Neurocase The Neural Basis of Cognition
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Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease Rickard L. Sjöberg, Björn Häggström, Johanna Philipsson, Jan Linder, Marwan Hariz & Patric Blomstedt To cite this article: Rickard L. Sjöberg, Björn Häggström, Johanna Philipsson, Jan Linder, Marwan Hariz & Patric Blomstedt (2015) Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease, Neurocase, 21:5, 601-606, DOI: 10.1080/13554794.2014.960427 To link to this article: http://dx.doi.org/10.1080/13554794.2014.960427
Published online: 25 Sep 2014.
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Date: 09 November 2015, At: 21:22
Neurocase, 2015 Vol. 21, No. 5, 601–606, http://dx.doi.org/10.1080/13554794.2014.960427
Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease Rickard L. Sjöberga*, Björn Häggströma, Johanna Philipssona, Jan Lindera, Marwan Hariza,b and Patric Blomstedta a
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden; bInstitute of Neurology, University College London, London, UK
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(Received 12 July 2013; accepted 26 August 2014) Ear advantage during a dichotic listening task tends to mirror speech lateralization. Previous studies in stroke patients have shown that lesions in the dominant hemisphere often seem to produce changes in ear advantage. In this study six Parkinson’s disease (PD) patients treated for motor symptoms with deep brain stimulation (DBS) of the left subthalamic nucleus (STN) were tested preoperatively and at approximately 6 and 18 months postoperatively with a dichotic listening task. Results show a significant decline of the right ear advantage over time. In three of the patients a right ear advantage preoperativley changed to a left ear advantage 18 months postoperatively. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in stroke patients. Keywords: dichotic listening; aphasia; hemispheric dominance; deep brain stimulation; subthalamic nucleus
When verbal material is simultaneously presented to both the ears, healthy subjects typically perceive and/or remember stimuli presented in the right ear better than stimuli presented in the left ear. This advantage is shown provided that their language functions reside in the left hemisphere, which is almost always the case for right-handed individuals (Hiscock & Kinsbourne, 2011; Hugdahl et al., 2009; Kimura, 1961). However, in patients with stroke-induced aphasia this tendency is often absent or even reversed. A consistent finding in studies of patients with strokeinduced aphasia, published primarily during the 1980s, was that they, unlike in healthy controls, often showed a left ear advantage (LEA) during dichotic listening tasks (Crosson & Warren, 1981; Moore & Papanicolaou, 1988; Niccum & Speaks, 1991; Papanicolaou, Moore, Deutsch, Levin, & Eisenberg, 1988). Even though longitudinal studies of ear advantage (EA) – as measured both before and after these kinds of lesions – are lacking, it has been assumed that this finding represents a change in EA produced by the stroke. One possible explanation for this change is that it mirrors a hemispheric shift with regard to certain language functions. According to this hypothesis, a compensatory reorganization of language functions takes place after a stroke in the dominant hemisphere so that lost functions will gradually be compensated for by homologous areas in the contralateral hemisphere (i.e., Crosson et al., 2007; Crosson & Warren, 1981; Moore & Papanicolaou, 1988). However, based on longitudinal data collected during the first 6 months after a series of aphasia-induced strokes, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
Niccum, Selnes, Speaks, Risse, and Rubens (1986) argued against this interpretation. These authors concluded that their “data did not support the hypothesis that language recovery is mediated by a progressive shift in language dominance from the left to the right hemisphere during the first 6 months post onset.” Instead, Niccum et al. (1986) suggested that the effect might be caused by lesions of the primary auditory system rather than compensatory mechanisms. However, because recovery of language function is a process that often continues over the first year after a lesion, it may be argued that short-term observations do not settle the issue. It has consequently been argued that an ideal study should follow patients longitudinally for a longer period of time (Moore & Papanicolaou, 1992). During the late 1990s, the subthalamic nucleus (STN) emerged as an increasingly popular target for treatment with deep brain stimulation (DBS) of advanced motor symptoms of Parkinson’s disease (PD) (Deuschl et al., 2006; Weaver et al., 2009; Williams et al., 2010). Neuropsychological studies of the effects of STN DBS in PD patients have relatively consistently demonstrated negative effects on verbal fluency (Heo et al., 2008; Parsons, Rogers, Braaten, Woods, & Tröster, 2006; Weaver et al., 2009; York et al., 2008). The neurophysiological nature of the changes induced by DBS is not fully understood but is most often believed to mimic the effects of a lesion. Recent data indicate that unilateral STN DBS of the speech-dominant hemisphere is associated with significantly lower declines in measures of verbal fluency as
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compared to bilateral stimulation (Sjöberg et al., 2012). One possible explanation for these findings is that unilateral STN DBS allows for similar compensatory mechanisms in the contralateral hemisphere as has been discussed as an explanation for shifts of ear preference in strokeinduced aphasia. The purpose of the present study was to examine how unilateral DBS of the STN affects EA as measured preoperatively and approximately 6 and 18 months postoperatively. More specifically, we explored whether there would be a tendency toward a shift in EA similar to that observed in stroke patients discussed earlier. A second aim was to investigate whether such an effect is immediate, which has been described as consistent with a lesional hypothesis, or develops over time, as would be expected if the explanation is a reorganization of cortical networks.
