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Journal of Clinical and Experimental Neuropsychology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncen19
Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type a
b
Erik J.A. Scherder , Anke Bouma & Louis Steen a
c
Institute of Physiotherapy , Amsterdam
b
Department of Clinical Psychology , Free University , Amsterdam c
University of Amsterdam , Published online: 04 Jan 2008.
To cite this article: Erik J.A. Scherder , Anke Bouma & Louis Steen (1992) Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type, Journal of Clinical and Experimental Neuropsychology, 14:6, 951-960, DOI: 10.1080/01688639208402546 To link to this article: http://dx.doi.org/10.1080/01688639208402546
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Journalof Clinical and Experimental Neuropsychology 1992, V O ~14, . NO. 6, pp. 951-960
0168-8634/92/1406-0951$3.00 0 Swets & Zeitlinger
Influence of Transcutaneous Electrical Nerve Stimulation on Memory in Patients With Dementia of the Alzheimer Type*
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Erik J.A. Scherder Institute of Physiotherapy, Amsterdam Anke Bouma Department of Clinical Psychology, Free University, Amsterdam and
Louis Steen University of Amsterdam
ABSTRACT This study examined the effect of transcutaneous electrical nerve stimulation (TENS) on memory in patients with dementia of the Alzheimer type. It was hypothesized that, in the early stage of the illness, electrical stimulation could activate the affected cortical regions by stimulating the neurotransmitter systems projecting to these areas. The results reveal that electrical stimulation improves the verbal long-term memory in these patients. Moreover, verbal fluency improves more in patients who received electrical stimulation than in patients who received control treatment. However, electrical stimulation does not influence the visual long-term memory of the patients, nor does it affect their verbal and nonverbal short-term memory. Underlying theoretical mechanisms are discussed.
Memory impairment is o n e of the earliest and most marked clinical features in patients with dementia of the Alzheimer type (DAT) (e.g., Bayles & Kaszniak, 1987; Hart & Semple, 1990). Compensation strategies that might help the patients t o cope with the memory disturbances are the most commonly employed approaches to rehabilitation of memory (Miller, 1985); however, these approaches do not restore or improve memory function per se (Miller, 1985). The present
* The authors are very grateful to the staff members of Het Schouw for their hospitality and help in conducting the study, and to the firm of Klees for their kind permission to use their apparatus for the treatment of the patients. We also wish to thank Len Holdstock, Ph.D., and Byron P. Rourke, Ph.D., for their critical reading of the manuscript. Requests for reprints should be addressed to: Drs. Erik Scherder, Institute of Physiotherapy, Veeteeltstraat 20, 1097 WV Amsterdam, The Netherlands. Accepted for publication: March 4, 1992.
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study focuses on the restorative approach by examining the effect of transcutaneous electrical nerve stimulation (TENS) - a peripheral, noncognitive type of training on memory in patients with DAT. From both human and animal studies, it appears that the hippocampus plays a crucial role in memory, mainly in close association with other brain regions such as the amygdala, the medial temporal cortex, and the medial prefrontal cortex (Brown, Wilson, & Riches, 1987; Gonser, Perret, & Wieser, 1986; Hart & Semple, 1990; Heit, Smith, & Halgren, 1988; McMillan, Powell, Janota, & Polkey, 1987; Olton, Meck, & Church, 1987; Raffaele & Olton, 1988; Saunders, Murray, & Mishkin, 1984; Zola-Morgan & Squire, 1985). The most important neurotransmitter systems projecting to these brain regions are acetylcholine, noradrenaline, and serotonin which have their sources in the subcortical areas of the basal forebrain (including the medial septa1 nucleus, the nucleus of the diagonal band of Broca, and the nucleus basalis of Meynert), the locus coeruleus, and the dorsal raphe nucleus, respectively (Mann, 1988; Rossor, 1988; Saper, 1988). Interestingly, lateral asymmetries of neurotransmitters have been found in the human brain. Glick, Ross, and Hough (1982) found a left-lateralization of acetylcholine activity, whereas a right-lateralization was found for noradrenaline (Oke, Keller, Mefford, & Adams, 1978) and for serotonin (Gottfries, Perris, & Roos, 1974). There is general consensus that these neurotransmitter systems are affected in patients with DAT (Mann, 1988; Rossor, 1988; Saper, 1988). Moreover, there are indications that deficiencies in the neurotransmitter systems are associated with those brain regions that show the typical neuropathological abnormalities in DAT, such as neurofibrillary tangles, neuritic plaques, and granulovacuolar degeneration (e.g., Bayles & Kaszniak, 1987). Neuropathological changes are most likely to be found in the hippocampus and amygdala, although they are also found in brain regions from which the neurotransmitters originate (e.g., Saper, 19881, the projection areas of these transmitters, and several other areas of the cortex such as the temporal, frontal, and parietal areas (Cutler & Narang, 1986; Hart & Semple, 1990; Mann, 1988; Mann & Yates, 1986; Rossor, 1988; Saper, 1988). Recent studies suggest that, during the course of DAT, higher-level brain structures are affected earlier than are lower-level structures (Mann, 1988; Saper, 1988). This so-called transneuronal retrograde process assumes that, in the early stage of the disease, the site of brain lesions is located within the cerebral cortex, while lower-level brain regions such as the basal forebrain, the dorsal raphe nucleus, and the locus coeruleus, degenerate later because of their connections with the cortex. According to this view, the hippocampus and amygdala are also regarded as cortical areas (Mann, 1988). The transneuronal retrograde process constitutes an important rationale underlying the treatment employed in our study. It is hypothesized that, in the early stage of DAT, the activity of the affected, higher-level brain areas may be enhanced by peripheral stimulation via ascending neuronal pathways. In the present study, we attempted to activate the hippocampal regions and the related neurotransmitter
