginko and placebo group on visual-spatial memory (Rey-Osterreith Complex Figure Test) and attention/concentration (Digit Span). However, the ginkgo-treated group (preintervention: M ⫽ 1,557 ms, standard error [SE] ⫽ 137 and postintervention: M ⫽ 1,373 ms, SE ⫽ 106) showed enhanced processing speed (1,840 ms faster) in contrast to the placebo group (preintervention: M ⫽ 1,737 ms, SE ⫽ 167 and postintervention: M ⫽ 1,881 ms, SE ⫽ 303, or 1,440 ms slower) on the Visual Threshold Serial Addition Test (Mann–Whitney U test: Z ⫽ ⫺1.9, P ⫽ .05, Cohen’s d ⫽ 0.60). The ginkgo-treated group also emitted fewer verbal intrusions on the California Verbal Learning Test than the placebo group (Mann–Whitney U test: Z ⫽ ⫺2.09, P ⫽ .03, Cohen’s d ⫽ 0.85). An analysis of the relationship between processing speed and fatigue change scores (Pre⫺Post-Intervention; r ⫽ .49, P ⫽ .01) suggested that fatigue accounted for approximately 24% of the shared variance. A partial correlation between fatigue and processing speed when we controlled for mood (Center for Epidemiological Studies Depression) suggested that mood accounted for approximately 3% of the shared variance between fatigue and processing speed (r ⫽ .52, P ⫽ .01). Faster processing speed may suggest enhanced executive control and sustained attention, which is supported by the finding that the ginkgo group also emitted fewer verbal intrusions, which may be attributable to improved executive control, enhanced search and retrieval, as well as more efficient self-monitoring. Fewer intrusions also may have been due to more salient stimulus encoding although not sufficient to improve recall, resulting in a greater activation differential at retrieval between potential intrusions and previously encountered words. There is evidence supporting the idea that enhanced activation at retrieval and improved executive control processes and monitoring are associated with reduced intrusion levels.9 Moreover, there is also evidence that faster processing speed is associated with enhanced acquisition and encoding and/or enhanced executive search and retrieval.10 These findings may have been mediated by ginkgo’s purported central cerebrovascular-modulating properties and neurotransmitter-potentiating activity resulting in modest increases in the strength of underlying memory, enhanced activation at encoding, and/or more efficient retrieval and executive control. These results may suggest modest benefits in taking ginkgo but more convincing evidence awaits future work using larger samples and additional cognitive measures. However, given the prominence of slower processing and dysexecutive function in MS, even modest improvements in executive function may enhance activities of daily living.
EXPLORE March/April 2013, Vol. 9, No. 2 http://dx.doi.org/10.1016/j.explore.2012.12.001
Acknowledgments The authors thank Uttara Desai for her editorial support. 6.
REFERENCES 1. Diamond BJ, Johnson SK, Kaufman M, Graves L. Relationships between information processing, depression, fatigue and cognition in Multiple Sclerosis. Arch Clin Neuropsychol. 2008;23:189-199. 2. Diamond BJ, Shiflett SC, Lothian A, et al. EGb; 761 (Ginkgo biloba): Efficacy in treating stroke and TBI. Arch Physical Med Rehabil. 2000;80:978. 3. Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil. 2000;81:1-11. 4. Johnson S, Diamond BJ, Rausch S, et al. The effect of gingko biloba on functional measures in multiple sclerosis: A pilot randomized controlled trial. Explore J Sci Heal. 2006;2:19-24. 5. Barth SA, Inselmann G, Engemann R, Heidemann HT. Influences of Ginkgo biloba on cyclosporin A induced lipid peroxidation in
7.
8.
9. 10.