Methods Participants The participants consisted of one woman and five men with PD who received unilateral electrode implantation on the left STN. The mean age at the time of surgery was 59.5 years (SD = 11.2). Mean time since PD diagnosis was 5.2 years (SD = 2.8). (Data on age and time since PD diagnosis were estimated by subtracting year of birth from year of PD diagnosis and year of surgery, respectively.) Further details on these patients have been presented by Sjöberg et al. (2012). The preoperative mean score on the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS III) was 16.2 (SD = 7.2) with 29.8 (SD = 5.8) without medication. With medication and stimulation on, the UPDRS III score was 10 (SD = 5.5) at the 6-month follow-up and 13.2 (SD = 5.3) at the 18-month follow up. All patients were treated with Levodopa; five with Pramipexole; four with Benserazide; three with Carbidopa, and one patient with Selegeline and Entacapone. Each patient was treated with virtually the same medications both pre- and postoperatively. The indication for unilateral left-sided DBS was in all patients right-sided hemi-parkinsonistic symptoms and insufficient relief with pharmacological treatment. The patients were selected for unilateral procedure on clinical grounds. They were considered by the responsible surgeon as having dominating right-sided motor symptoms, which led to the decision of unilateral left-sided STN DBS. The data included in this manuscript were obtained in compliance with the regulations of our institution and the guidelines of the Helsinki Declaration.
Surgical procedure Targets, coordinates, and trajectories for the stereotactic procedures were derived from T2-weighted MR images
using the Frame Link planning station (Medtronic, Minneapolis, MN, USA). The target was chosen about 1.5 mm lateral of the STN’s medial border, at the level of the maximum diameter of the red nucleus and at a line joining the anterior borders of these nuclei. The procedure was performed with local anesthesia. Microelectrode recording was not used, but the effect of stimulation from the DBS electrode (model 3389, Medtronic, Minneapolis, MN, USA) was evaluated clinically during the procedure. A stereotactic CT was performed during surgery, and the images were fused with the preoperative MRI for verification of electrode positions. Dichotic listening test Patients were, as part of a comprehensive neuropsychological evaluation that has previously been described elsewhere (Sjöberg et al., 2012), subjected to a dichotic listening task preoperatively and at approximately 6 and 18 months postoperatively. The Bergen Dichotic Listening Task (Hugdahl & Asbjørnsen, 1994) consists of dichotic stimuli in the form of six different consonant-vowel syllables (CV-syllables). Each CV-syllable is constructed from the vowel “a” in combination with the six stop-consonants “b,” “d,” “g,” “p,” “t,” and “k,” thus forming the following six basic CV-syllables: “ba,” “da,” “ga,” “pa,” “ta,” and “ka.” In making the dichotic pairs of stimuli, each syllable is combined with each of the other syllables including with itself, thus making a total of 6 × 6 = 36 dichotic pairs of syllables including six pairs with the same stimulus to both the ears (homonyms) and 30 pairs with different syllables to each ear, which are the “real” dichotic stimuli. The homonyms are used to get a check that the subject is able to correctly perceive each syllable when it is presented in isolation, which is a prerequisite for adequate interpretation of the dichotic results. The syllables are read by a synthetic, male, Swedish-sounding voice with intonation and intensity held constant. Each syllable has a duration of approximately 350 ms, and there is a short interval of approximately 4 s between each pair of syllables. This dichotic material is recorded three times with a pause of approximately 45 s between recordings. The pause allows the implementation of three different listening conditions – in this case a non-forced attention condition and two forced attention conditions. The order of the dichotic pairs is randomized during each of the three recordings. In this study a compact disc (CD) produced by the Swedish Psykologiförlaget (2000) was used to present the material to the subjects with stereophonic earphones. The test begins with the non-forced listening condition in which the subject listens with “free floating” attention and is simply instructed to report the syllable that is perceived most clearly after each pair. The accuracy of the reporting of the stimuli from each ear is calculated as a “percentage correct” score of the 30 dichotic stimuli to
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Neurocase each ear. The total from the non-forced condition is the percentage correct score of the total number of dichotic items presented to the right and left ear; that is, 30 + 30 = 60 items. After the completion of the non-forced condition, it is possible to compute an “EA,” which is defined as the difference of the percent correct score of the two ears. As previously mentioned, a right-handed individual is expected to have a “right ear advantage” (REA) due to language dominance of the left hemisphere (Kimura, 1961). People with right-hemisphere dominance for speech (e.g., left handers) are expected to show a LEA. In order to avoid false positives we followed recommendations by Professor Hugdahl (personal communication, 14 February 2014), who developed the Bergen Dichotic Listening Task, by requiring at least a 10% difference between the two ears to establish a REA or LEA as indicative of language dominance for the contralateral hemisphere instead of relying on a smaller difference. The non-forced condition is followed by a forced right condition in which the subject is instructed to pay attention only to the stimuli perceived in the right ear and only report these stimuli. The last phase is the forced left condition in which the subject is instructed to pay attention to and report only the stimuli from the left ear. Hugdahl et al. (2009) argue that by varying instructions about attention focus, a cognitive conflict situation is set up that demands a higher degree of cognitive control. The forced attention condition is thereby thought to involve a top-down modulation of a bottom-up lateralized REA effect. The forcedleft condition thus involves inhibitory control to a greater extent than the forced-right condition and requires executive attention in individuals showing a REA. The opposite effect should be expected in individuals with a LEA. The three conditions measure three different kinds of cognitive processes: a lateralized perceptual process (nonforced condition), an attention process (forced-right), and an executive cognitive control process (forced-left condition). The non-forced condition is the condition normally used to determine speech lateralization. The results from the forced attention conditions are calculated as a percent correct score of the 30 dichotic stimuli presented to the right and left ear respectively.
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Data analysis An initial analysis by means of a 2 (right or left ear) × 3 (testing preoperatively, and at 6 and 18 months postoperatively) repeated measures ANOVA was performed for both the forced and the non-forced conditions, respectively. If effects were found, these were further explored using qualitative measures (mainly for non-forced EA) and paired Student’s t-test for related samples. Our data on EA were of course parametric. However, because of the small number of observations, we also validated all our reported t-tests with a non-parametric test (Wilcoxon signed-rank test). The results were similar to those reported in the manuscript. That is, all t-tests that were reported as significant were also significant with the nonparametric test, all t-tests that were non-significant were also non-significant using the non-parametric test, and all tests that were reported as “not quite significant” (i.e., p > .05 but p < .1) were at the same level of significance using the non-parametric test.