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systems by means of peripheral stimulation in DAT patients. Since the hippocampal regions play a critical role in long-term memory (e.g., Kolb & Whishaw, 1990), it was expected that peripheral stimulation would especially improve this aspect of memory in DAT. Evidence for increased activation of the hippocampal areas by means of peripheral stimulation arose from studies investigating animals with well-functioning brains. Dutar, Lamour. and Jobert (1985) reported that most of the septohippocampal neurons react with excitatory responses to peripheral somatic stimulation, especially to noxious (painful) stimulation such as strong, noxious mechanical (brushing, rubbing, or pinching) and/or thermal stimulation (the immersion of the tail of an animal in a water bath with increasing temperatures of 45Oto 55' Celsius). Dudar, Whishaw, and Szerb (1979) also observed an increased activation of the hippocampus during non-noxious sensory stimulation. The peripheral stimulation employed in their study was either tactile (stroking or touching the body fur or the tail, or picking up the animal) or auditory (vocalization, whistles, etc.). Moreover, they found that the increased activation of the hippocampus was associated with a release of acetylcholine. As yet, no studies (as far as the authors know) have dealt specifically with the effects of peripheral stimulation on the activity of the hippocampal regions of human patients. In the present study, electrical stimulation was applied to the skin of human subjects, instead of mechanical or thermal activation as employed in the animal studies. The impetus for employing peripheral electrical stimulation came from many studies concerning pain and pain suppression. In particular, the conditions under which electrical stimulation could activate the neurotransmitter systems affected in DAT were derived from these studies. The results of these experiments have shown that TENS, under specific conditions of intensity, frequency, pulse width etc., can bring about changes in the activity of various neurotransmitter systems, including the cholinergic system (Chen, 1981; Romo et al., 1987; Youing, Jie, & Shuangkun, 1985), the serotonergic system (Autrum, Ottoson, Perl, & Schmidt, 1982; Bklanger, 1985; Cheng & Pomeranz, 1981; Tyce & Yaksh, 1981; Youing, Jie, & Shuangkun, 1985), and the noradrenergic system (Cedarbaum & Aghajanian, 1978a, 1978b; Nakamura, 1977; Sherman & Liebeskind, 1980; Tyce & Yaksh, 1981). Pharmacological studies have also attempted to improve the functioning of neurotransmitter systems by examining the effects of drugs on memory functions in patients with DAT. Although some positive results have been obtained, as yet the results of these investigations are generally disappointing (Dillmann, 1990; Hart & Semple, 1990). A major problem of this type of treatment is that the drug has to cross the blood-brain barrier and somehow be targeted for the denervated areas, primarily the cerebral cortex (Saper, 1988). The peripheral electrical stimulation method does not have this problem because the central nervous system is stimulated directly.
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METHOD Subjects The initial sample consisted of 40 subjects drawn from a larger sample of 350 elderly persons who lived in a residential home for elderly people. The subjects ranged in age from 74 to 9 1 years, with a mean age of 81.4 years. The selection of subjects for this study was based on a progressive impairment of memory. Level of cognitive functioning was assessed by using a Dutch cognitive screening test (CST; Deelman. Maring, & Otten. 1989). a modified version of the Short Portable Mental State Questionnaire of Pfeiffer (1975). The CST consists of 20 items evaluating recent and remote memory, personal orientation, and orientation to time and place. Subjects were classified as having cognitive decline if they had a score of 12 or less (maximum total score = 20). All of these subjects had completed elementary school. All subjects met the NINCDS-ADRDA criteria for the clinical diagnosis of dementia of fie Alzheimer type (McKhann et al., 1984). The clinical symptoms of the dementia were present for at least six months. In addition, all patients scored 17 or less on the Hamilton Rating Scale for Depression (Hamilton, 1960). Patients were excluded from participation in this study if they had a history of psychiatric disorder, alcoholism, cerebral trauma, cerebrovasculair disease, hydrocephalus, neoplasm, infection, epilepsy, kidney or lung diseases, disturbances of consciousness, or focal brain abnormalities. None of the subjects had a pacemaker. On the basis of these criteria, 14 subjects were selected. After this screening procedure, the subjects were divided into two groups: a treatment group and a placebo group. Each group consisted of 7 subjects. The patients in the two groups were matched for age and performance on the CST. The subjects of each group were familiarized with the electrostimulation method and they were informed about the procedure of this investigation (see below). Out of the 14 persons, 8 subjects (7 females, 1 male) were willing to participate in our study, with each group consisting of 4 persons. Materials and procedure Neuropsychological tests All subjects received a number of neuropsychological tests in order to evaluate the effects of treatment on various aspects of memory, including short-term memory, long-term memory, verbal memory, visual memory, and semantic memory. The test battery consisted of the following tasks: Digit Span. The Digit Span subtest of the Wechsler Memory Scale-Revised (WMS-R, Wechsler, 1984) was employed to assess the patients’ verbal short-term memory abilities. This test is a standard digit span forwardbackward task. Visual Memory Span from the W M S - R (Wechsler, 1984). This task can be considered as the nonverbal equivalent of the Digit Span test. The Visual Memory Span subtest consists of a forward and a backward condition. In the forward condition, the examiner taps a number of blocks in a given order, which is then copied by the subject. As in the Digit Span, the number of blocks in a sequence is gradually increased. In the backward condition, the subject must repeat the sequence in reverse. The score is the total number of correct sequences.
The 15 Words Test (Heslinga & van den Burg, 1983) is used as a measure of auditory, verbal long-term memory. This task requires the subject to memorize 15 Dutch unrelated words, both immediately and after a delay. The 15 Words Test is f i s t presented orally five times by the examiner. Subjects are required to recall as many words as possible after
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each presentation. The Immediate Recall score is the subjects’ total number of correctly recalled words minus the expected recall score. The expected recall score is a standardized score which, by means of a regression formula, predicts the subjects’ performance on the basis of age and education. A negative score means that the subjects’ performance is less than hisher expected performance level. After an occupied interval of 10 minutes, the subjects are again asked to recall as many words as possible. The Delayed Recall score is the total number of correctly recalled words minus the expected delayed recall score. The subjects are then read 30 words (the 15 presented before and 15 new ones) in random order, and they are asked to recognize as many words as possible. The Recognition score is the number of correctly recognized answers minus the number of incorrectly recognized answers.