EGb 761 on Information Processing and Executive Function in MS
human liver microsomes in comparison to vitamin E, glutathione and N-acetyllcysteine. Biochem Pharmacol. 1991;41:1521-1526. Lovera J, Bagert B, Smoot K, et al. Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial. Mult Scler. 2007;13:376-385. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14. Kenney C, Norman M, Jacobson M, Lampinen S, Nguyen DP, Corey-Bloom J. A double-blind, placebo controlled, modified crossover pilot study of the effects of gingko biloba on cognitive and functional abilities in multiple sclerosis. Neurology. 2002;58:A458A459. McDermott KB, Watson JM. The rise and fall of false recall: the impact of presentation duration. J Mem Lang. 2001;45:160-176. Lövdén M, Rönnlund M, Göran-Lars N. Remembering and knowing in adulthood: effects of enacted encoding and relations to processing speed. Aging Neuropsychol Cogn. 2002;9:184200.
EXPLORE March/April 2013, Vol. 9, No. 2 107
A RANDOMIZED CONTROLLED PILOT TRIAL: THE EFFECTS OF EGB 761 ON INFORMATION PROCESSING AND EXECUTIVE FUNCTION IN MULTIPLE SCLEROSIS Bruce J. Diamond, MEd, PhD,1# Susan K. Johnson, PhD,2 Michael Kaufman, MD,3 Samuel C. Shiflett, PhD,4 and Linda Graves, MD5 Multiple sclerosis (MS) is a chronic neurological disease primarily affecting young and middle-age adults and often accompanied by problems in motor and sensory function, affect, and fatigue with slower processing speed figuring prominently.1 EGb 761 (Dr Wilmar P. Schwabe Company, GmbH, Germany) is a ginkgo extract standardized to 24% Ginkgo-flavone glycosides, 6% terpenoids, and major constituents (ie, ⬎0.1%).2 Ginkgo biloba’s peripheral and central effects are thought to be mediated by a variety of mechanisms, including antioxidant and antiplatelet-activating factor properties, cerebrovascular modulating properties (ie, enhancing blood flow), neurotransmitter potentiating activity, and effects on glucose metabolism.3 Although rare, adverse side effects have included skin reactions, headache, and mild gastrointestinal upset.3 Ginkgo has shown some efficacy in improving neurologic and cognitive functions in patients with Alzheimer disease, multiinfarct dementia, aging, idiopathic cognitive impairment,4,5 and in the symptomatic treatment of impairments in memory, concentration, and depression.3,5 Although individuals taking EGb 761 have shown some improvement in mood and fatigue, few investigators have assessed its efficacy in ameliorating cognitive impairments in MS.4 In a recent study authors reported that the use of Ginkgo may positively impact susceptibility to interference and mental flexibility6 and some evidence points to improvements on the Paced Auditory Serial Addition Test and a Perceived Deficits scale of a Quality of Life Index compared to placebo-treated patients (240 mg/day for 90 days).7,8 In this pilot study we examined the effects of EGb 761 on cognitive performance in MS. The data are derived from a previous study4 in which we performed a randomized, placebocontrolled, double-blinded, parallel group design in accordance with appropriate institutional review and the ethical standards set forth in the Helsinki Declaration of 1975. The final analyses were performed with 12 participants in the Ginkgo intent-totreat group and nine participants in the placebo group. The goal was to determine the effect of ginkgo versus placebo on information processing and executive function and evaluate the relative contributions of fatigue and mood in mediating changes in cognition.