Results Ear advantage in non-forced attention An initial 2 × 3 ANOVA revealed a main effect of ear (F(5) = 68.957, p < 0.0001) and a significant interaction between ear and time of testing (F(4) = 17.968, p = 0.010). As seen in Table 1, the right ear performance tended to decrease over time, and by 18 months postoperatively there had been a 29% change in REA (decrease of 14 percentage points) from the preoperative test. However, at this time there had also been a compensatory increase in the left ear performance of 38% (9.4 percentage points) and as a consequence the REA shown at the group level had been reduced to only 1.1%. When these trends were investigated with Student’s t-test, the difference between the right and left ear conditions was significant preoperatively (t(5) = 3.194, p = 0.024) and at the 6-month follow-up (t(5) = 4.326, p = 0.008), whereas the 1.1% difference seen at the 18-month follow-up was not significant.
Table 1. Means and standard deviations for right and left ear performances in forced and non-forced conditions during a dichotic listening tasks for six Parkinson’s disease patients receiving deep brain stimulation of the left subthalamic nucleus. Non-forced
Preoperatively 6 months postoperatively 18 months postoperatively
Right ear Left ear Right ear Left ear Right ear Left ear
Forced
Mean (%)
SD (%)
Mean (%)
SD (%)
49.4 24.5 46.1 23.3 35.0 33.9
8.8 11.3 12.4 4.2 9.6 9.0
59.4 34.4 53.3 37.7 46.1 38.3
15.3 15.3 19.3 17.4 18.5 20.1
Note: Testing made preoperatively, and at 6 and 18 months postoperatively.
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Regarding right ear performance deterioration over time, the difference between right ear performance preoperatively and at the 6-month follow-up was not significant, whereas the difference between the 6- and 18-month follow-ups was significant (t(5) = 3.627, p = 0.015). The difference between the preoperative testing and the 18-month follow-up did not quite reach significance (t(5) = 2.025, p = 0.099). With regard to the increase in left ear performance, there was actually a slight, but non-significant deterioration between the preoperative testing and the 6-month follow-up. However there was a clear increase between the 6-month and 18-month follow-up that was significant (t(5) = –3.629, p = 0.015). The difference between the preoperative testing and the 18month follow-up was close to significant (t(5) = –2.025, p = 0.099). When we used the qualitative criterion applied at our clinic of a 10% difference between right and left ear performance in the non-forced conditions to establish a clear REA or LEA at the individual level, we found that five of the six (83%) individuals in the group operated on the left side showed a clear REA before surgery, whereas the result for the remaining individual was inconclusive. At the first postoperative follow-up, all participants had a clear REA, but at the 18-month follow-up only two (33%) of the studied patients showed a clear REA. Two individuals showed a LEA, and results for the remaining two were inconclusive (Figure 1).
Forced attention As seen in Table 1, data from the forced attention tests showed somewhat similar trends as those of the nonforced attention tests. That is, right ear performance tended to decrease, whereas left ear performance tended to 6 5 4 REA LEA Inconclusive
3 2 1 0
Preop
6 months 18 months
Figure 1. Number of patients (y-axis) with right ear advantage (REA) or left ear advantage (LEA) as measured by the nonforced condition of the dichotic listening task preoperatively and at 6 and 18 months follow-up for six patients with Parkinson’s disease who received deep brain stimulation of the subthalamic nucleus. An ear advantage of less than 10% was deemed inconclusive.
increase. However, because the initial 2 × 3 ANOVA did not reveal any significant main or interaction effects, we did not statistically further explore these trends. Discussion The results of this study indicate that a postoperative decrease of the REA occurred as a result of the STN DBS treatment. This was noted on the group level and in addition, in two of the patients a preoperative REA changed to a LEA at 18 months postoperatively. Test–retest correlations are far from perfect in dichotic listening tasks; however, changes in EA between testing occasions, such as those seen in the present study, are quite unusual in healthy subjects (i.e., Gadea, Gomez, & Espert, 2000; Hugdahl & Hammar, 1997). These results are reminiscent of previous findings described in patients with left-sided stroke-induced lesions involving language areas. However, unlike the previous stroke studies, the six patients presented here were tested with a dichotic listening task both before and at two time periods after surgery. There are several possible explanations for the tendency of patients with stroke-induced aphasia to develop a LEA. According to the lesional hypothesis advocated by Niccum et al. (1986), Schulhoff and Goodglass (1969), and others, this phenomenon is best explained by selective brain damage. Both our finding and those by Niccum et al. (1986) show no detectable compensatory development of left ear performance during the first 6 months. In our opinion this would seem to speak against an interpretation of this phenomenon as an immediate effect caused by a lesion. That is, a lesion would in our view be an event expected to cause more or less immediate effects (e.g., Fytagoridis et al., 2013). A functional reorganization on the other hand could be considered a process rather than an event and should be expected to develop over time. According to such a functional reorganization hypothesis advocated by Crosson and Warren (1981), Moore and Papanicolaou (1988) and others, shifts in EA in stroke patients are best understood as effects of cortical and subcortical reorganization where the functions of damaged areas are relocated to homologous structures in the contralateral hemisphere. The seemingly revolutionary idea that the shift of EA commonly seen in patients with stroke-induced aphasia mirrors a partial or even complete shift in hemispheric language function was discussed as early as the late nineteenth century (Barlow, 1877). Circumstantial evidence for this hypothesis has since been presented using data from several different modalities (e.g., Crosson et al., 2007; Kinsbourne, 1971; Moore & Papanicolaou, 1988; Papanicolaou et al., 1988; Partovi et al., 2012). Meanwhile, clinical observations and research increasingly suggest that the brain is a dynamic entity capable of functional reorganization in the wake of structural