Face Recognition from the Rivermead Behavioural Memory Test (RBMT, Wilson, Cockburn, & Baddeley, 1987) provides a measure of visual, nonverbal long-term memory. Five faces are shown successively to the subject. After an occupied interval of 5 minutes, the subjects are required to select the original five faces from a set of 10. The recognition score is the number of correct answers minus the number of incorrect answers. Picture Recognition from the RBMT provides a measure of visual, verbal long-term memory. Line drawings of 10 common objects are presented one at a time. After an occupied interval of 5 minutes, the subjects are asked to select the original 10 pictures from a set of 20. The recognition score is calculated in the same way as in the Face Recognition test.
Word Fluency from the Groninger Intelligence Test (Snijders & Verhage, 1983). a Dutch intelligence test. This task measures the ability of subjects to retrieve familiar information from semantic memory. Subjects are required to name as many words as possible in one minute (names of occupations in one condition and names of animals in another condition). The score is the mean scaled score of the two conditions ( M = 50; SD = 10). All subjects received these tests the day before and the day after the treatment. The tests were given in the following order: Digit Span, Visual Memory Span, 15 Words Test (Immediate Recall), Face Recognition (stimulus presentation), Word Fluency (names of occupations), Face Recognition (response), Picture Recognition (stimulus presentation), Word Fluency (names of animals), Picture Recognition (response), and 15 Words Test (Delayed Recall and Recognition). Treatment Both the Treatment group and the Placebo group were treated with a transcutaneous electro-stimulator, type Premier 10s. Two 2 x 3 cm (h x w) rubber electrodes were placed on the back of the patient between the shoulder blades (Thl-5). This source of sympathetic afferents is strongly connected with brainstem areas (Takigawa & Mogenson, 1977). Also, the back was chosen as location of the electrodes to enable the patients to cany out their usual activities as freely as possible without the risk of disconnecting the wires and interrupting the current. Studies concerning pain and pain suppression have investigated the conditions under which electrical stimulation leads to beneficial clinical effects. Based on these data, for the treatment group an asymmetric biphasic rectangular impulse was chosen which consisted of two types of frequencies: (1) a frequency of 100 Hz with a pulse width of 40 microseconds, which is supposed to have an effect on both the serotonergic system (Cheng & Pomeranz, 1979, 1981; Youing & Shuangkun, 1985) and the cholinergic system (Romo et al., 1987; Youing & Shuangkun, 1985). and ( 2 ) a frequency of 2 Hz with a pulse width of 250 microseconds, which is supposed to have an effect on the noradrenergic system (Cedarbaum & Aghajanian, 1978a, 1978b). The intensity of the stimulation was such that the stimulation with a frequency of 100 Hz was just perceptible, while the stimulation
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with a frequency of 2 Hz was strongly perceptible, but not painful. The intensity of the stimulation was individually adjusted due to the fact that the subjective experience of the intensity depends on a number of factors, such as the resistance of the skin. A flickering green light placed on the electro-stimulator indicated stimulation. In order to optimize the effects of electrical stimulation, the DAT patients were treated during a six-week period, for six hours per day (Frampton, 1982; Van Doom & Spierdijk, 1981; Wolf, Gersh, & Rao, 1981). The type of stimulation was alternated after each period of one hour and a half. All subjects started with the just perceptible level of stimulation. The Placebo group was treated in the same way as the Treatment group, including the alternation of type of stimulation after each period of one hour and a half; however, no current was administered to the subjects. The patients in the Placebo group were told that they could not feel anything, but that the stimulation started from the moment that the green light showed.
RESULTS For the Treatment group as well as for the Placebo group, the mean pre- and posttest scores on the various neuropsychological tests are presented in Table 1. While the test scores are normally distributed in the population and we found no outliers in our sample, we submitted the pretest scores to a multivariate analysis of variance (MANOVA) in order to verify that no difference existed between the two groups at the start of the experiment. Because of missing data, the 15 Words Test was analyzed separately (within each group, one subject was unwilling to perform this task). In the multivariate analysis, no significant difference was found between the Treatment and Placebo group on any of the pretest scores. Also, the pretest scores of the 15 Words Test (Immediate Recall, Delayed Recall and Recognition) did not differ significantly between the two groups, as indicated by a t test. Treatment effects were examined by means of one-factor analyses of covariance (ANCOVA) with the posttest scores as dependent variable and the pretest scores as covariate (see Table 1). As this table shows, significant treatment effects were
Table 1, Means and Analyses of Covariance on the neuropsychological tests. Test Digit Span Visual Memory Span 15 Words Test Immediate Recall Delayed Recall Recognition Face Recognition Picture Recognition Verbal Fluency
Treatment Pre Post 7.75 10.00 10.25 9.00 -20.50 -6.43
-9.50 -5.43 8.00 21.33 5.50 6.50 13.50 15.00 29.75 34.00
Placebo Pre Post 7.25
F
ANCOVA df
8.50 7.00
1.21 .37
1,5
-18.50 -18.17 -6.17 -6.17 10.67 7.33 4.50 3.50 13.00 11.00 36.50 32.75
14.86 .04 9.90 .37 1.77 7.31
1.3 1.3 1.3 1,5
8.50
1,5
1,5 1.5
p
ns ns .03 ns .05
ns ns .04
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particularly observed for verbal tasks. Patients receiving electrical stimulation performed better on the 15 Words Test and the Verbal Fluency task. The treatment effect on the 15 Words Test is evident on both the Immediate Recall and Recognition subtest scores, although not on the Delayed Recall score. In contrast to the improved verbal scores of all subjects in the Treatment group, subjects in the Placebo group showed minimal improvement or even decline in performance. N o treatment effects were found on the Digit Span task and the visual memory tasks (Visual Memory Span, Face Recognition, and Picture Recognition).
