Chronic Electrical Stimulation of the Left Ventrointermediate (Vim) Thalamic Nucleus for the Treatment of Pharmacotherapy-Resistant Parkinson's Disease: A Differential Impact on Access to Semantic and Episodic Memory?

38, 125–149 (1998) BR981025 BRAIN AND COGNITION ARTICLE NO. Chronic Electrical Stimulation of the Left Ventrointermediate (Vim) Thalamic Nucleus for the Treatment of Pharmacotherapy-Resistant Parkinson’s Disease: A Differential Impact on Access to Semantic and Episodic Memory? Alexander I. Tröster,* Steven B. Wilkinson,† Julie A. Fields,‡ Karen Miyawaki,i and William C. Koller i *Department of Neurology, University of Kansas Medical Center and Center for Neuropsychology and Cognitive Neuroscience, University of Kansas Hospital; †Division of Neurological Surgery, University of Kansas Medical Center; ‡Center for Neuropsychology and Cognitive Neuroscience, University of Kansas Hospital; and iDepartment of Neurology, University of Kansas Medical Center Thalamotomy for medically refractory Parkinson’s disease (PD) is considered to be efficacious and relatively safe. Because a minority of patients experience decrements in language and memory (often mild and transient) after thalamotomy, chronic thalamic deep brain stimulation (DBS) might be a safer treatment given its reversibility and the modifiability of stimulation parameters. Two preliminary studies support the relative cognitive safety of unilateral DBS of the ventral intermediate (Vim) thalamic nucleus, but it is unclear whether possibly subtle changes in language and memory represent effects of ‘‘microthalamotomy’’ or of stimulation per se. This report provides preliminary data concerning effects of left thalamic stimulation on information processing speed, semantic memory (verbal fluency and visual confrontation naming), and verbal episodic memory in a patient with PD. In addition to being evaluated before and 3 and 6 months after surgery, the patient was tested 18 months after surgery either on or off medications and with the stimulator turned either on or off (order counterbalanced across medication conditions). Test performance differences between the stimulation conditions were attenuated ‘‘off ’’ as compared to ‘‘on’’ medication. Vim stimulation consistently, albeit subtly, improved semantic verbal fluency but interfered with immediate recall of word lists. Parallels to findings from acute, intraoperative thalamic stimulation studies are ex- The authors thank Dr. Harry A. Whitaker for discussing this case and for suggesting postsurgical cognitive evaluation with the stimulator on and off. Address correspondence and reprint requests to Alexander I. Tröster, Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 661607314. Fax: (913) 588-6965. E-mail: atroster@kumc.edu. 125 0278-2626/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved. 126 TRÖSTER ET AL. plored. The hypothesis is offered that left Vim stimulation might facilitate access to semantic memory, but interfere with episodic memory processes.  1998 Academic Press INTRODUCTION Surgical treatments for movement disorders evolved through several relatively distinct phases (for reviews see Guridi & Lozano, 1997; Siegfried & Blond, 1997; Tröster, 1998). The first surgical procedures begun in the late 19th century were ‘‘open’’ operations targeting the pyramidal system (e.g., Horsley, 1909). The ‘‘open’’ pyramidal system operations were only slowly replaced during the 1940s with ‘‘open’’ operations targeting the extrapyramidal system after Meyers carried out the first such operation in 1939 (Meyers, 1942). The first stereotactic pallidotomy was carried out in 1948 (Spiegel & Wycis, 1952). Stereotactic operations were widely carried out for Parkinson’s disease (PD) in the 1950s and 1960s, although pallidotomy was almost entirely abandoned after Hassler and Riechert’s (1954) report extolled the virtues of thalamotomy, and campotomy (e.g., Spiegel, Wycis, Szekely, Adams, Flanagan, & Baird, 1963) never found widespread appeal. Just as the advent of levodopa treatment in 1968 heralded a dramatic decline in the surgical treatment for PD, the empirical documentation of the limitations of pharmacotherapy for PD, together with an improved understanding of basal ganglia (patho)physiology and technical advances in radiology, stereotaxis, and electrophysiology, has prompted a resurgence in the neurosurgical treatment of PD (Diederich & Alesch, 1997; Goetz & Diederich, 1996; Klockgether, Löschmann, & Wüllner, 1994; Obeso, Guridi, & DeLong, 1997; Olanow, Marsden, Lang, & Goetz, 1994; Ostertag, Lücking, Mehdorn, & Deuschl, 1997). The 1980s and 1990s have witnessed a renaissance of pallidotomy (e.g., Bakay, DeLong, & Vitek, 1992; Dogali, Fazzini, Kolodny, Eidelberg, Sterio, Devinsky, & Berić, 1995; Johansson, Malm, Nordh, & Hariz, 1997; Kishore, Turnbull, Snow, de la Fuente-Fernandez, Schulzer, Mak, Yardley, & Calne, 1997; Laitinen, 1995; Laitinen, Bergenheim, & Hariz, 1992) and to a lesser extent of thalamotomy (e.g., Fox, Ahlskog, & Kelly, 1991; Lund-Johansen, Hugdahl, & Wester, 1996; Rossitch, Zeidman, Nashold, Horner, Walker, Osborne, & Bullard, 1988; Tasker, Munz, Junn, Kiss, Davis, Dostrovsky, & Lozano, 1997; van Manen, Speelman, & Tans, 1984; Wester & Hauglie-Hanssen, 1990). In addition, early attempts to treat a variety of movement disorders by chronic, intermittent electrical stimulation of the thalamus (Andy, 1983; Bechtereva, Bondartchuk, Smirnov, Meliutcheva, & Shandurina, 1975; Brice & McLellan, 1980; Merienne & Mazars, 1982; Siegfried & Rea, 1988) were refined, modified, and found application in larger patient series (e.g., Alesch, 1995; Benabid, Pollak, Gervason, Hoffman, Benazzouz, Gao, Laurent, Gentil, & Perret, CHRONIC THALAMIC STIMULATION 127 1991; Benabid, Pollack, Gao, Hoffman, Limousin, Gay, Payen, & Benazzouz, 1996; Blond & Siegfried, 1991; Caparros-Lefebvre, Blond, Vermersch, Pécheux, Guieu, & Petit, 1993; Moringlane, Alesch, Gharehbaghi, Haass, Dillmann, Grundmann, Ohlmann, Schimrigk, & Thümler, 1995; Speelman & Bosch, 1995; Tasker, 1998). Electrical deep brain stimulation (DBS) for PD has also been rapidly extended to other targets such as the globus pallidus (e.g., Gross, Rougier, Guehl, Boraud, Julien, & Bioulac, 1997; Iacono, Lonser, Maeda, Kuniyoshi, Warner, Mandybur, & Yamada, 1995a; Iacono, Lonser, Mandybur, & Yamada, 1995b; Pahwa, Wilkinson, Smith, Lyons, Miyawaki, & Koller, 1997; Siegfried & Lippitz, 1994a,b; Siegfried & Wellis, 1997) and subthalamic nucleus (Benabid, Pollak, Gross, Hoffmann, Benazzouz, Gao, Laurent, Gentil, & Perret, 1994; Limousin, Pollak, Benazzouz, Hoffman, LeBas, Brousolle, Perret, & Benabid, 1995; Pollak, Benabid, Gross, Gao, Benazzouz, Hoffman, Fentil, & Perret, 1993; Pollak, Benabid, Limousin, Benazzouz, Hoffman, LeBas, & Perret, 1996; Pollak, Benabid, Limousin, & Benazzouz, 1997). Modern thalamotomy appears relatively safe (Koller & Hristova, 1996; Lund-Johansen, Hugdahl, & Wester, 1996), but direct comparisons of cognitive outcomes during and before the levodopa era are complicated by several factors (see Wilkinson & Tröster, 1998). Nonetheless, numerous studies made it clear that early thalamotomy entailed a considerable risk of postoperative speech, language, and memory difficulties (Allan, Turner, & Gadea-Ciria, 1966; Almgren, Andersson, & Kullberg, 1969, 1972; Bell, 1968; Burchiel, 1995; Darley, Brown, & Swenson, 1975; Hermann, Turner, Gillingham, & Gaze, 1965; Jurko & Andy, 1973; Krayenbühl, Siegfried, Kohenof, & Yasargil, 1965; Lebrun & Leleux, 1993; Perret & Siegfried, 1969; Petrovici, 1980; Quaglieri & Celesia, 1977; Riklan & Cooper, 1975; Riklan & Levita, 1969, 1970; Riklan, Levita, Zimmerman, & Cooper, 1969; Samra, Riklan, Levita, Zimmerman, Waltz, Bergman, & Cooper, 1969; Shapiro, Sadowsky, Henderson, & VanBuren, 1973; VanBuren, Li, Shapiro, Henderson, & Sadowsky, 1973; Vilkki & Laitinen, 1974, 1976; Waltz, Riklan, Stellar, & Cooper, 1966). The methodological limitations of many of these early studies notwithstanding (Crosson, 1984, 1992; Wilkinson & Tröster, 1998), early studies of thalamotomy significantly informed us about the cognitive and motor functions of