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Neurocase challenges and injuries (e.g., Benzagmout, Gatignol, & Duffau, 2007; Duffau, 2012; Hamilton, Chrysikou, & Coslett, 2011; Musso et al., 1999). Even though our findings may be interpreted as consistent with a reorganizational hypothesis, it is of course not possible to pinpoint exactly if and, in such case, to what extent such reorganization involves hemispheric transfer of specific language functions. Thus, perhaps the most important conclusion that can be drawn from our results is that additional longitudinal studies of patients who have been subject to unilateral STN DBS procedures, for instance with functional MRI techniques, can provide useful clues in understanding this issue. Another possibility would be to do a similar study in on/off conditions to determine the impact of DBS stimulation. However, our results indicate that there is considerable need of time for shift of EA to take place and short-term effects are unlikely. Some limitations of our findings are that the main results rely on a few statistical analyses and, from a statistical point of view, a limited number of patients. The small sample size may of course make the results sensitive to outliers but may also lead to false-negative findings because of a lack of statistical power to detect differences. It should also be noted that even though previous literature demonstrates that changes in ear performance on the individual level are unusual, we did not apply the dichotic testing procedures presented in this study to non-operated PD controls. The lack of a control group means that there is a theoretical possibility that the tendency of the right EA to disappear over time may have other causes than the surgery. One such possible cause would be aging. Age effects in the dichotic listening task have previously been reported. The results are to our knowledge inconclusive. This might be due to differences in study design and different versions of the dichotic listening task have also been used. Hugdahl et al. (2009) suggested that elderly individuals (aged 60 and above) show impaired performance in the forced-left condition, due to cognitive decline with regard to cognitive control and executive functioning. In the other two conditions (forced-right and non-forced) the elderly group showed no significant differences. A similar conclusion was drawn in a study by Gootjes, Van Strien, and Bouma (2004), where an increased asymmetry was found in the focused attention task in an elderly population. This was however not seen in the non-forced attention condition, suggesting declined frontal activity in the elderly. Since we determined EA using the non-forced attention task, these findings are not directly relevant to our results. However, it should be noted that Passow et al. (2012) found weaker or absent REA in their study of attentional control of auditory perception and suggested that this might be due to bilateralized functional language networks and more perceptionally driven behavior and less efficient attentional control in older adults.
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All patients received traditional medication for their Parkinson, both prior to surgery and after. This may of course have an effect on neuropsychological tests of attention. However, earlier studies on the same group of patients (Sjöberg et al., 2012) revealed no significant changes on neuropsychological tests pre- or postoperatively. As stated earlier, the dichotic listening task measures three different kinds of cognitive processes: a lateralized perceptual process, an attention process, and an executive cognitive control process. We only see changes in the first lateralized perceptual condition. This is the condition during which EA as an indication of speech lateralization is commonly tested. In sum, the result of the present study, which to our knowledge is the first to longitudinally apply a dichotic listening task to PD patients operated with left-sided STN DBS, demonstrated significant effects of the treatment on EA as measured with the dichotic listening task under the nonforced condition. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in, for example, stroke patients. Disclosure statement M.H. has received occasional travel expenses and honoraria from Medtronic and St Jude for speaking at meetings. J.L. served on the scientific advisory board for Glaxo Smith Kline, H Lundbeck, and Boehringer Ingelheim and received lecture honoraria from Medtronic Inc., Solvay, Orion Pharma, UCB Pharma, and Nordic Infu Care.
Funding This work was supported by grants from Olle Engkvist Byggmästare, the University of Umeå and the Foundation for Clinical Neuroscience at the University Hospital of Umeå. M.H. is supported by the Edmond J. Safra Philanthropic Foundation, the Monument Trust and the Parkinsons Appeal, UK.
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Musso, M., Weiller, C., Kiebel, S., Müller, S. P., Bülau, P., & Rijntjes, M. (1999). Training-induced brain plasticity in aphasia. Brain, 122, 1781–1790. doi:10.1093/brain/ 122.9.1781 Niccum, N., Selnes, O. A., Speaks, C., Risse, G. L., & Rubens, A. B. (1986). Longitudinal dichotic listening patterns for aphasic patients III: Relationship to language and memory variables. Brain and Language, 28, 303–317. doi:10.1016/ 0093-934X(86)90107-0 Niccum, N., & Speaks, C. (1991). Interpretation of outcome on dichotic listening tests following stroke. Journal of Clinical and Experimental Neuropsychology, 13, 614–628. doi:10.1080/01688639108401076 Papanicolaou, A. C., Moore, B. D., Deutsch, G., Levin, H. S., & Eisenberg, H. M. (1988). Evidence for right-hemisphere involvement in recovery from aphasia. Archives of Neurology, 45, 1025–1029. doi:10.1001/archneur.1988.0052 0330117020 Parsons, T. D., Rogers, S. A., Braaten, A. J., Woods, S. P., & Tröster, A. (2006). Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: A meta analysis. The Lancet Neurology, 5, 578–588. doi:10.1016/S1474-4422(06)70475-6 Partovi, S., Jacobi, B., Rapps, N., Zipp, L., Karimi, S., Rengier, F., … Stippich, C. (2012). Clinical standardized fMRI reveals altered language lateralization in patients with brain tumor. American Journal of Neuroradiology, 33, 2151–2157. doi:10.3174/ajnr.A3137 Passow, S., Westerhausen, R., Wartenburger, I., Hugdahl, K., Heekeren, H. R., Lindenberger, U., & Li, S.-C. (2012). Human aging compromises attentional control of auditory perception. Psychology and Aging, 27, 99–105. doi:10.1037/a0025667 Schulhoff, C., & Goodglass, H. (1969). Dichotic listening, side of brain injury and cerebral dominance. Neuropsychologia, 7, 149–160. doi:10.1016/0028-3932(69)90012-8 Sjöberg, R. L., Lidman, E., Häggström, B., Hariz, M. I., Linder, J., Fredricks, A., & Blomstedt, P. (2012). Verbal fluency in patients receiving bilateral versus left-sided deep brain stimulation of the subthalamic nucleus for Parkinson’s disease. Journal of the International Neuropsychological Society, 18, 606–611. doi:10.1017/S1355617711001925 Weaver, F. M., Follet, K., Stern, M., Hur, K., Harris, C., Marks Jr., W. J., … Huang, G. D. (2009). Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: A randomized controlled trial. JAMA, 301, 63–73. doi:10.1001/jama.2008.929 Williams, A., Gill, S., Varma, T., Jenkinson, C., Quinn, N., Mitchell, R., … Wheatley, K. (2010). Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): A randomised, open-label trial. The Lancet Neurology, 9, 581–591. doi:10.1016/S1474-4422(10)70093-4 York, M. K., Dulay, M., Macias, A., Levin, H. S., Grossman, R., Simpson, R., & Jankovic, J. (2008). Cognitive declines following bilateral subthalamic nucleus deep brain stimulation for the treatment of Parkinson’s disease. Journal of Neurology, Neurosurgery and Psychiatry, 79, 789–795. doi:10.1136/jnnp.2007.118786