DISCUSSION The results of this study indicate that TENS has a differential effect on the memory of the DAT patients. On the one hand, it improves their verbal long-term memory, as measured by the Immediate Recall and Recognition scores of the 15 Words Test; on the other hand, it does not influence their Delayed Recall of the 15 Words Test. Since Delayed Recall requires more active retrieval from longterm memory than does Immediate Recall and Recognition, it appears that treatment effects emerge first in the least demanding aspects of memory. Moreover, TENS does not affect visual long-term memory as measured by Face Recognition and Picture Recognition. It also docs not affect verbal and nonverbal short-term memory. Interestingly, Verbal Fluency improves more in DAT patients who received TENS than in DAT patients who received control treatment. The present findings suggest that TENS improves not only the patients’ ability to learn new verbal information, but also their ability to retrieve familiar, categorized information from their memory store. The fact that only functions pertaining to the verbal modality improved, suggests that the systems within the left cerebral hemisphere that are hypothesized to subserve rote, overlearned aspects of coded material (Goldberg & Costa, 1981) are especially affected by TENS. Of great importance is the question of which brain mechanisms underlie the observed treatment effects. The employment of TENS was based upon three assumptions concerning these mechanisms. First, we assumed that TENS would activate the hippocampal regions, since this area is primarily involved in longterm memory. The improved performance on the 15 Words Test supports this assumption; however, it is unlikely that the improved performance on verbal fluency is associated with improved functioning of the hippocampus. It might be that TENS activates not only the left hippocampal regions or closely related regions, but also other brain regions in a more indirect way. It might also be that TENS particularly improves the activity of the cholinergic system which is involved more strongly in left-hemisphere functioning than it is in right-hemisphere functioning (Glick, Ross, & Hough, 1982). Second, the hypothesis was made that TENS would be effective in patients with DAT in the light of the fact that Alzheimer’s disease is considered to be a transneural retrograde process whereby, during the course of the illness, higher-
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level brain structures are affected earlier than are lower-level brain structures (Saper, 1988). TENS is, in fact, a bottom-up treatment, by which higher-level brain structures are activated by lower-level brain structures. It is interesting to note that this type of stimulation is in keeping with the hierarchical organization of the central nervous system (Kolb & Whishaw, 1990). According to this model, the development of higher brain structures depends on the development of lower brain structures. One could speculate that restoration of functions of higher brain regions is most effective when these regions are stimulated by lower brain structures that are not affected by brain damage. Third, we hypothesized that the improvement in memory functioning observed in DAT patients following treatment could be attributed to changes in the activities of various neurotransmitter systems. Studies in the field of pain research have found support for these changes by investigating the blood and the cerebrospinal fluid of the subjects (Sherman 8z Liebeskind, 1980; Soric & Devlin, 1985). Although the present study was not focused on these effects, it would be interesting to study whether changes in the neurotransmitters can also be found in DAT patients when treated with the TENS technique. It should be emphasized that the results of this study must be considered with caution, especially in view of the small number of subjects. Moreover, the choice of stimulation characteristics, including such factors as pulse width, pulse interval, type, and number of frequencies, intensity, size, and location of the electrodes, and duration of stimulation, has been derived from investigations in the field of pain and pain suppression. Of course, the question arises whether TENS, as employed in this study, is the most appropriate method for obtaining beneficial effects in patients with DAT. In future research, it would be useful to investigate whether other types of peripheral nerve stimulation e.g., mechanical stimulation such as massage will produce similar beneficial results.
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McMillan, T.M., Powell, G.E., Janota, I., & Polkey. C.E. (1987). Relationships between neuropathology and cognitive functioning in temporal lobectomy patients. Journal of Neurology, Neurosurgery and Psychiatry, 50, 167-176. Miller, E. (1985). Recovery and management of neuropsychological impairments.New York: Wiley. Nakamura, S. (1977). Some electrophysiological properties of neurons of rat locus coeruleus. Journal of Physiology, 267, 641- 658. Oke, A., Keller, R., Mefford, I., & Adams, R. (1978). Lateralization of norepinephrine in human thalamus. Science, 200, 1411-1413. Olton, D.S., Meck, W.H., & Church, R.M. (1987). Separation of hippocampal and arnygdaloid involvement in temporal memory dysfunctions. Brain Research, 404, 180-188. Pfeiffer, E. (1975). A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. Journal of the American Geriatric Sociery, 23, 433-441. Raffaele, K.C., & Olton, D.S. (1988). Hippocampal