the thalamus. Furthermore, the cognitive sequelae of early thalamotomy probably drove, at least partly, neurosurgeons’ attempts to define the effects of intraoperative electrical stimulation of the thalamus. That is, the putative parallel between the effects of brief stimulation and of a permanent lesion allowed neurosurgeons to ‘‘model’’ or predict during the operation the cognitive and motor effects that a lesion in a given part of the thalamus might have. Several neurosurgeons explored the effects of intraoperative thalamic stimulation on speech and language (e.g., Guiot, Hertzog, Rondot, & Molina, 1961), but perhaps the most exten- 128 TRÖSTER ET AL. sive and systematic studies in this regard were reported by Ojemann and colleagues (for reviews, see Ojemann, 1975, 1988). The modern technique of thalamic DBS, which involves chronic stimulation, affords the opportunity to study the cognitive effects of thalamic stimulation outside the methodological constraints imposed by the operative environment. Furthermore, the criticism that the cognitive effects of intraoperative stimulation are difficult to localize to a specific thalamic region given spread of electrical current (e.g., Nadeau & Crosson, 1997a) is less applicable (if at all) to modern DBS since current spread with this technique has been estimated not to exceed 1 to 2 mm (Tasker & Kiss, 1995). To date only two studies (Caparros-Lefebvre, Blond, Pécheux, Pasquier, & Petit, 1992; Tröster, Fields, Wilkinson, Busenbark, Miyawaki, Overman, Pahwa, & Koller, 1997a) have addressed the potential cognitive consequences of thalamic electrode implantation. Both studies support the cognitive safety of DBS of the ventral intermediate (Vim) thalamic nucleus. However, both studies only evaluated short-term cognitive outcome with the stimulator turned on, leaving unaddressed the cognitive effects of stimulation per se. This article seeks to provide preliminary data concerning the more enduring cognitive effects of thalamic electrode implantation in PD and also the effects of thalamic stimulation per se. Given reports that speech, language, and memory are transiently but reliably affected by brief, acute, intraoperative stimulation of the ventrolateral (VL) nucleus of the left thalamus (see Crosson, 1992 and Ojemann, 1988), we sought to explore whether parallels exist between the effects of acute and chronic thalamic stimulation. Specifically, prior studies have shown that rate of speech can increase or decrease in response to thalamic stimulation (Guiot, Hertzog, Rondot, & Molina, 1961; Kukka, Vilkki, & Laitinen, 1976; Mateer, 1978) and that thalamic stimulation can affect attention (Ojemann, 1974), lead to perseveration (Guiot et al., 1961; Ojemann, 1988), anomia (Ojemann & Ward, 1971), and either facilitation (Ojemann, Blick, & Ward, 1971) or disruption of verbal memory (Fedio & VanBuren, 1975; Hugdahl & Wester, 1997; Ojemann, Hoyenga, & Ward, 1971). Given these findings, this study focused especially on the effects of thalamic stimulation on tasks of attention, verbal fluency, visual confrontation naming, and verbal memory. It is emphasized at the outset that comparability of acute and chronic thalamic stimulation effects and of stimulation effects in older and more recent patient series is limited by at least three difficulties. First, acute thalamic stimulation studies employed different (i.e., simpler and briefer) evaluation protocols as necessitated by the intraoperative environment. Second, the electrodes and stimulation parameters used in early studies differ from those currently in use. Third, targets of stimulation and ablation in early and more modern studies are different, and inconsistent use of terminology further CHRONIC THALAMIC STIMULATION 129 complicates comparisons among studies. Early thalamotomy studies targeted the ventrolateral (VL) thalamic nuclear group, whereas modern studies target the ventral intermediate nucleus. Tasker and Kiss’s (1995) and Macchi and Jones’s (1997) comparisons of the Hassler (1982) and Jones (1985) nomenclatures of thalamic nuclei indicate that Vim (Hassler nomenclature) corresponds to the ventral part of the ventrolateral posterior (VLp) nucleus (Jones nomenclature). In brief, the modern stimulation target (Vim) is more homogeneous and much smaller than that in earlier studies which targeted not only VLp, but also the ventrolateral anterior (VLa), pulvinar, and centromedian nuclei. CASE REPORT Case History Patient TS1, a 42-year-old Caucasian, right-handed male with a college education reported first noticing motor difficulties at age 31 years. The symptoms increased with worsening of stiffness and tremor on the right side and subsequent affectation of the left side. He received a formal diagnosis of Parkinson’s disease at age 34 years. TS1 denied history of neurologic illness other than PD, substance and alcohol abuse, and psychiatric and major medical illness. On neurologic examination the patient had a severe resting tremor and slight tremor in the postural and kinetic positions of both upper extremities, more pronounced on the left than the right. The patient had mild generalized rigidity in all four extremities and generalized bradykinesia, slightly worse on the right as compared to the left. His gait was markedly slow with a shuffling nature and moderate flexion of the trunk. There was significant reduction of armswing bilaterally on walking. Postural reflexes were poor. The patient was able to rise out of the chair slowly with use of his arm. He had difficulty handling objects and with other fine manipulations. The patient had been tried on a variety of medications. Levodopa/carbidopa and other dopamine agonists had to be discontinued because of side effects before therapeutic dosages were reached. Medications at presurgical evaluation included trihexyphenidyl (2 mg twice daily) and amantadine (100 mg once per day). Limitations in activities of daily living (ADL), e.g., dressing and eating, precluded independent living. He was considered a good candidate for thalamic stimulation given his young age, the prominence of tremor among parkinsonian signs, his inability to tolerate dopamine agonists, and the extreme functional disability brought about by the slow progression of signs and symptoms. At preoperative neuropsychological evaluation, TS1 observed that cognitive changes most evident to him were his ‘‘extreme slowness’’ in remembering vocabulary, difficulty in word finding (as opposed to word production), 130 TRÖSTER ET AL. and poor recall of persons’ names. Word-finding difficulties were sufficiently pronounced to be remarkable on clinical interview. Surgical Procedure A Cosman-Roberts-Wells (CRW) head frame (Radionics, Inc.) was attached to the patient’s head under local anesthesia. A localizing CT scan was performed with the gantry angled to approximate the Anterior Commissure– Posterior Commissure (AC–PC) plane. Cuts were made at 1.5-mm intervals through the region of the thalamus. Calculation of the Vim target was based on the AC–PC length divided by 12. This product was then multiplied by 2.5, giving a distance of 6 mm from the PC. The lateral coordinate was the sum of half of the third ventricle width and 11.5, which was 12 mm lateral to the AC–PC line. The initial target depth was chosen as the AC–PC plane. This point, and the fiducial points for the CT localizing frame, were recorded from the CT scanner, and this information was processed to determine the X, Y, and Z values for the calculated Vim target. The patient was then taken to the operating room where, under local anesthesia, a burr hole was placed just anterior to the coronal suture and 2.5 cm from the midline. Through this hole an electrode 300 mm in length, 1.1 mm in diameter, and with an uninsulated tip of 3 mm was passed through the brain using the CRW arc system and microdrive. At various levels above and below the target, electrical stimulation was used to initially provoke a paresthesia in the right arm and face and then to determine its effect upon the tremor. The voltage was varied from below 1 volt to 8 volts with a frequency of 130 Hz and a pulse width of 60 µs. At