ISSN: 1355-4794 (Print) 1465-3656 (Online) Journal homepage: http://www.tandfonline.com/loi/nncs20
Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease Rickard L. Sjöberg, Björn Häggström, Johanna Philipsson, Jan Linder, Marwan Hariz & Patric Blomstedt To cite this article: Rickard L. Sjöberg, Björn Häggström, Johanna Philipsson, Jan Linder, Marwan Hariz & Patric Blomstedt (2015) Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease, Neurocase, 21:5, 601-606, DOI: 10.1080/13554794.2014.960427 To link to this article: http://dx.doi.org/10.1080/13554794.2014.960427
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Date: 09 November 2015, At: 21:22
Neurocase, 2015 Vol. 21, No. 5, 601–606, http://dx.doi.org/10.1080/13554794.2014.960427
Laterality and deep brain stimulation of the subthalamic nucleus: applying a dichotic listening task to patients treated for Parkinson’s disease Rickard L. Sjöberga*, Björn Häggströma, Johanna Philipssona, Jan Lindera, Marwan Hariza,b and Patric Blomstedta a
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden; bInstitute of Neurology, University College London, London, UK
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(Received 12 July 2013; accepted 26 August 2014) Ear advantage during a dichotic listening task tends to mirror speech lateralization. Previous studies in stroke patients have shown that lesions in the dominant hemisphere often seem to produce changes in ear advantage. In this study six Parkinson’s disease (PD) patients treated for motor symptoms with deep brain stimulation (DBS) of the left subthalamic nucleus (STN) were tested preoperatively and at approximately 6 and 18 months postoperatively with a dichotic listening task. Results show a significant decline of the right ear advantage over time. In three of the patients a right ear advantage preoperativley changed to a left ear advantage 18 months postoperatively. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in stroke patients. Keywords: dichotic listening; aphasia; hemispheric dominance; deep brain stimulation; subthalamic nucleus
When verbal material is simultaneously presented to both the ears, healthy subjects typically perceive and/or remember stimuli presented in the right ear better than stimuli presented in the left ear. This advantage is shown provided that their language functions reside in the left hemisphere, which is almost always the case for right-handed individuals (Hiscock & Kinsbourne, 2011; Hugdahl et al., 2009; Kimura, 1961). However, in patients with stroke-induced aphasia this tendency is often absent or even reversed. A consistent finding in studies of patients with strokeinduced aphasia, published primarily during the 1980s, was that they, unlike in healthy controls, often showed a left ear advantage (LEA) during dichotic listening tasks (Crosson & Warren, 1981; Moore & Papanicolaou, 1988; Niccum & Speaks, 1991; Papanicolaou, Moore, Deutsch, Levin, & Eisenberg, 1988). Even though longitudinal studies of ear advantage (EA) – as measured both before and after these kinds of lesions – are lacking, it has been assumed that this finding represents a change in EA produced by the stroke. One possible explanation for this change is that it mirrors a hemispheric shift with regard to certain language functions. According to this hypothesis, a compensatory reorganization of language functions takes place after a stroke in the dominant hemisphere so that lost functions will gradually be compensated for by homologous areas in the contralateral hemisphere (i.e., Crosson et al., 2007; Crosson & Warren, 1981; Moore & Papanicolaou, 1988). However, based on longitudinal data collected during the first 6 months after a series of aphasia-induced strokes, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
Niccum, Selnes, Speaks, Risse, and Rubens (1986) argued against this interpretation. These authors concluded that their “data did not support the hypothesis that language recovery is mediated by a progressive shift in language dominance from the left to the right hemisphere during the first 6 months post onset.” Instead, Niccum et al. (1986) suggested that the effect might be caused by lesions of the primary auditory system rather than compensatory mechanisms. However, because recovery of language function is a process that often continues over the first year after a lesion, it may be argued that short-term observations do not settle the issue. It has consequently been argued that an ideal study should follow patients longitudinally for a longer period of time (Moore & Papanicolaou, 1992). During the late 1990s, the subthalamic nucleus (STN) emerged as an increasingly popular target for treatment with deep brain stimulation (DBS) of advanced motor symptoms of Parkinson’s disease (PD) (Deuschl et al., 2006; Weaver et al., 2009; Williams et al., 2010). Neuropsychological studies of the effects of STN DBS in PD patients have relatively consistently demonstrated negative effects on verbal fluency (Heo et al., 2008; Parsons, Rogers, Braaten, Woods, & Tröster, 2006; Weaver et al., 2009; York et al., 2008). The neurophysiological nature of the changes induced by DBS is not fully understood but is most often believed to mimic the effects of a lesion. Recent data indicate that unilateral STN DBS of the speech-dominant hemisphere is associated with significantly lower declines in measures of verbal fluency as
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compared to bilateral stimulation (Sjöberg et al., 2012). One possible explanation for these findings is that unilateral STN DBS allows for similar compensatory mechanisms in the contralateral hemisphere as has been discussed as an explanation for shifts of ear preference in strokeinduced aphasia. The purpose of the present study was to examine how unilateral DBS of the STN affects EA as measured preoperatively and approximately 6 and 18 months postoperatively. More specifically, we explored whether there would be a tendency toward a shift in EA similar to that observed in stroke patients discussed earlier. A second aim was to investigate whether such an effect is immediate, which has been described as consistent with a lesional hypothesis, or develops over time, as would be expected if the explanation is a reorganization of cortical networks.