and amygdaloid involvement in working memory for nonspatial stimuli. Behavioral Neuroscience, 102, 349-355. Romo, R., Morot Gaudry-Talarmain, Y., Chbramy, A,, Godeheu, G., Leviel, V.,Chesselet, M.F., Glowinski, J., & Israel, M. (1987). Different effects of electrical stimulation of the mesencephalic and pontine reticular formation on the release of dopamine and acetylcholine in the cat caudate nucleus. Neuroscience Letters, 78, 57-62. Rossor, M. (1988), Neurochemical studies in dementia. Handbook of Psychopharmacology, 20, 107-130. Saper, C.B. (1988). Chemical neuroanatomy of Alzheimer’s disease. Handbook of Psychopharmacology, 20, 131-156. Saunders, R.C., Murray, E.A., & Mishkin, M. (1984). Further evidence that amygdala and hippocampus contribute equally to recognition memory. Neuropsychologia,22,785-796. Sherman, J.E., & Liebeskind, J.C. (1980). An endorphinergic, centrifugal substrate of pain modulation: Recent findings, current concepts and complexities. In J.J. Bonica (Ed.), Pain (pp. 191-204). New York Raven. Snijders, J.Th., & Verhage, F. (1983). GroningerIntelligentie Test. Lisse: Swets & Zeitlinger. Soric, R., & Devlin, M. (1985). Transcutaneous electrical nerve stimulation. Postgraduate Medicine, 78, 101-106. Takigawa,M., & Mogenson, G.J. (1977). A study of inputs to antidromically identified neurons of the locus coeruleus. Brain Research, 135, 217-230. Tyce, G.M., & Yaksh, T.L. (1981). Mono-amine release from cat spinal cord by somatic stimuli: An intrinsic modulatory system. Journal of Physiology, 314, 513-529. Van Doom, J.N., & Spierdijk, J. (1981). Transcutaneous electrical nerve stimulation for relief of pain. Acta Anaesthesiologica Belgica, I , 21-31. Wechsler, D. (1984). Wechsler Memory Scale-Revised. New York The Psychological Corporation. Wilson, B., Cockbum, J., & Baddeley, A. (1987). The Rivermead Behavioural Memory Test. Titchfield: Thames Valley Test Company. Wolf, S.L., Gersh, M.R., & Rao, V.R. (1981). Examination of electrode placements and stimulatingparameters in treating chronic pain with conventionaltranscutaneous electrical nerve stirnulation (TENS), Pain, 11, 37-47. Youing, W., Jie, W., & Shuangkun, W. (1985). The role of acetylcholine in the rat brain and its effect on 5-hydroxytryptamine metabolism during electro-acupuncture analgesia. Journal of Traditional Chinese Medicine, 4, 297-300. Zola-Morgan, S., & Squire, L.R. (1985). Medial temporal lesions in monkeys impair memory on a variety of tasks, sensitive to human amnesia. Behavioral Neuroscience, 99, 22-34.
Journal of Clinical and Experimental Neuropsychology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncen19
Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type a
b
Erik J.A. Scherder , Anke Bouma & Louis Steen a
c
Institute of Physiotherapy , Amsterdam
b
Department of Clinical Psychology , Free University , Amsterdam c
University of Amsterdam , Published online: 04 Jan 2008.
To cite this article: Erik J.A. Scherder , Anke Bouma & Louis Steen (1992) Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type, Journal of Clinical and Experimental Neuropsychology, 14:6, 951-960, DOI: 10.1080/01688639208402546 To link to this article: http://dx.doi.org/10.1080/01688639208402546
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Journalof Clinical and Experimental Neuropsychology 1992, V O ~14, . NO. 6, pp. 951-960
0168-8634/92/1406-0951$3.00 0 Swets & Zeitlinger
Influence of Transcutaneous Electrical Nerve Stimulation on Memory in Patients With Dementia of the Alzheimer Type*
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Erik J.A. Scherder Institute of Physiotherapy, Amsterdam Anke Bouma Department of Clinical Psychology, Free University, Amsterdam and
Louis Steen University of Amsterdam
ABSTRACT This study examined the effect of transcutaneous electrical nerve stimulation (TENS) on memory in patients with dementia of the Alzheimer type. It was hypothesized that, in the early stage of the illness, electrical stimulation could activate the affected cortical regions by stimulating the neurotransmitter systems projecting to these areas. The results reveal that electrical stimulation improves the verbal long-term memory in these patients. Moreover, verbal fluency improves more in patients who received electrical stimulation than in patients who received control treatment. However, electrical stimulation does not influence the visual long-term memory of the patients, nor does it affect their verbal and nonverbal short-term memory. Underlying theoretical mechanisms are discussed.
Memory impairment is o n e of the earliest and most marked clinical features in patients with dementia of the Alzheimer type (DAT) (e.g., Bayles & Kaszniak, 1987; Hart & Semple, 1990). Compensation strategies that might help the patients t o cope with the memory disturbances are the most commonly employed approaches to rehabilitation of memory (Miller, 1985); however, these approaches do not restore or improve memory function per se (Miller, 1985). The present
* The authors are very grateful to the staff members of Het Schouw for their hospitality and help in conducting the study, and to the firm of Klees for their kind permission to use their apparatus for the treatment of the patients. We also wish to thank Len Holdstock, Ph.D., and Byron P. Rourke, Ph.D., for their critical reading of the manuscript. Requests for reprints should be addressed to: Drs. Erik Scherder, Institute of Physiotherapy, Veeteeltstraat 20, 1097 WV Amsterdam, The Netherlands. Accepted for publication: March 4, 1992.