a point 1 mm below the AC–PC line, there was good tremor control with transitory paresthesias in the arm and face. The deep brain stimulating electrode was positioned next in this location. This electrode (Medtronics, Inc., DBS electrode) has 4 contacts. Each is 1 mm in length and separated from the next by a distance of 1.5 mm. Placement of the DBS electrode is illustrated in Figs. 1a and 1b (lateral and anterior–posterior (AP) skull X rays). The location of the electrode relative to the third ventricle and thalamus are shown in Figs. 2a and 2b (axial CT scans), and key structures visible in the CT scans are identified in corresponding Figs. 3a and 3b. Subsequently, under general anesthesia, a pulse generator was implanted in the subcutaneous tissue of the left subclavicular area and connected subcutaneously to the DBS electrode. After the patient recovered, the device was adjusted to optimally reduce tremor. Clinical Outcome Only the most salient results are presented here (for a group study of the 3-month outcome see Tröster et al., 1997a). At the time of evaluation, stimu- CHRONIC THALAMIC STIMULATION 131 lation parameters were as follows: amplitude 3.6 V, rate 145 Hz, pulse width 120 µs. Polarity of electrode 1 was set positive and of electrode 3 negative. Trihexyphenidyl dosage had been increased from 4 to 6 mg per day, but amantadine dosage was unchanged at 100 mg per day. The patient’s modified Unified Parkinson’s Disease Rating Scale (UPDRS; Fahn, Elton, & members of the UPDRS Development Committee, 1987) motor score improved from 80 to 70. The patient demonstrated few significant changes from baseline on a broad battery of neuropsychological tests (see Tröster et al., 1997a; Tröster, Fields, Wilkinson, Pahwa, Miyawaki, Lyons, & Koller, 1997b) commonly used in the evaluation of PD (Raskin, Borod, & Tweedy, 1990; Tröster, in press). The most noticeable change to the patient and his family was his improved word finding. Although his score on the Boston Naming Test (BNT) was at ceiling (59 and 60/60 before and after surgery), the response latency improved from a mean of 3.52 s to 1.42 s. The significance of this change is difficult to assess since, to our knowledge, there are no normative data concerning response latency for the BNT. Despite the improved response latency on the BNT (which employs structured stimuli), the patient’s score on a relatively unstructured semantic word fluency task declined significantly. Semantic (category) verbal fluency, unlike lexical (letter) verbal fluency, decreased after surgery by almost 2 standard deviations, despite use of the same test form (26 animal names in 60 s before surgery vs 17 animal names after surgery). Patient TS1’s score on the Mattis Dementia Rating Scale (Mattis, 1988) was 9 points higher after surgery (140 vs 131/144), and this was almost entirely attributable to his improved score on the Construction subtests (6 vs 0/6). Concentration might have improved in that on the Wisconsin Card Sorting Test (WCST; Heaton, 1981; Heaton, Chelune, Talley, Kay, & Curtiss, 1993) the Failure-to-Maintain Set score improved from 2 to 0 losses of set, which represents a gain of over 2 standard deviations. Immediate recall across five learning trials of the California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober, 1987) decreased by 1.3 standard deviations from T 5 53 to T 5 40. Although this does not represent a change of two standard deviations, the change is noteworthy given that on retesting even 1 year later a small gain (of about 2 T score points) is typically still observed (Delis et al., 1987). Learning slope was shallower after surgery (declining from 13 to 11.8, which represents a change of two standard deviations) even though semantic clustering (the observed/expected semantic clustering ratio) improved by 1 standard deviation from 2.5 to 3.2. Longdelay free recall and recognition were unchanged. In summary, visuospatial construction and perhaps some aspects of concentration improved after surgery. Although response latency on a structured semantic memory (visual confrontation naming) task improved, decrements were observed on a semantic verbal fluency task and in learning and immediate recall of a word list (i.e., episodic verbal memory). 132 TRÖSTER ET AL. FIG. 1. (a) Lateral and (b) A-P skull X rays after surgery showing the positioning of the DBS electrode. CHRONIC THALAMIC STIMULATION 133 Because of the decrements experienced in semantic fluency and immediate word list recall, the patient was referred for reevaluation to determine if poorer performance on these measures persisted 6 months after surgery. As concerns semantic fluency, performance improved minimally (20 vs 17 words) but remained below baseline (26 words). On the CVLT, immediate recall improved so that the score (T 5 60) was somewhat better than preoperatively (T 5 53) and significantly better than 3 months after surgery (T 5 40). Although this might in part reflect practice, the typical test–retest gains observed are much smaller (Delis et al., 1987). 134 TRÖSTER ET AL. FIG. 2. Axial CT scans after surgery showing the position of the DBS electrode in relation to the (a) third ventricle and, at a level lower, showing the position of the electrode in the (b) thalamus. CHRONIC THALAMIC STIMULATION 135 136 TRÖSTER ET AL. FIG. 3. (a and b) Drawings illustrating the spatial relationship of the DBS electrode to brain structures depicted in the CT scans in Figs. 2a and 2b. EFFECTS OF STIMULATION ON LANGUAGE, ATTENTION, AND VERBAL MEMORY Procedure To evaluate the effect of stimulation per se on attention, language, and on episodic and semantic memory, the patient underwent testing 18 months after surgery. The stimulator was either on or off on two occasions: once while the patient was on medication and 3 weeks later, while off medication. The order of stimulation (on vs off) was counterbalanced across the two medication conditions. Eighteen months after surgery, the patient’s UPDRS score was 72 (Hoehn & Yahr Stage III). Materials Category fluency. The patient was given alternate forms of the task on each of the four testing conditions: animals, fruits, vegetables, and objects. When on medication, the patient was asked to orally name as many different fruits as possible in 60 s with the stimulator on. With the stimulator off, he was asked to name vegetables. Raw scores were transformed to z scores using the means and standard deviations from the Monsch, Bondi, Butters, Paulsen, Salmon, Brugger, & Swensen (1994; personal communication) middle-aged sample. The task employed animals (stimulator off) and objects (stimulator on) when the patient was not taking medication. Raw scores were transformed to z scores using the age-appropriate normative data of Kolb and Whishaw (1990). Letter fluency (Benton, Hamsher, & Sivan, 1994). Three alternate forms of this task were used (CFL, PRW, FAS) with CFL being used during both medication conditions. The examinee was asked to orally name as many different words (excluding proper names) as possible in 60 s, beginning with each of three letters. Raw scores were converted to z scores using Monsch et al.’s (1994) data. Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983). The BNT was divided into two 30-item alternate forms (odd–even items), with administration order counterbalanced across medication conditions. Raw scores were not transformed to z scores given unavailability of age-appropriate normative data for the short-form of the test. CHRONIC THALAMIC STIMULATION 137 Stroop Neuropsychological Screening Test (SNST: Trenerry, Crosson, DeBoe, & Leber, 1989). This selective attention task consists of two parts, each timed (maximum time allowed is 120 s). For the first part, the examinee is asked to read 112 words (names of four colors) printed in four different-color inks. For the second part of the test, the examinee is instructed to name the color of the ink (four possible colors) in which each of 112 words (color names incongruent with ink color) is printed. Raw scores were converted to z scores using the ageappropriate means and standard deviations provided in the test manual. The SNST was chosen as the attention task, given a previous report (Laitinen, 1994) that left thalamotomy was associated with slower and more error-prone performance on the Stroop task. Rey Auditory Verbal Learning Test (RAVLT; Rey, 1964). Four alternate forms (A, C, E, and G) of this 15-word list-learning task were employed. The examinee is presented the first word list on each of five learning trials. Following each learning trial immediate recall is assessed. A second 15-word list is presented after completion of the five learning trials. Thereafter, short-delay free recall for the first word list is assessed, and 20 min later long-delay free recall is evaluated. Upon completion of free-recall assessment, recognition of the first word list is assessed. The examinee is presented with a list of 50 printed words with the 15 target words, the 15 List B words, and 20 distractors arranged in random order. Raw scores for the sum of words recalled across the five learning trials, the List B immediate recall trial, and the delayed free-recall and recognition (hits and false positives) trials were converted to z scores using the age- and gender-appropriate means and standard deviations published by Geffen, Moar, O’Hanlon, Clark, and Geffen (1990). Three other indices were computed according to methods outlined by Geffen et al. (1990). Forgetting rate was computed as the ratio of the number of words recalled on the long- and short-delay free-recall trials. The smaller this ratio, the more rapid the rate of forgetting. Green and Swets’ (1966) nonparametric signal detection measure of recognition (p[A]) was computed according to the following expression: p[A] 5 0.5 (1 1 HR 2 FP), where HR (hit rate) 5 List A targets recognized 4 15 and FP (false positive rate) 5 number of distractors endorsed as List A words 4 35. Finally, a retrieval efficiency index (Geffen et al., 1990) was computed as follows: (number of words recalled at long delay 4 15) 4 (p[A]). The lower this ratio, the less efficient is recall. Stimulation Effects: ‘‘On Medication’’ Condition Results of evaluations with and without stimulation under conditions of on and off medication are presented in Table 1. The patient was tested first with stimulation and then without stimulation. The following stimulation parameters were used: amplitude 3.6 V, rate 145 Hz, and pulse width 120 µs. After testing under stimulation was completed, the stimulator was turned off and retesting without stimulation began 20 min thereafter, when right hand tremor was observable. Comparison between performances on the attention measure (SNST) with the stimulator on and off might be influenced by a ceiling effect. That is, although number of correct responses on the color–word condition was lower during stimulation (108 vs 112 words), performance was not significantly (0.4 SD) different from that with the stimulator turned off. However, when the stimulator was turned off, the patient completed all 112 items in less than the maximum time allotted (in 116 vs 120 s). Performance on the semantic fluency tasks was somewhat better with than without stimulation (11.2 SD), and lexical fluency was marginally improved On medication Stimulator on Letter Fluency BNT (30-item; raw) Form Mean latency (s) SNST Words Correct Time (s) Color–Word Correct Time (s) a b Off medication Stimulator off Change 0.66 20.05 (53) (6) 2.47 0.43 (68) (7) 2 20.28 (9) 1.32 (13) 20.93 (8) 0.19 (11) 21.11 0.80 0.99 1.33 21.38 20.50 (0.89) (15) (0) (1.00) (0.53) (12) fruits (58) CFL (30) odd 21.33 20.20 0.62 0.50 0.13 21.74 (0.85) (14) (1) (0.95) (0.77) (6) vegetables (49) PRW (29) even 1.80 1.50 0.26 60 0.30 120 0.94 b (108) 0.26 62 0.70 116 Change b Stimulator off 1.51 20.52 (60) (5) 2.35 0.90 (67) (8) 2 1.32 (13) 0.92 (12) 2 20.56 (9) 21.30 (7) 22.22 0.80 0.24 0.83 20.81 0.37 (0.69) (15) (2) (0.97) (0.62) (28) objects (61) FAS (30) even 22.83 22.20 0.99 20.33 21.44 21.02 (0.58) (12) (0) (0.90) (0.52) (17) animals (58) CFL (30) odd 1 2 1 2.07 (112) Stimulator on 2.09 1.00 (112) (112) Test scores are expressed as z-scores (raw scores in parentheses). Pluses and minuses indicate a score increase/decrement of at least 1 standard deviation. 0.26 61 0.70 105 1.80 1.33 (112) (112) 0.26 70 0.70 110 (112) (112) 2 1 1 1 TRÖSTER ET AL. RAVLT Trials 1–5 Total List B Short-Delay Free Recall Long-Delay Free Recall Forgetting (LDF : SDF) Recognition Hits False Positives p[A] Retrieval Efficiency Category Fluency 138 TABLE 1 Test Performance on Measures of Attention and Episodic and Semantic Memory with Stimulator On and Off while Patient is On and Off Medications a CHRONIC THALAMIC STIMULATION 139 (10.86 SD). Visual confrontation naming test performance was subject to a ceiling effect (29/30 and 30/30 correct with the stimulator turned off and on, respectively). The mean response latency on the confrontation naming test was only subtly better with the stimulator on than off (on average, shorter by more than 0.5 s), but this might be limited by a ceiling effect. On the RAVLT immediate recall across the five learning trials and delayed recall were poorer by 1.8 and 1.1 SD with the stimulator turned on while the number of recognition hits was 1 SD higher under stimulation. Stimulation Effects: ‘‘Off Medication’’ Condition The stimulation parameters were identical to those used in the ‘‘on medication’’ condition: amplitude 3.6 V, rate 145 Hz, and pulse width 120 µs. Ceiling effects render unfeasible any comparisons among scores attained on the attention and visual confrontation naming measures with and without stimulation. Performance on the semantic fluency task was again somewhat better (11.4 SD) with the stimulator on. Lexical fluency scores were not significantly different during and without stimulation, although the direction of the difference (10.29 SD) continues to favor the stimulator ‘‘on’’ condition. On the RAVLT, immediate recall of the second word list was poorer (21.4 SD) with the stimulator turned on, while immediate recall across five trials for List A was only marginally poorer (20.84 SD). Recognition (hits) was again significantly better on than off stimulation (13 SD). DISCUSSION Clinical findings of this case study are consistent with the reports of Caparros-Lefebvre et al. (1992) and Tröster et al. (1997a) in that relatively few significant changes were observed in patient TS1’s neuropsychological test performance 3 months after left thalamic DBS electrode implantation. Given the patient’s improvement in motor functioning, his improvement on a visuoconstructional task is not unexpected. Also observed was an improvement in visual confrontation naming latency (maintained 18 months after surgery). Studies of chronic thalamic stimulation have not reported naming latency findings, but intraoperative thalamic stimulation has been reported to reduce recall response latency for items presented for visual confrontation naming (Ojemann, 1974), although acute thalamic stimulation can also cause anomia (Ojemann & Ward, 1971). The transient impairment in immediate recall of a word list (no longer evident 6 months after surgery) is consistent with reports that thalamotomy can result in typically transient verbal memory impairment (Perret and Siegfried, 1969; Krayenbühl, Siegfried, Kohenof, & Yasargil, 1965; Almgren, Andersson, & Kullberg, 1969; Shapiro, Sadowsky, Henderson, & VanBuren, 1973) and that intraoperative stimulation can disrupt verbal memory (Fedio & VanBuren, 1975; Hugdahl & Wester, 1997; Ojemann, Hoyenga, & 140 TRÖSTER ET AL. Ward, 1971). Since this study shows that stimulation per se interferes somewhat with word list recall, it is likely that both thalamic stimulation and lesioning can interfere with verbal memory. The disruption of verbal memory parallels findings from studies of intraoperative stimulation of the left VL thalamus. Ojemann, Hoyenga, and Ward (1971) reported that left VL stimulation not only disrupted performance on a Peterson and Peterson paradigm short-term memory task, but that intraoperative performance on this task predicted verbal memory outcome following thalamotomy. Whether intraoperative VL stimulation interferes with