Methods Participants The participants consisted of one woman and five men with PD who received unilateral electrode implantation on the left STN. The mean age at the time of surgery was 59.5 years (SD = 11.2). Mean time since PD diagnosis was 5.2 years (SD = 2.8). (Data on age and time since PD diagnosis were estimated by subtracting year of birth from year of PD diagnosis and year of surgery, respectively.) Further details on these patients have been presented by Sjöberg et al. (2012). The preoperative mean score on the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS III) was 16.2 (SD = 7.2) with 29.8 (SD = 5.8) without medication. With medication and stimulation on, the UPDRS III score was 10 (SD = 5.5) at the 6-month follow-up and 13.2 (SD = 5.3) at the 18-month follow up. All patients were treated with Levodopa; five with Pramipexole; four with Benserazide; three with Carbidopa, and one patient with Selegeline and Entacapone. Each patient was treated with virtually the same medications both pre- and postoperatively. The indication for unilateral left-sided DBS was in all patients right-sided hemi-parkinsonistic symptoms and insufficient relief with pharmacological treatment. The patients were selected for unilateral procedure on clinical grounds. They were considered by the responsible surgeon as having dominating right-sided motor symptoms, which led to the decision of unilateral left-sided STN DBS. The data included in this manuscript were obtained in compliance with the regulations of our institution and the guidelines of the Helsinki Declaration.
Surgical procedure Targets, coordinates, and trajectories for the stereotactic procedures were derived from T2-weighted MR images
using the Frame Link planning station (Medtronic, Minneapolis, MN, USA). The target was chosen about 1.5 mm lateral of the STN’s medial border, at the level of the maximum diameter of the red nucleus and at a line joining the anterior borders of these nuclei. The procedure was performed with local anesthesia. Microelectrode recording was not used, but the effect of stimulation from the DBS electrode (model 3389, Medtronic, Minneapolis, MN, USA) was evaluated clinically during the procedure. A stereotactic CT was performed during surgery, and the images were fused with the preoperative MRI for verification of electrode positions. Dichotic listening test Patients were, as part of a comprehensive neuropsychological evaluation that has previously been described elsewhere (Sjöberg et al., 2012), subjected to a dichotic listening task preoperatively and at approximately 6 and 18 months postoperatively. The Bergen Dichotic Listening Task (Hugdahl & Asbjørnsen, 1994) consists of dichotic stimuli in the form of six different consonant-vowel syllables (CV-syllables). Each CV-syllable is constructed from the vowel “a” in combination with the six stop-consonants “b,” “d,” “g,” “p,” “t,” and “k,” thus forming the following six basic CV-syllables: “ba,” “da,” “ga,” “pa,” “ta,” and “ka.” In making the dichotic pairs of stimuli, each syllable is combined with each of the other syllables including with itself, thus making a total of 6 × 6 = 36 dichotic pairs of syllables including six pairs with the same stimulus to both the ears (homonyms) and 30 pairs with different syllables to each ear, which are the “real” dichotic stimuli. The homonyms are used to get a check that the subject is able to correctly perceive each syllable when it is presented in isolation, which is a prerequisite for adequate interpretation of the dichotic results. The syllables are read by a synthetic, male, Swedish-sounding voice with intonation and intensity held constant. Each syllable has a duration of approximately 350 ms, and there is a short interval of approximately 4 s between each pair of syllables. This dichotic material is recorded three times with a pause of approximately 45 s between recordings. The pause allows the implementation of three different listening conditions – in this case a non-forced attention condition and two forced attention conditions. The order of the dichotic pairs is randomized during each of the three recordings. In this study a compact disc (CD) produced by the Swedish Psykologiförlaget (2000) was used to present the material to the subjects with stereophonic earphones. The test begins with the non-forced listening condition in which the subject listens with “free floating” attention and is simply instructed to report the syllable that is perceived most clearly after each pair. The accuracy of the reporting of the stimuli from each ear is calculated as a “percentage correct” score of the 30 dichotic stimuli to
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Neurocase each ear. The total from the non-forced condition is the percentage correct score of the total number of dichotic items presented to the right and left ear; that is, 30 + 30 = 60 items. After the completion of the non-forced condition, it is possible to compute an “EA,” which is defined as the difference of the percent correct score of the two ears. As previously mentioned, a right-handed individual is expected to have a “right ear advantage” (REA) due to language dominance of the left hemisphere (Kimura, 1961). People with right-hemisphere dominance for speech (e.g., left handers) are expected to show a LEA. In order to avoid false positives we followed recommendations by Professor Hugdahl (personal communication, 14 February 2014), who developed the Bergen Dichotic Listening Task, by requiring at least a 10% difference between the two ears to establish a REA or LEA as indicative of language dominance for the contralateral hemisphere instead of relying on a smaller difference. The non-forced condition is followed by a forced right condition in which the subject is instructed to pay attention only to the stimuli perceived in the right ear and only report these stimuli. The last phase is the forced left condition in which the subject is instructed to pay attention to and report only the stimuli from the left ear. Hugdahl et al. (2009) argue that by varying instructions about attention focus, a cognitive conflict situation is set up that demands a higher degree of cognitive control. The forced attention condition is thereby thought to involve a top-down modulation of a bottom-up lateralized REA effect. The forcedleft condition thus involves inhibitory control to a greater extent than the forced-right condition and requires executive attention in individuals showing a REA. The opposite effect should be expected in individuals with a LEA. The three conditions measure three different kinds of cognitive processes: a lateralized perceptual process (nonforced condition), an attention process (forced-right), and an executive cognitive control process (forced-left condition). The non-forced condition is the condition normally used to determine speech lateralization. The results from the forced attention conditions are calculated as a percent correct score of the 30 dichotic stimuli presented to the right and left ear respectively.