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study focuses on the restorative approach by examining the effect of transcutaneous electrical nerve stimulation (TENS) - a peripheral, noncognitive type of training on memory in patients with DAT. From both human and animal studies, it appears that the hippocampus plays a crucial role in memory, mainly in close association with other brain regions such as the amygdala, the medial temporal cortex, and the medial prefrontal cortex (Brown, Wilson, & Riches, 1987; Gonser, Perret, & Wieser, 1986; Hart & Semple, 1990; Heit, Smith, & Halgren, 1988; McMillan, Powell, Janota, & Polkey, 1987; Olton, Meck, & Church, 1987; Raffaele & Olton, 1988; Saunders, Murray, & Mishkin, 1984; Zola-Morgan & Squire, 1985). The most important neurotransmitter systems projecting to these brain regions are acetylcholine, noradrenaline, and serotonin which have their sources in the subcortical areas of the basal forebrain (including the medial septa1 nucleus, the nucleus of the diagonal band of Broca, and the nucleus basalis of Meynert), the locus coeruleus, and the dorsal raphe nucleus, respectively (Mann, 1988; Rossor, 1988; Saper, 1988). Interestingly, lateral asymmetries of neurotransmitters have been found in the human brain. Glick, Ross, and Hough (1982) found a left-lateralization of acetylcholine activity, whereas a right-lateralization was found for noradrenaline (Oke, Keller, Mefford, & Adams, 1978) and for serotonin (Gottfries, Perris, & Roos, 1974). There is general consensus that these neurotransmitter systems are affected in patients with DAT (Mann, 1988; Rossor, 1988; Saper, 1988). Moreover, there are indications that deficiencies in the neurotransmitter systems are associated with those brain regions that show the typical neuropathological abnormalities in DAT, such as neurofibrillary tangles, neuritic plaques, and granulovacuolar degeneration (e.g., Bayles & Kaszniak, 1987). Neuropathological changes are most likely to be found in the hippocampus and amygdala, although they are also found in brain regions from which the neurotransmitters originate (e.g., Saper, 19881, the projection areas of these transmitters, and several other areas of the cortex such as the temporal, frontal, and parietal areas (Cutler & Narang, 1986; Hart & Semple, 1990; Mann, 1988; Mann & Yates, 1986; Rossor, 1988; Saper, 1988). Recent studies suggest that, during the course of DAT, higher-level brain structures are affected earlier than are lower-level structures (Mann, 1988; Saper, 1988). This so-called transneuronal retrograde process assumes that, in the early stage of the disease, the site of brain lesions is located within the cerebral cortex, while lower-level brain regions such as the basal forebrain, the dorsal raphe nucleus, and the locus coeruleus, degenerate later because of their connections with the cortex. According to this view, the hippocampus and amygdala are also regarded as cortical areas (Mann, 1988). The transneuronal retrograde process constitutes an important rationale underlying the treatment employed in our study. It is hypothesized that, in the early stage of DAT, the activity of the affected, higher-level brain areas may be enhanced by peripheral stimulation via ascending neuronal pathways. In the present study, we attempted to activate the hippocampal regions and the related neurotransmitter
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systems by means of peripheral stimulation in DAT patients. Since the hippocampal regions play a critical role in long-term memory (e.g., Kolb & Whishaw, 1990), it was expected that peripheral stimulation would especially improve this aspect of memory in DAT. Evidence for increased activation of the hippocampal areas by means of peripheral stimulation arose from studies investigating animals with well-functioning brains. Dutar, Lamour. and Jobert (1985) reported that most of the septohippocampal neurons react with excitatory responses to peripheral somatic stimulation, especially to noxious (painful) stimulation such as strong, noxious mechanical (brushing, rubbing, or pinching) and/or thermal stimulation (the immersion of the tail of an animal in a water bath with increasing temperatures of 45Oto 55' Celsius). Dudar, Whishaw, and Szerb (1979) also observed an increased activation of the hippocampus during non-noxious sensory stimulation. The peripheral stimulation employed in their study was either tactile (stroking or touching the body fur or the tail, or picking up the animal) or auditory (vocalization, whistles, etc.). Moreover, they found that the increased activation of the hippocampus was associated with a release of acetylcholine. As yet, no studies (as far as the authors know) have dealt specifically with the effects of peripheral stimulation on the activity of the hippocampal regions of human patients. In the present study, electrical stimulation was applied to the skin of human subjects, instead of mechanical or thermal activation as employed in the animal studies. The impetus for employing peripheral electrical stimulation came from many studies concerning pain and pain suppression. In particular, the conditions under which electrical stimulation could activate the neurotransmitter systems affected in DAT were derived from these studies. The results of these experiments have shown that TENS, under specific conditions of intensity, frequency, pulse width etc., can bring about changes in the activity of various neurotransmitter systems, including the cholinergic system (Chen, 1981; Romo et al., 1987; Youing, Jie, & Shuangkun, 1985), the serotonergic system (Autrum, Ottoson, Perl, & Schmidt, 1982; Bklanger, 1985; Cheng & Pomeranz, 1981; Tyce & Yaksh, 1981; Youing, Jie, & Shuangkun, 1985), and the noradrenergic system (Cedarbaum & Aghajanian, 1978a, 1978b; Nakamura, 1977; Sherman & Liebeskind, 1980; Tyce & Yaksh, 1981). Pharmacological studies have also attempted to improve the functioning of neurotransmitter systems by examining the effects of drugs on memory functions in patients with DAT. Although some positive results have been obtained, as yet the results of these investigations are generally disappointing (Dillmann, 1990; Hart & Semple, 1990). A major problem of this type of treatment is that the drug has to cross the blood-brain barrier and somehow be targeted for the denervated areas, primarily the cerebral cortex (Saper, 1988). The peripheral electrical stimulation method does not have this problem because the central nervous system is stimulated directly.