verbal memory might depend on when stimulation is applied during the memory task. Ojemann (1975, 1979, 1988) and Ojemann, Blick, and Ward (1971) noted that stimulation at the time of stimulus presentation enhances later recall of the material, that stimulation during retrieval interferes with recall, and that effects of stimulation applied at both encoding and retrieval cancel each other out. More recently, using higher stimulation frequencies than Ojemann and colleagues, Hugdahl and Wester (1997) confirmed that intraoperative thalamic stimulation interferes with verbal recall, but this disruption was apparent regardless of whether stimulation occurred during encoding or retrieval. Since our study involved stimulation during both encoding and retrieval, we cannot address the effects of stimulation on encoding and retrieval. Nonetheless, the relatively better recognition but poorer immediate recall during stimulation suggests that chronic stimulation interferes at least with access to information in verbal episodic memory. The persistent impairment in semantic verbal fluency is consistent with the findings of Caparros-Lefebvre et al. (1992), who reported subtle decrements in five of nine thalamic DBS patients, but laterality of stimulation was not reported. Studies of thalamotomy in PD have also reported verbal fluency deficits after surgery and especially after surgery on the left (Petrovici, 1980; Riklan & Levita, 1970; Riklan et al., 1969; Vilkki & Laitinen, 1974, 1976). Semantic verbal fluency deficits after thalamic stimulation or thalamotomy might also be expected given that the semantic system is commonly disrupted by thalamic and basal ganglia infarcts (Crosson, 1997; Kennedy & Murdoch, 1993; Graff-Radford, 1997), although this line of reasoning must be pursued cautiously since controversy persists about the pattern of language dysfunction after subcortical infarcts (see Nadeau & Crosson, 1997a,b), and since a vascular lesion in a previously healthy brain might have different behavioral manifestations than a lesion in a parkinsonian brain in which the thalamus is already excessively inhibited by basal ganglia outflow. Whether a lesion or stimulation per se accounts for the observed cognitive changes cannot be addressed with confidence, yet this issue is likely of importance in addressing the apparently paradoxical effect of the operation and of stimulation on semantic fluency. That is, the patient demonstrated a marked and persistent decline in semantic verbal fluency after surgery, yet our experimental study examining effects of stimulation per se indicates that CHRONIC THALAMIC STIMULATION 141 stimulation enhances semantic verbal fluency. This observation is vexing, regardless of the cognitive mechanism which is invoked to underlie these changes. To some extent it appears that a lesion must account for the postoperative decline in semantic verbal fluency if stimulation subtly enhances it. How is this possible? Although the neurophysiologic mechanism underlying the effects of chronic thalamic stimulation has not been elucidated (Benabid, Pollak, Hoffman, Limousin, Gao, LeBas, Benazzouz, Segebarth, & Grand, 1998), it has been suggested that the neurophysiologic effect of highfrequency stimulation is not the same as that of a lesion. More specifically, stimulation does not act via a thalamic excitatory (disinhibitory) effect as does a thalamic lesion in the parkinsonian brain; nor does stimulation have an inhibitory effect specific to the high frequency used. Rather, Benabid et al. (1998) propose that high-frequency stimulation works by introducing noise into a system so as to disrupt the oscillatory behavior of the system. This does not explain the apparently opposite effects of a lesion and of stimulation on semantic verbal fluency, but it can be speculated that such effects are at least theoretically possible on the basis of different neurophysiologic effects of lesioning and stimulation. In summary, the clinical findings of this case study indicate that left thalamic Vim electrode implantation might be associated with decrements in verbal episodic memory and semantic verbal fluency, but an improvement in visual confrontation naming latency. Comparing performance with the stimulator turned on and off 18 months after electrode implantation, we observed that the gain in naming latency was maintained. Stimulation exerted only subtle but consistent effects on naming, fluency, and memory for words. That the effects of stimulation are subtle might be expected given that the stimulator is programmed to optimize motor benefits while minimizing other clinically evident side effects. We observed that stimulation subtly improves semantic verbal fluency and minimally (albeit positively) affects lexical verbal fluency. In contrast, stimulation applied during both encoding and retrieval of a word list subtly interferes with immediate recall while facilitating recognition. Several hypotheses can be advanced to account for these observations. The first hypothesis for cognitive changes associated with thalamic stimulation is an attentional one. This hypothesis, advanced by Ojemann (1988) on the basis of his observation of the effects of intraoperative stimulation, posits that thalamic stimulation focuses attention on the external environment and incoming stimuli while blocking activation of already-internalized information. An attentional hypothesis is supported by the finding of better performance on an attention task (rate of counting backwards by threes) (Ojemann, 1974) and by findings of improved right ear or overall performance on dichotic listening tasks (Bhatnagar, Andy, Korabic, Tikofsky, Saxena, Hellman, Collier, & Krohn 1989; Hugdahl, Wester, & Asbjørnsen, 1990; Ojemann, 1985) during left thalamic stimulation. Although such an attentional hypothesis is plausible, it does not, without modification, account for the 142 TRÖSTER ET AL. findings observed in this study. Specifically, the attentional hypothesis does not address why blocking of ‘‘internalized’’ information might be occurring during word list recall but not verbal fluency. To account for this study’s findings, the hypothesis would need to be modified and posit that stimulation blocks access to very recently, but not remotely internalized information. An alternative hypothesis, which we offer for consideration, is that stimulation has opposite effects on access to information in episodic and semantic memory. Specifically, whereas stimulation interferes with access to information in episodic memory, it facilitates access to information stored in semantic memory. The proposal that stimulation facilitates access to semantic memory is consonant with the observations that visual confrontation naming latency is decreased after surgery (although stimulation effects were small given ceiling effects) and that semantic verbal fluency (and to a lesser extent, lexical verbal fluency) is subtly improved by stimulation. The interference of stimulation with access to episodic memory is consonant with the patient’s poorer recall of a word list during stimulation. Two other possible mechanisms for improvements in verbal fluency and visual confrontation naming latency need to be considered, although they clearly cannot account for poorer episodic memory with thalamic stimulation. One mechanism that might underlie faster naming and fluency after surgery and/or during stimulation is an increased rate of speech. The support for such a mechanism operating in this patient is not strong. Prior studies have shown that speech can be accelerated (tachyphemia), slowed, or arrested with thalamic stimulation (Guiot et al., 1961) and that centromedian nucleus stimulation can ameliorate stuttering (Bhatnagar & Andy, 1989). It appears, however, that slowing or arrest of speech and increased response latencies are far more likely consequences of intraoperative left thalamic stimulation than is acceleration of speech (Guiot et al., 1961; Kukka, Vilkki, & Laitinen 1976; Mateer, 1978). Furthermore, in this study, performance on the first part of the Stroop task (word reading), which unlike the second part of the task does