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Data analysis An initial analysis by means of a 2 (right or left ear) × 3 (testing preoperatively, and at 6 and 18 months postoperatively) repeated measures ANOVA was performed for both the forced and the non-forced conditions, respectively. If effects were found, these were further explored using qualitative measures (mainly for non-forced EA) and paired Student’s t-test for related samples. Our data on EA were of course parametric. However, because of the small number of observations, we also validated all our reported t-tests with a non-parametric test (Wilcoxon signed-rank test). The results were similar to those reported in the manuscript. That is, all t-tests that were reported as significant were also significant with the nonparametric test, all t-tests that were non-significant were also non-significant using the non-parametric test, and all tests that were reported as “not quite significant” (i.e., p > .05 but p < .1) were at the same level of significance using the non-parametric test.
Results Ear advantage in non-forced attention An initial 2 × 3 ANOVA revealed a main effect of ear (F(5) = 68.957, p < 0.0001) and a significant interaction between ear and time of testing (F(4) = 17.968, p = 0.010). As seen in Table 1, the right ear performance tended to decrease over time, and by 18 months postoperatively there had been a 29% change in REA (decrease of 14 percentage points) from the preoperative test. However, at this time there had also been a compensatory increase in the left ear performance of 38% (9.4 percentage points) and as a consequence the REA shown at the group level had been reduced to only 1.1%. When these trends were investigated with Student’s t-test, the difference between the right and left ear conditions was significant preoperatively (t(5) = 3.194, p = 0.024) and at the 6-month follow-up (t(5) = 4.326, p = 0.008), whereas the 1.1% difference seen at the 18-month follow-up was not significant.
Table 1. Means and standard deviations for right and left ear performances in forced and non-forced conditions during a dichotic listening tasks for six Parkinson’s disease patients receiving deep brain stimulation of the left subthalamic nucleus. Non-forced
Preoperatively 6 months postoperatively 18 months postoperatively
Right ear Left ear Right ear Left ear Right ear Left ear
Forced
Mean (%)
SD (%)
Mean (%)
SD (%)
49.4 24.5 46.1 23.3 35.0 33.9
8.8 11.3 12.4 4.2 9.6 9.0
59.4 34.4 53.3 37.7 46.1 38.3
15.3 15.3 19.3 17.4 18.5 20.1
Note: Testing made preoperatively, and at 6 and 18 months postoperatively.
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Regarding right ear performance deterioration over time, the difference between right ear performance preoperatively and at the 6-month follow-up was not significant, whereas the difference between the 6- and 18-month follow-ups was significant (t(5) = 3.627, p = 0.015). The difference between the preoperative testing and the 18-month follow-up did not quite reach significance (t(5) = 2.025, p = 0.099). With regard to the increase in left ear performance, there was actually a slight, but non-significant deterioration between the preoperative testing and the 6-month follow-up. However there was a clear increase between the 6-month and 18-month follow-up that was significant (t(5) = –3.629, p = 0.015). The difference between the preoperative testing and the 18month follow-up was close to significant (t(5) = –2.025, p = 0.099). When we used the qualitative criterion applied at our clinic of a 10% difference between right and left ear performance in the non-forced conditions to establish a clear REA or LEA at the individual level, we found that five of the six (83%) individuals in the group operated on the left side showed a clear REA before surgery, whereas the result for the remaining individual was inconclusive. At the first postoperative follow-up, all participants had a clear REA, but at the 18-month follow-up only two (33%) of the studied patients showed a clear REA. Two individuals showed a LEA, and results for the remaining two were inconclusive (Figure 1).
Forced attention As seen in Table 1, data from the forced attention tests showed somewhat similar trends as those of the nonforced attention tests. That is, right ear performance tended to decrease, whereas left ear performance tended to 6 5 4 REA LEA Inconclusive
3 2 1 0
Preop
6 months 18 months
Figure 1. Number of patients (y-axis) with right ear advantage (REA) or left ear advantage (LEA) as measured by the nonforced condition of the dichotic listening task preoperatively and at 6 and 18 months follow-up for six patients with Parkinson’s disease who received deep brain stimulation of the subthalamic nucleus. An ear advantage of less than 10% was deemed inconclusive.