1 William Paterson University, Wayne, NJ 2 University of North Carolina–Charlotte, NC 3 Carolinas Healthcare System, MS Center, Charlotte, NC 4 Department of Psychology, University of Arizona, Tucson, AZ 5 Comprehensive Rehabilitation Center, PC, Paterson, NJ # Corresponding Author. Address: William Paterson University, 300 Pompton Rd, Wayne, NJ 07470 e-mail: [email protected]
106
© 2013 Elsevier Inc. All rights reserved ISSN 1550-8307/$36.00
There were no significant differences between the ginko and placebo group on visual-spatial memory (Rey-Osterreith Complex Figure Test) and attention/concentration (Digit Span). However, the ginkgo-treated group (preintervention: M ⫽ 1,557 ms, standard error [SE] ⫽ 137 and postintervention: M ⫽ 1,373 ms, SE ⫽ 106) showed enhanced processing speed (1,840 ms faster) in contrast to the placebo group (preintervention: M ⫽ 1,737 ms, SE ⫽ 167 and postintervention: M ⫽ 1,881 ms, SE ⫽ 303, or 1,440 ms slower) on the Visual Threshold Serial Addition Test (Mann–Whitney U test: Z ⫽ ⫺1.9, P ⫽ .05, Cohen’s d ⫽ 0.60). The ginkgo-treated group also emitted fewer verbal intrusions on the California Verbal Learning Test than the placebo group (Mann–Whitney U test: Z ⫽ ⫺2.09, P ⫽ .03, Cohen’s d ⫽ 0.85). An analysis of the relationship between processing speed and fatigue change scores (Pre⫺Post-Intervention; r ⫽ .49, P ⫽ .01) suggested that fatigue accounted for approximately 24% of the shared variance. A partial correlation between fatigue and processing speed when we controlled for mood (Center for Epidemiological Studies Depression) suggested that mood accounted for approximately 3% of the shared variance between fatigue and processing speed (r ⫽ .52, P ⫽ .01). Faster processing speed may suggest enhanced executive control and sustained attention, which is supported by the finding that the ginkgo group also emitted fewer verbal intrusions, which may be attributable to improved executive control, enhanced search and retrieval, as well as more efficient self-monitoring. Fewer intrusions also may have been due to more salient stimulus encoding although not sufficient to improve recall, resulting in a greater activation differential at retrieval between potential intrusions and previously encountered words. There is evidence supporting the idea that enhanced activation at retrieval and improved executive control processes and monitoring are associated with reduced intrusion levels.9 Moreover, there is also evidence that faster processing speed is associated with enhanced acquisition and encoding and/or enhanced executive search and retrieval.10 These findings may have been mediated by ginkgo’s purported central cerebrovascular-modulating properties and neurotransmitter-potentiating activity resulting in modest increases in the strength of underlying memory, enhanced activation at encoding, and/or more efficient retrieval and executive control. These results may suggest modest benefits in taking ginkgo but more convincing evidence awaits future work using larger samples and additional cognitive measures. However, given the prominence of slower processing and dysexecutive function in MS, even modest improvements in executive function may enhance activities of daily living.
EXPLORE March/April 2013, Vol. 9, No. 2 http://dx.doi.org/10.1016/j.explore.2012.12.001
Acknowledgments The authors thank Uttara Desai for her editorial support. 6.
REFERENCES 1. Diamond BJ, Johnson SK, Kaufman M, Graves L. Relationships between information processing, depression, fatigue and cognition in Multiple Sclerosis. Arch Clin Neuropsychol. 2008;23:189-199. 2. Diamond BJ, Shiflett SC, Lothian A, et al. EGb; 761 (Ginkgo biloba): Efficacy in treating stroke and TBI. Arch Physical Med Rehabil. 2000;80:978. 3. Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil. 2000;81:1-11. 4. Johnson S, Diamond BJ, Rausch S, et al. The effect of gingko biloba on functional measures in multiple sclerosis: A pilot randomized controlled trial. Explore J Sci Heal. 2006;2:19-24. 5. Barth SA, Inselmann G, Engemann R, Heidemann HT. Influences of Ginkgo biloba on cyclosporin A induced lipid peroxidation in
7.
8.
9. 10.
EGb 761 on Information Processing and Executive Function in MS
human liver microsomes in comparison to vitamin E, glutathione and N-acetyllcysteine. Biochem Pharmacol. 1991;41:1521-1526. Lovera J, Bagert B, Smoot K, et al. Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial. Mult Scler. 2007;13:376-385. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14. Kenney C, Norman M, Jacobson M, Lampinen S, Nguyen DP, Corey-Bloom J. A double-blind, placebo controlled, modified crossover pilot study of the effects of gingko biloba on cognitive and functional abilities in multiple sclerosis. Neurology. 2002;58:A458A459. McDermott KB, Watson JM. The rise and fall of false recall: the impact of presentation duration. J Mem Lang. 2001;45:160-176. Lövdén M, Rönnlund M, Göran-Lars N. Remembering and knowing in adulthood: effects of enacted encoding and relations to processing speed. Aging Neuropsychol Cogn. 2002;9:184200.
EXPLORE March/April 2013, Vol. 9, No. 2 107