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METHOD Subjects The initial sample consisted of 40 subjects drawn from a larger sample of 350 elderly persons who lived in a residential home for elderly people. The subjects ranged in age from 74 to 9 1 years, with a mean age of 81.4 years. The selection of subjects for this study was based on a progressive impairment of memory. Level of cognitive functioning was assessed by using a Dutch cognitive screening test (CST; Deelman. Maring, & Otten. 1989). a modified version of the Short Portable Mental State Questionnaire of Pfeiffer (1975). The CST consists of 20 items evaluating recent and remote memory, personal orientation, and orientation to time and place. Subjects were classified as having cognitive decline if they had a score of 12 or less (maximum total score = 20). All of these subjects had completed elementary school. All subjects met the NINCDS-ADRDA criteria for the clinical diagnosis of dementia of fie Alzheimer type (McKhann et al., 1984). The clinical symptoms of the dementia were present for at least six months. In addition, all patients scored 17 or less on the Hamilton Rating Scale for Depression (Hamilton, 1960). Patients were excluded from participation in this study if they had a history of psychiatric disorder, alcoholism, cerebral trauma, cerebrovasculair disease, hydrocephalus, neoplasm, infection, epilepsy, kidney or lung diseases, disturbances of consciousness, or focal brain abnormalities. None of the subjects had a pacemaker. On the basis of these criteria, 14 subjects were selected. After this screening procedure, the subjects were divided into two groups: a treatment group and a placebo group. Each group consisted of 7 subjects. The patients in the two groups were matched for age and performance on the CST. The subjects of each group were familiarized with the electrostimulation method and they were informed about the procedure of this investigation (see below). Out of the 14 persons, 8 subjects (7 females, 1 male) were willing to participate in our study, with each group consisting of 4 persons. Materials and procedure Neuropsychological tests All subjects received a number of neuropsychological tests in order to evaluate the effects of treatment on various aspects of memory, including short-term memory, long-term memory, verbal memory, visual memory, and semantic memory. The test battery consisted of the following tasks: Digit Span. The Digit Span subtest of the Wechsler Memory Scale-Revised (WMS-R, Wechsler, 1984) was employed to assess the patients’ verbal short-term memory abilities. This test is a standard digit span forwardbackward task. Visual Memory Span from the W M S - R (Wechsler, 1984). This task can be considered as the nonverbal equivalent of the Digit Span test. The Visual Memory Span subtest consists of a forward and a backward condition. In the forward condition, the examiner taps a number of blocks in a given order, which is then copied by the subject. As in the Digit Span, the number of blocks in a sequence is gradually increased. In the backward condition, the subject must repeat the sequence in reverse. The score is the total number of correct sequences.
The 15 Words Test (Heslinga & van den Burg, 1983) is used as a measure of auditory, verbal long-term memory. This task requires the subject to memorize 15 Dutch unrelated words, both immediately and after a delay. The 15 Words Test is f i s t presented orally five times by the examiner. Subjects are required to recall as many words as possible after
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each presentation. The Immediate Recall score is the subjects’ total number of correctly recalled words minus the expected recall score. The expected recall score is a standardized score which, by means of a regression formula, predicts the subjects’ performance on the basis of age and education. A negative score means that the subjects’ performance is less than hisher expected performance level. After an occupied interval of 10 minutes, the subjects are again asked to recall as many words as possible. The Delayed Recall score is the total number of correctly recalled words minus the expected delayed recall score. The subjects are then read 30 words (the 15 presented before and 15 new ones) in random order, and they are asked to recognize as many words as possible. The Recognition score is the number of correctly recognized answers minus the number of incorrectly recognized answers.
Face Recognition from the Rivermead Behavioural Memory Test (RBMT, Wilson, Cockburn, & Baddeley, 1987) provides a measure of visual, nonverbal long-term memory. Five faces are shown successively to the subject. After an occupied interval of 5 minutes, the subjects are required to select the original five faces from a set of 10. The recognition score is the number of correct answers minus the number of incorrect answers. Picture Recognition from the RBMT provides a measure of visual, verbal long-term memory. Line drawings of 10 common objects are presented one at a time. After an occupied interval of 5 minutes, the subjects are asked to select the original 10 pictures from a set of 20. The recognition score is calculated in the same way as in the Face Recognition test.
Word Fluency from the Groninger Intelligence Test (Snijders & Verhage, 1983). a Dutch intelligence test. This task measures the ability of subjects to retrieve familiar information from semantic memory. Subjects are required to name as many words as possible in one minute (names of occupations in one condition and names of animals in another condition). The score is the mean scaled score of the two conditions ( M = 50; SD = 10). All subjects received these tests the day before and the day after the treatment. The tests were given in the following order: Digit Span, Visual Memory Span, 15 Words Test (Immediate Recall), Face Recognition (stimulus presentation), Word Fluency (names of occupations), Face Recognition (response), Picture Recognition (stimulus presentation), Word Fluency (names of animals), Picture Recognition (response), and 15 Words Test (Delayed Recall and Recognition). Treatment Both the Treatment group and the Placebo group were treated with a transcutaneous electro-stimulator, type Premier 10s. Two 2 x 3 cm (h x w) rubber electrodes were placed on the back of the patient between the shoulder blades (Thl-5). This source of sympathetic afferents is strongly connected with brainstem areas (Takigawa & Mogenson, 1977). Also, the back was chosen as location of the electrodes to enable the patients to cany out their usual activities as freely as possible without the risk of disconnecting the wires and interrupting the current. Studies concerning pain and pain suppression have investigated the conditions under which electrical stimulation leads to beneficial clinical effects. Based on these data, for the treatment group an asymmetric biphasic rectangular impulse was chosen which consisted of two types of frequencies: (1) a frequency of 100 Hz with a pulse width of 40 microseconds, which is supposed to have an effect on both the serotonergic system (Cheng & Pomeranz, 1979, 1981; Youing & Shuangkun, 1985) and the cholinergic system (Romo et al., 1987; Youing & Shuangkun, 1985). and ( 2 ) a frequency of 2 Hz with a pulse width of 250 microseconds, which is supposed to have an effect on the noradrenergic system (Cedarbaum & Aghajanian, 1978a, 1978b). The intensity of the stimulation was such that the stimulation with a frequency of 100 Hz was just perceptible, while the stimulation
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with a frequency of 2 Hz was strongly perceptible, but not painful. The intensity of the stimulation was individually adjusted due to the fact that the subjective experience of the intensity depends on a number of factors, such as the resistance of the skin. A flickering green light placed on the electro-stimulator indicated stimulation. In order to optimize the effects of electrical stimulation, the DAT patients were treated during a six-week period, for six hours per day (Frampton, 1982; Van Doom & Spierdijk, 1981; Wolf, Gersh, & Rao, 1981). The type of stimulation was alternated after each period of one hour and a half. All subjects started with the just perceptible level of stimulation. The Placebo group was treated in the same way as the Treatment group, including the alternation of type of stimulation after each period of one hour and a half; however, no current was administered to the subjects. The patients in the Placebo group were told that they could not feel anything, but that the stimulation started from the moment that the green light showed.