not require response inhibition and selective attention and thus might be a relatively good measure of word production speed, was only minimally faster with than without stimulation (2 s faster when the patient was on medication, 9 s faster off medication). Another potential mechanism for cognitive changes during thalamic stimulation is improved information processing speed or more efficient use of information processing strategies. Certainly, several authors (e.g., Taylor, Saint-Cyr, & Lang, 1990) have suggested that the core defect which underlies poor performance in PD on memory, fluency, and card-sorting tasks is a difficulty in spontaneously generating efficient problem-solving, encoding, and retrieval strategies (for reviews, see Bondi & Tröster, 1997; Tröster & Fields, 1995). Such a hypothesis, however, would not explain why thalamic stimulation interferes with access to information in episodic memory, but apparently enhances access to semantic memory. CHRONIC THALAMIC STIMULATION 143 In summary, comparison of left thalamic stimulation effects on semantic (i.e., verbal fluency and confrontation naming) and episodic (i.e., word list) memory tasks leads us to raise the hypothesis that stimulation might interfere with access to episodic memory, but enhance access to semantic memory. The effects are unlikely to reflect practice or order effects given that alternate test forms were used and order of stimulation and nonstimulation was counterbalanced across medication conditions. Granted, the effects are often subtle (which might be expected since the stimulator is programmed to maximize motor benefit while minimizing side effects), but their consistency (i.e., replicability) across medication conditions is noteworthy. The merits of the hypothesis we offer cannot be adequately judged by a single case study, and future studies with larger samples and an appropriate control group (e.g., a PD surgical waiting list control group) can evaluate the hypothesis advanced here. Further study also might establish the generalizability of the findings and extend our understanding of thalamic functions. An exciting opportunity to enhance our knowledge of thalamic function is afforded to future studies evaluating the cognitive effects of a range of stimulation parameters, perhaps using different electrode pairs when a quadripolar electrode is implanted. REFERENCES Alesch, F. 1995. Neurochirurgische Verfahren bei Morbus Parkinson. Wiener Medizinsche Wochenschrift, 145, 305–309. Allan, C., Turner, J., & Gadea-Ciria, M. 1966. Investigations into speech disturbances following stereotaxic surgery for parkinsonism. British Journal of Disorders of Communication, 1, 55–59. Almgren, P.-E., Andersson, A. L., & Kullberg, G. 1969. Differences in verbally expressed cognition following left and right ventrolateral thalamotomy. Scandinavian Journal of Psychology, 10, 243–249. Almgren, P.-E., Andersson, A. L., & Kullberg, G. 1972. Long-term effects on verbally expressed cognition following left and right ventrolateral thalamotomy. Confinia Neurologica, 34, 162–168. Andy, O. J. 1983. Thalamic stimulation for control of movement disorders. Applied Neurophysiology, 46, 107–111. Bakay, R. A. E., DeLong, M. R., & Vitek, J. L. 1992. Posteroventral pallidotomy for Parkinson’s disease. Journal of Neurosurgery, 77, 487–488. Bechtereva, N. P., Bondartchuk, A. N., Smirnov, V. M., Meliutcheva, L. A., & Shandurina, A. N. 1975. Method of electrostimulation of the deep brain structures in treatment of some chronic diseases. Confinia Neurologica, 37, 136–140. Bell, D. S. 1968. Speech functions of the thalamus inferred from the effects of thalamotomy. Brain, 91, 619–638. Benabid, A.-L., Pollak, P., Gao, D., Hoffman, D., Limousin, P., Gay, E., Payen, I., & Benazzouz, A. 1996. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. Journal of Neurosurgery, 84, 203–214. Benabid, A.-L., Pollak, P., Gervason, C., Hoffman, D., Gao, D. M., Hommel, M., Perret, 144 TRÖSTER ET AL. J. E., & deRougemont, J. 1991. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet, 337, 403–406. Benabid, A. L., Pollak, P., Gross, C., Hoffmann, D., Benazzouz, A., Gao, D. M., Laurent, A., Gentil, M., & Perret, J. 1994. Acute and long-term effects of subthalamic nucleus stimulation in Parkinson’s disease. Stereotactic and Functional Neurosurgery, 62, 76– 84. Benabid, A.-L., Pollak, P., Hoffman, D., Limousin, P., Gao, D. M., LeBas, J.-F., Benazzouz, A., Segebarth, C., & Grand, S. 1998. Chronic stimulation for Parkinson’s disease and other movement disorders. In P. L. Gildenberg & R. R. Tasker (Eds.), Textbook of stereotactic and functional neurosurgery. New York: McGraw–Hill. Pp. 1199–1212. Benton, A. L., Hamsher, K. deS., & Sivan, A. B. 1994. Multilingual Aphasia Examination (3rd ed.). lowa City, IA: AJA Associates. Bhatnagar, S. C., & Andy, O. J. 1989. Alleviation of acquired stuttering with human centremedian thalamic stimulation. Journal of Neurology, Neurosurgery, and Psychiatry, 52, 1182–1184. Bhatnagar, S. C., Andy, O. J., Korabic, E. W., Tikofsky, R. S., Saxena, V. K., Hellman, R. S., Collier, B. D., & Krohn, L. D. 1989. The effect of thalamic stimulation in processing of verbal stimuli in dichotic listening tasks: A case study. Brain and Language, 36, 236– 251. Blond, S., & Siegfried, J. 1991. Thalamic stimulation for the treatment of tremor and other motor movement disorders. Acta Neurochirurgica, 52(Suppl.), 109–111. Bondi, M. W., & Tröster, A. I. 1997. Parkinson’s disease: Neurobehavioral consequences of basal ganglia dysfunction. In P. D. Nussbaum (Ed.), Handbook of neuropsychology and aging. New York: Plenum Press. Pp. 216–245. Brice, J., & McLellan, L. 1980. Suppression of intention tremor by contingent deep-brain stimulation. Lancet, 2, 1221–1222. Burchiel, K. J. 1995. Thalamotomy for movement disorders. Neurosurgery Clinics of North America, 6, 55–71. Caparros-Lefebvre, D., Blond, S., Pécheux, N., Pasquier, F., & Petit, H. 1992. Evaluation neuropsychologique avant et après stimulation thalamique chez 9 parkinsoniens. Revue Neurologique, 148, 117–122. Caparros-Lefebvre, D., Blond, S., Vermersch, P., Pécheux, N., Guieu, J.-D., & Petit, H. 1993. Chronic thalamic stimulation improves tremor and levodopa induced dyskinesias in Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 268–273. Crosson, B. 1984. Role of the dominant thalamus in language: A review. Psychological Bulletin, 96, 491–517. Crosson, B. 1992. Subcortical functions in language and memory. New York: Guilford. Crosson, B. 1997. Syndromes due to acquired basal ganglia damage. In T. E. Feinberg & M. J. Farah (Eds.), Behavioral neurology and neuropsychology. New York: McGraw– Hill. Pp. 427–432. Darley, F. L., Brown, J. R., & Swenson, W. M. 1975. Language changes after neurosurgery for parkinsonism. Brain and Language, 2, 65–69. Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. 1987. California Verbal Learning Test: Research Edition. San Antonio, TX: The Psychological Corporation. Diederich, N. J., & Alesch, F. 1997. Neurochirurgische Verfahren zur Behandlung des Morbus Parkinson: Eine Bestandsaufnahme. Nervenarzt, 68, 466–476. Dogali, M., Fazzini, E., Kolodny, E., Eidelberg, D., Sterio, D., Devinsky, O., & Berić, A. 1995. Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology, 45, 753–761. Fahn, S., Elton, R. L., & members of the UPDRS Development Committee. 1987. Unified CHRONIC THALAMIC STIMULATION 145 Parkinson’s Disease Rating Scale. In S. Fahn, C. D. Marsden, D. B. Calne, & M. Goldstein (Eds.), Recent developments in Parkinson’s disease, Vol. 2. Florham Park, NJ: Macmillan Health Care Information. Pp. 153–164. Fedio, P., & VanBuren, J. M. 1975. Memory and perceptual deficits during electrical stimulation in the left and right thalamus and parietal subcortex. Brain and Language, 2, 78– 100. Fox, M. W., Ahlskog, J. E., & Kelly, P. J. 1991. Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson’s disease patients. Journal of Neurosurgery, 75, 723–730. Geffen, G., Moar, K. J., O’Hanlon, A. P., Clark, C. R., & Geffen, L. B. 1990. Performance measures of 16- to 86-year-old males and females on the Auditory Verbal Learning Test. The Clinical Neuropsychologist, 4, 45–63. Goetz, C. G., & Diederich, N. J. 1996. There is a renaissance of interest in pallidotomy for Parkinson’s disease. Nature Medicine, 2, 510–514. Graff-Radford, N. R. 1997. Syndromes due to acquired thalamic damage. In T. E. Feinberg & M. J. Farah (Eds.), Behavioral neurology and neuropsychology. New York: McGrawHill. Pp. 433–443. Green, D. M., & Swets, T. A. 1966. Signal detection theory and psychophysics. New York: Wiley. Gross, C., Rougier, A., Guehl, D., Boraud, T., Julien, J., & Bioulac, B. 1997. High-frequency stimulation of the globus pallidus internalis in Parkinson’s disease: A study of seven cases. Journal of Neurosurgery, 87, 491–498. Guiot, G., Hertzog, E., Rondot, P., & Molina, P. 1961. Arrest or acceleration of speech evoked by thalamic stimulation in the course of stereotaxic procedures for parkinsonism. Brain, 84, 363–379. Guridi, J., & Lozano, A. M. 1997. A brief history of pallidotomy. Neurosurgery, 41, 1169– 1183. Hassler, R. 1982. Architectonic organization of the thalamic nuclei. In G. Schaltenbrand & E. A. Walker (Eds.), Stereotaxy of the human brain: Anatomical, physiological and clinical applications (2nd ed.). New York: Thieme-Stratton. Pp. 140–180. Hassler, R., & Riechert, T. 1954. Indikationen und Lokalisationsmethode der gezielten Hirnoperationen. Nervenarzt, 25, 441–447. Heaton, R. K. 1981. Wisconsin Card Sorting Test Manual. Odessa, FL: Psychological Assessment Resources. Heaton, R. K., Chelune, G. J., Talley, J. L., Kay, G. G., & Curtiss, G. 1993. Wisconsin Card Sorting Test Manual: Revised and expanded. Odessa, FL: Psychological Assessment Resources. Hermann, K., Turner, J. W., Gillingham, F. J., & Gaze, R. M. 1965. The effects of destructive lesions and stimulation of the basal ganglia on speech mechanisms. Confinia Neurologica, 27, 197–207. Horsley, V. 1909. The Linacre lecture: The function of the so-called motor area of the brain. British Medical Journal, 2, 125–132. Hugdahl, K., & Wester, K. 1997. Lateralized thalamic stimulation: Effects on verbal memory. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 10, 155–161. Hugdahl, K., Wester, K., & Asbjørnsen, A. 1990. The role of the left and right thalamus in language asymmetry: Dichotic listening in Parkinson patients undergoing stereotactic thalamotomy. Brain and Language, 39, 1–13. Iacono, R. P., Lonser, R. R., Maeda, G., Kuniyoshi, S., Warner, D., Mandybur, G., & Yamada, 146 TRÖSTER ET AL. S. 1995a. Chronic anterior pallidal stimulation for Parkinson’s disease. Acta Neurochirurgica, 137, 106–112. Iacono, R. P., Lonser, R. R., Mandybur, G., & Yamada, S. 1995b. Stimulation of the globus pallidus in Parkinson’s disease. British Journal of Neurosurgery, 9, 505–510. Johansson, F., Malm, J., Nordh, E., & Hariz, M. 1997. Usefulness of pallidotomy in advanced Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 125–132. Jones, E. G. 1985. The thalamus. New York: Plenum. Jurko, M. F., & Andy, O. J. 1973. Psychological changes correlated with thalamotomy site. Journal of Neurology, Neurosurgery, and Psychiatry, 36, 846–852. Kaplan, E., Goodglass, H., & Weintraub, S. 1983. Boston Naming Test. Philadelphia, PA: Lea & Febiger. Kennedy, M., & Murdoch, B. E. 1993. Chronic aphasia subsequent to striato-capsular and thalamic lesions in the left hemisphere. Brain and Language, 44, 284–295. Kishore, A., Turnbull, I. M., Snow, B. J., de la Fuente-Fernandez, R., Schulzer, M., Mak, E., Yardley, S., & Calne, D. B. 1997. Efficacy, stability and predictors of outcome of pallidotomy for Parkinson’s disease: Six-month follow-up with additional 1-year observations. Brain, 120, 729–737. Klockgether, T., Löschmann, P.-A., & Wüllner, U. 1994. New medical and surgical treatments for Parkinson’s disease. Current Opinion in Neurology, 7, 346–352. Kolb, B., & Whishaw, I. Q. 1990. Fundamentals of human neuropsychology (3rd ed.). New York: W. H. Freeman. Koller, W. C., & Hristova, A. 1996. Efficacy and safety of stereotaxic surgical treatment of tremor disorders. European Journal of Neurology, 3, 507–514. Krayenbühl, H., Siegfried, J., Kohenof, M., & Yasargil, M. G. 1965. Is there a dominant thalamus? Confinia Neurologica, 26, 246–249. Kukka, E.-K., Vilkki, J., & Laitinen, L. 1976. Effects of subcortical stimulation and coagulation on subtraction performance. Neuropsychologia, 14, 137–140. Laitinen, L. V. 1994. Ventroposterolateral pallidotomy. Stereotactic and Functional Neurosurgery, 62, 41–52. Laitinen, L. V. 1995. Pallidotomy in Parkinson’s disease. Neurosurgical Clinics of North America, 6, 105–112. Laitinen, L. V., Bergenheim, A. T., & Hariz, M. I. 1992. Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. Journal of Neurosurgery, 76, 53–61. Lebrun, Y., & Leleux, C. 1993. The effects of electrostimulation and of resective and stereotactic surgery on language and speech. Acta Neurochirurgica, 56(Suppl.), 40–51. Limousin, P., Pollak, P., Benazzouz, A., Hoffman, D., LeBas, J.-F., Broussolle, E., Perret, J. E., Benabid, A.-L. 1995. Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet, 345, 91–95. Lund-Johansen, M., Hugdahl, K., & Wester, K. 1996. Cognitive function in patients with Parkinson’s disease undergoing stereotaxic thalamotomy. Journal of Neurology, Neurosurgery, and Psychiatry, 60, 564–571. Macchi, G., & Jones, E. G. 1997. Toward an agreement on terminology of nuclear and subnuclear divisions of the motor thalamus. Journal of Neurosurgery, 86, 77–92. Mateer, C. 1978. Asymmetric effects of thalamic stimulation on rate of speech. Neuropsychologia, 16, 497–499. Mattis, S. 1988. Dementia Rating Scale. Odessa, FL: Psychological Assessment Resources. Merienne, L., & Mazars, G. 1982. Traitement de certaines dyskinesies par stimulation thalamique intermittente. Neurochirurgie, 28, 201–205. CHRONIC THALAMIC STIMULATION 147 Meyers, R. 1942. Surgical interruption of the pallidofugal fibres: Its effect on the syndrome paralysis agitans and technical considerations in its application. New York State Journal of Medicine, 42, 317–325. Monsch, A. U., Bondi, M. W., Butters, N., Paulsen, J. S., Salmon, D. P., Brugger, P., & Swenson, M. R. 1994. A comparison of category and letter fluency in Alzheimer’s disease and Huntington’s disease. Neuropsychology, 8, 25–30. Moringlane, J. R., Alesch, F., Gharehbaghi, H., Haass, A., Dillmann, M., Grundmann, M., Ohlmann, M., Schimrigk, K., & Thümler, R. 1995. Chronische Elektrostimulation des Nucleus ventralis intermedius des Thalamus zur Tremorbehandlung. Aktuelle Neurologie, 22, 176–180. Nadeau, S. E., & Crosson, B. 1997a. Subcortical aphasia. Brain and Language, 58, 355–402. Nadeau, S. E., & Crosson, B. 1997b. Subcortical aphasia: Response to reviews. Brain and Language, 58, 436–458. Obeso, J. A., Guridi, J., & DeLong, M. 1997. Surgery for Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 2–8. Olanow, C. W., Marsden, C. D., Lang, A. E., & Goetz, C. G. 1994. The role of surgery in Parkinson’s disease management. Neurology, 44(Suppl. 1), S17–S20. Ojemann, G. A. 1974. Mental arithmetic during human thalamic stimulation. Neuropsychologia, 12, 1–10. Ojemann, G. A. 1975. Language and the thalamus: Object naming and recall during and after thalamic stimulation. Brain and Language, 2, 101–120. Ojemann, G. A. 1979. Altering memory with human ventrolateral thalamic stimulation. In H. Ballantine & B. Myerson (Eds.), Modern concepts in psychiatric surgery. New York: Elsevier. Pp. 103–109. Ojemann, G. A. 1985. Enhancement of memory with human ventrolateral thalamic stimulation: Effect evident on a dichotic listening task. Applied Neurophysiology, 48, 212–215. Ojemann, G. A. 1988. Effect of cortical and subcortical stimulation on human language and verbal memory. In F. Plum (Ed.), Language, communication and the brain. New York: Raven. Pp. 101–115. Ojemann, G. A., & Ward, A. A. 1971. Speech representation in ventrolateral thalamus. Brain, 94, 669–680. Ojemann, G. A., Blick, K. I., & Ward, A. A. 1971. Improvement and disturbance of shortterm verbal memory with human ventrolateral thalamic stimulation. Brain, 94, 225–240. Ojemann, G. A., Hoyenga, K. B., & Ward, A. A. 1971. Prediction of short term verbal memory disturbance after ventrolateral thalamotomy. Journal of Neurosurgery, 35, 203–210. Ostertag, C. B., Lücking, C. H., Mehdorn, H. M., & Deuschı, G. 1997. Stereotaktische Behandlung der Bewegungsstörungen. Nervenarzt, 68, 477–484. Pahwa, R., Wilkinson, S., Smith, D., Lyons, K., Miyawaki, E., & Koller, W. C. 1997. Highfrequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology, 49, 249–253. Perret, E., & Siegfried, J. 1969. Memory and learning performance of Parkinson patients before and after thalamotomy. In F. J. Gillingham & I. M. L. Donaldson (Eds.), Third symposium on Parkinson’s disease. Edinburgh: E & S Livingstone. Pp. 164–168. Petrovici, J.