increase. However, because the initial 2 × 3 ANOVA did not reveal any significant main or interaction effects, we did not statistically further explore these trends. Discussion The results of this study indicate that a postoperative decrease of the REA occurred as a result of the STN DBS treatment. This was noted on the group level and in addition, in two of the patients a preoperative REA changed to a LEA at 18 months postoperatively. Test–retest correlations are far from perfect in dichotic listening tasks; however, changes in EA between testing occasions, such as those seen in the present study, are quite unusual in healthy subjects (i.e., Gadea, Gomez, & Espert, 2000; Hugdahl & Hammar, 1997). These results are reminiscent of previous findings described in patients with left-sided stroke-induced lesions involving language areas. However, unlike the previous stroke studies, the six patients presented here were tested with a dichotic listening task both before and at two time periods after surgery. There are several possible explanations for the tendency of patients with stroke-induced aphasia to develop a LEA. According to the lesional hypothesis advocated by Niccum et al. (1986), Schulhoff and Goodglass (1969), and others, this phenomenon is best explained by selective brain damage. Both our finding and those by Niccum et al. (1986) show no detectable compensatory development of left ear performance during the first 6 months. In our opinion this would seem to speak against an interpretation of this phenomenon as an immediate effect caused by a lesion. That is, a lesion would in our view be an event expected to cause more or less immediate effects (e.g., Fytagoridis et al., 2013). A functional reorganization on the other hand could be considered a process rather than an event and should be expected to develop over time. According to such a functional reorganization hypothesis advocated by Crosson and Warren (1981), Moore and Papanicolaou (1988) and others, shifts in EA in stroke patients are best understood as effects of cortical and subcortical reorganization where the functions of damaged areas are relocated to homologous structures in the contralateral hemisphere. The seemingly revolutionary idea that the shift of EA commonly seen in patients with stroke-induced aphasia mirrors a partial or even complete shift in hemispheric language function was discussed as early as the late nineteenth century (Barlow, 1877). Circumstantial evidence for this hypothesis has since been presented using data from several different modalities (e.g., Crosson et al., 2007; Kinsbourne, 1971; Moore & Papanicolaou, 1988; Papanicolaou et al., 1988; Partovi et al., 2012). Meanwhile, clinical observations and research increasingly suggest that the brain is a dynamic entity capable of functional reorganization in the wake of structural
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Neurocase challenges and injuries (e.g., Benzagmout, Gatignol, & Duffau, 2007; Duffau, 2012; Hamilton, Chrysikou, & Coslett, 2011; Musso et al., 1999). Even though our findings may be interpreted as consistent with a reorganizational hypothesis, it is of course not possible to pinpoint exactly if and, in such case, to what extent such reorganization involves hemispheric transfer of specific language functions. Thus, perhaps the most important conclusion that can be drawn from our results is that additional longitudinal studies of patients who have been subject to unilateral STN DBS procedures, for instance with functional MRI techniques, can provide useful clues in understanding this issue. Another possibility would be to do a similar study in on/off conditions to determine the impact of DBS stimulation. However, our results indicate that there is considerable need of time for shift of EA to take place and short-term effects are unlikely. Some limitations of our findings are that the main results rely on a few statistical analyses and, from a statistical point of view, a limited number of patients. The small sample size may of course make the results sensitive to outliers but may also lead to false-negative findings because of a lack of statistical power to detect differences. It should also be noted that even though previous literature demonstrates that changes in ear performance on the individual level are unusual, we did not apply the dichotic testing procedures presented in this study to non-operated PD controls. The lack of a control group means that there is a theoretical possibility that the tendency of the right EA to disappear over time may have other causes than the surgery. One such possible cause would be aging. Age effects in the dichotic listening task have previously been reported. The results are to our knowledge inconclusive. This might be due to differences in study design and different versions of the dichotic listening task have also been used. Hugdahl et al. (2009) suggested that elderly individuals (aged 60 and above) show impaired performance in the forced-left condition, due to cognitive decline with regard to cognitive control and executive functioning. In the other two conditions (forced-right and non-forced) the elderly group showed no significant differences. A similar conclusion was drawn in a study by Gootjes, Van Strien, and Bouma (2004), where an increased asymmetry was found in the focused attention task in an elderly population. This was however not seen in the non-forced attention condition, suggesting declined frontal activity in the elderly. Since we determined EA using the non-forced attention task, these findings are not directly relevant to our results. However, it should be noted that Passow et al. (2012) found weaker or absent REA in their study of attentional control of auditory perception and suggested that this might be due to bilateralized functional language networks and more perceptionally driven behavior and less efficient attentional control in older adults.
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All patients received traditional medication for their Parkinson, both prior to surgery and after. This may of course have an effect on neuropsychological tests of attention. However, earlier studies on the same group of patients (Sjöberg et al., 2012) revealed no significant changes on neuropsychological tests pre- or postoperatively. As stated earlier, the dichotic listening task measures three different kinds of cognitive processes: a lateralized perceptual process, an attention process, and an executive cognitive control process. We only see changes in the first lateralized perceptual condition. This is the condition during which EA as an indication of speech lateralization is commonly tested. In sum, the result of the present study, which to our knowledge is the first to longitudinally apply a dichotic listening task to PD patients operated with left-sided STN DBS, demonstrated significant effects of the treatment on EA as measured with the dichotic listening task under the nonforced condition. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in, for example, stroke patients. Disclosure statement M.H. has received occasional travel expenses and honoraria from Medtronic and St Jude for speaking at meetings. J.L. served on the scientific advisory board for Glaxo Smith Kline, H Lundbeck, and Boehringer Ingelheim and received lecture honoraria from Medtronic Inc., Solvay, Orion Pharma, UCB Pharma, and Nordic Infu Care.
Funding This work was supported by grants from Olle Engkvist Byggmästare, the University of Umeå and the Foundation for Clinical Neuroscience at the University Hospital of Umeå. M.H. is supported by the Edmond J. Safra Philanthropic Foundation, the Monument Trust and the Parkinsons Appeal, UK.
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