RESULTS For the Treatment group as well as for the Placebo group, the mean pre- and posttest scores on the various neuropsychological tests are presented in Table 1. While the test scores are normally distributed in the population and we found no outliers in our sample, we submitted the pretest scores to a multivariate analysis of variance (MANOVA) in order to verify that no difference existed between the two groups at the start of the experiment. Because of missing data, the 15 Words Test was analyzed separately (within each group, one subject was unwilling to perform this task). In the multivariate analysis, no significant difference was found between the Treatment and Placebo group on any of the pretest scores. Also, the pretest scores of the 15 Words Test (Immediate Recall, Delayed Recall and Recognition) did not differ significantly between the two groups, as indicated by a t test. Treatment effects were examined by means of one-factor analyses of covariance (ANCOVA) with the posttest scores as dependent variable and the pretest scores as covariate (see Table 1). As this table shows, significant treatment effects were
Table 1, Means and Analyses of Covariance on the neuropsychological tests. Test Digit Span Visual Memory Span 15 Words Test Immediate Recall Delayed Recall Recognition Face Recognition Picture Recognition Verbal Fluency
Treatment Pre Post 7.75 10.00 10.25 9.00 -20.50 -6.43
-9.50 -5.43 8.00 21.33 5.50 6.50 13.50 15.00 29.75 34.00
Placebo Pre Post 7.25
F
ANCOVA df
8.50 7.00
1.21 .37
1,5
-18.50 -18.17 -6.17 -6.17 10.67 7.33 4.50 3.50 13.00 11.00 36.50 32.75
14.86 .04 9.90 .37 1.77 7.31
1.3 1.3 1.3 1,5
8.50
1,5
1,5 1.5
p
ns ns .03 ns .05
ns ns .04
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particularly observed for verbal tasks. Patients receiving electrical stimulation performed better on the 15 Words Test and the Verbal Fluency task. The treatment effect on the 15 Words Test is evident on both the Immediate Recall and Recognition subtest scores, although not on the Delayed Recall score. In contrast to the improved verbal scores of all subjects in the Treatment group, subjects in the Placebo group showed minimal improvement or even decline in performance. N o treatment effects were found on the Digit Span task and the visual memory tasks (Visual Memory Span, Face Recognition, and Picture Recognition).
DISCUSSION The results of this study indicate that TENS has a differential effect on the memory of the DAT patients. On the one hand, it improves their verbal long-term memory, as measured by the Immediate Recall and Recognition scores of the 15 Words Test; on the other hand, it does not influence their Delayed Recall of the 15 Words Test. Since Delayed Recall requires more active retrieval from longterm memory than does Immediate Recall and Recognition, it appears that treatment effects emerge first in the least demanding aspects of memory. Moreover, TENS does not affect visual long-term memory as measured by Face Recognition and Picture Recognition. It also docs not affect verbal and nonverbal short-term memory. Interestingly, Verbal Fluency improves more in DAT patients who received TENS than in DAT patients who received control treatment. The present findings suggest that TENS improves not only the patients’ ability to learn new verbal information, but also their ability to retrieve familiar, categorized information from their memory store. The fact that only functions pertaining to the verbal modality improved, suggests that the systems within the left cerebral hemisphere that are hypothesized to subserve rote, overlearned aspects of coded material (Goldberg & Costa, 1981) are especially affected by TENS. Of great importance is the question of which brain mechanisms underlie the observed treatment effects. The employment of TENS was based upon three assumptions concerning these mechanisms. First, we assumed that TENS would activate the hippocampal regions, since this area is primarily involved in longterm memory. The improved performance on the 15 Words Test supports this assumption; however, it is unlikely that the improved performance on verbal fluency is associated with improved functioning of the hippocampus. It might be that TENS activates not only the left hippocampal regions or closely related regions, but also other brain regions in a more indirect way. It might also be that TENS particularly improves the activity of the cholinergic system which is involved more strongly in left-hemisphere functioning than it is in right-hemisphere functioning (Glick, Ross, & Hough, 1982). Second, the hypothesis was made that TENS would be effective in patients with DAT in the light of the fact that Alzheimer’s disease is considered to be a transneural retrograde process whereby, during the course of the illness, higher-
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level brain structures are affected earlier than are lower-level brain structures (Saper, 1988). TENS is, in fact, a bottom-up treatment, by which higher-level brain structures are activated by lower-level brain structures. It is interesting to note that this type of stimulation is in keeping with the hierarchical organization of the central nervous system (Kolb & Whishaw, 1990). According to this model, the development of higher brain structures depends on the development of lower brain structures. One could speculate that restoration of functions of higher brain regions is most effective when these regions are stimulated by lower brain structures that are not affected by brain damage. Third, we hypothesized that the improvement in memory functioning observed in DAT patients following treatment could be attributed to changes in the activities of various neurotransmitter systems. Studies in the field of pain research have found support for these changes by investigating the blood and the cerebrospinal fluid of the subjects (Sherman 8z Liebeskind, 1980; Soric & Devlin, 1985). Although the present study was not focused on these effects, it would be interesting to study whether changes in the neurotransmitters can also be found in DAT patients when treated with the TENS technique. It should be emphasized that the results of this study must be considered with caution, especially in view of the small number of subjects. Moreover, the choice of stimulation characteristics, including such factors as pulse width, pulse interval, type, and number of frequencies, intensity, size, and location of the electrodes, and duration of stimulation, has been derived from investigations in the field of pain and pain suppression. Of course, the question arises whether TENS, as employed in this study, is the most appropriate method for obtaining beneficial effects in patients with DAT. In future research, it would be useful to investigate whether other types of peripheral nerve stimulation e.g., mechanical stimulation such as massage will produce similar beneficial results.
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