-N. 1980. Speech disturbances following stereotaxic surgery in ventrolateral thalamus. Neurosurgical Review, 3, 189–195. Pollak, P., Benabid, A.-L., Gross, C., Gao, D. M., Benazzouz, A., Hoffman, D., Fentil, M., & Perret, J. 1993. Effets de la stimulation du noyau sous-thalamique dans la maladie de Parkinson. Revue Neurologique, 149, 175–176. 148 TRÖSTER ET AL. Pollak, P., Benabid, A.-L., Limousin, P., & Benazzouz, A. 1997. Chronic intracerebral stimulation in Parkinson’s disease. In J. A. Obeso, M. R. DeLong, C. Ohye, & C. D. Marsden (Eds.), Advances in neurology: Vol. 74. The basal ganglia and new surgical approaches for Parkinson’s disease. Philadelphia: Lippincott-Raven. Pp. 213–220. Pollak, P., Benabid, A.-L., Limousin, P., Benazzouz, A., Hoffman, D., LeBas, J.-F., and Perret, J. 1996. Subthalamic nucleus stimulation alleviates akinesia and rigidity in parkinsonian patients. In L. Battistin, G. Scarlato, T. Caraceni, & S. Ruggieri (Eds.), Advances in neurology: Vol. 69. Parkinson’s disease. Philadelphia: Lippincott-Raven. Pp. 591–594. Quaglieri, C. E., & Celesia, G. G. 1977. Effect of thalamotomy and levodopa therapy on the speech of Parkinson patients. European Neurology, 15, 34–39. Raskin, S. A., Borod, J. C., & Tweedy, J. 1990. Neuropsychological aspects of Parkinson’s disease. Neuropsychology Review, 1, 185–221. Rey, A. 1964. L’éxamen clinique en psychologie. Paris, France: Presses Universitaires de France. Riklan, M., & Cooper, I. S. 1975. Psychometric studies of verbal functions following thalamic lesions in humans. Brain and Language, 2, 45–64. Riklan, M., & Levita, E. 1969. Subcortical correlates of human behavior: A psychological study of basal ganglia and thalamic surgery. Baltimore: Williams & Wilkins. Riklan, M., & Levita, E. 1970. Psychological studies of thalamic lesions in humans. Journal of Nervous and Mental Disease, 150, 251–265. Riklan, M., Levita, E., Zimmerman, J., & Cooper, I. S. 1969. Thalamic correlates of language and speech. Journal of Neurological Sciences, 8, 307–328. Rossitch, E., Zeidman, S. M., Nashold, B. S., Horner, J., Walker, J., Osborne, D., & Bullard, D. E. 1988. Evaluation of memory and language function pre- and postthalamotomy with an attempt to define those patients at risk for postoperative dysfunction. Surgical Neurology, 29, 11–16. Samra, K., Riklan, M., Levita, E., Zimmerman, J., Waltz, J. M., Bergman, L., & Cooper, I. S. Language and speech correlates of anatomically verified lesions in thalamic surgery for parkinsonism. Journal of Speech and Hearing Research, 12, 510–540. Shapiro, D. Y., Sadowsky, D. A., Henderson, W. G., & VanBuren, J. M. 1973. An assessment of cognitive function in postthalamotomy Parkinson patients. Confinia Neurologica, 35, 144–166. Siegfried, J., & Blond, S. 1997. The neurosurgical treatment of Parkinson’s disease and other movement disorders. London: Williams & Wilkins. Siegfried, J., & Lippitz, B. 1994a. Chronic electrical stimulation of the VL-VPL complex and of the pallidum in the treatment of movement disorders: Personal experience since 1982. Stereotactic and Functional Neurosurgery, 62, 71–75. Siegfried, J., & Lippitz, B. 1994b. Bilateral chronic electrostimulation of ventroposterolateral pallidum: A new therapeutic approach for alleviating all Parkinsonian symptoms. Neurosurgery, 35, 1126–1130. Siegfried, J., & Rea, G. L. 1988. Deep brain stimulation for the treatment of motor disorders. In L. D. Lunsford (Ed.), Modern stereotactic surgery. Boston: Martinus Nijhoff. Pp. 409–412. Siegfried, J., & Wellis, G. 1997. Chronic electrostimulation of ventroposterolateral pallidum: Follow-up. Acta Neurochirurgica, 68(Suppl.), 11–13. Speelman, J. D., & Bosch, D. A. 1995. Continue elektrische thalamusstimulatie voor de behandeling van farmacotherapie-resistente tremor. Nederlands Tijdschrift voor Geneeskunde, 139, 926–930. Spiegel, E., & Wycis, H. 1952. Thalamotomy and pallidotomy for treatment of choreic movements. Acta Neurochirurgica, 2, 417–422. CHRONIC THALAMIC STIMULATION 149 Spiegel, E. A., Wycis, H. T., Szekely, E. G., Adams, J., Flanagan, M., & Baird, H. W. 1963. Campotomy in various extrapyramidal disorders. Journal of Neurosurgery, 20, 871–884. Tasker, R. R. 1998. Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surgical Neurology, 49, 145–154. Tasker, R. R., & Kiss, Z. H. T. 1995. The role of the thalamus in functional neurosurgery. Neurosurgery Clinics of North America, 6, 73–104. Tasker, R. R., Munz, M., Junn, F. S. C. K., Kiss, Z. H. T., Davis, K., Dostrovsky, J. O., & Lozano, A. M. 1997. Deep brain stimulation and thalamotomy for tremor compared. Acta Neurochirurgica, 68(Suppl.), 49–53. Taylor, A. E., Saint-Cyr, J. A., & Lang, A. E. 1990. Memory and learning in early Parkinson’s disease: Evidence for a ‘‘frontal lobe syndrome’’. Brain and Cognition, 13, 211–232. Trenerry, M. R., Crosson, B., DeBoe, J., & Leber, W. R. 1989. Stroop Neuropsychological Screening Test. Odessa, FL: Psychological Assessment Resources. Tröster, A. I. 1998. An historical synopsis of the development of neurosurgical treatments for Parkinson’s disease. Journal of the International Neuropsychological Society, 4, 37. Tröster, A. I. 1998. Assessment of movement and demyelinating disorders. In P. J. Snyder & P. D. Nussbaum (Eds.), Clinical neuropsychology: A pocket handbook for assessment. Washington, DC: American Psychological Association. Tröster, A. I., & Fields, J. A. 1995. Frontal cognitive function and memory in Parkinson’s disease: Toward a distinction between prospective and declarative memory impairments? Behavioural Neurology, 8, 59–74. Tröster, A. I., Fields, J. A., Wilkinson, S. B., Busenbark, K., Miyawaki, E., Overman, J., Pahwa, R., & Koller, W. C. 1997a. Neuropsychological functioning before and after unilateral thalamic stimulating electrode implantation in Parkinson’s disease (electronic manuscript). Neurosurgical Focus, 2(3), Manuscript 9. Tröster, A. I., Fields, J. A., Wilkinson, S. B., Pahwa, R., Miyawaki, E., Lyons, K. E., & Koller, W. C. 1997b. Unilateral pallidal stimulation for Parkinson’s disease: Neurobehavioral functioning before and three months after electrode implantation. Neurology, 49, 1078– 1083. VanBuren, J. M., Li, C.-L., Shapiro, D. Y., Henderson, W. G., & Sadowsky, D. A. 1973. A qualitative and quantitative evaluation of Parkinsonians three to six years following thalamotomy. Confinia Neurologica, 35, 202–235. van Manen, J., Speelman, J. D., & Tans, R. J. J. 1984. Indications for surgical treatment of Parkinson’s disease after levodopa therapy. Clinical Neurology and Neurosurgery, 86, 207–212. Vilkki, J., & Laitinen, L. V. 1974. Differential effects of left and right ventrolateral thalamotomy on receptive and expressive verbal performances and face-matching. Neuropsychologia, 12, 11–19. Vilkki, J., & Laitinen, L. V. 1976. Effects of pulvinotomy and ventrolateral thalamotomy on some cognitive functions. Neuropsychologia, 14, 67–78. Waltz, J. M., Riklan, M., Stellar, S., & Cooper, I. S. 1966. Cryothalamectomy for Parkinson’s disease: A statistical analysis. Neurology, 16, 994–1002 and 1021. Wester, K., & Hauglie-Hanssen, E. 1990. Stereotaxic thalamotomy: Experiences from the levodopa era. Journal of Neurology, Neurosurgery, and Psychiatry, 53, 427–430. Wilkinson, S. B., & Tröster, A. I. 1998. Surgical interventions in neurodegenerative disease: Impact on memory and cognition. In A. I. Tröster (Ed.), Memory in neurodegenerative disease: Biological, cognitive, and clinical perspectives. Cambridge, UK: Cambridge University Press.