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A Basal Ganglia Pacemaker Formed by the Subthalamic Nucleus And letters to nature Although the speci®c locations used in these tests varied between subjects, 3±6 of the same questions on each test were administered to E.P. and at least four of the ®ve controls. In addition, the `familiar navigation' and `novel A basal ganglia pacemaker navigation' tasks were matched across subjects with respect to the distance travelled (mean, 3.0 and 3.3 miles, respectively) and the number of turns formed by the subthalamic needed (mean, 3.0 and 2.7 turns, respectively) to reach each destination. The routes that subjects reported in the verbal navigation tasks were scored as nucleus and external correct if they incorporated the correct sequence and direction of turns necessary to reach the destination. All subjects typically reported street names globus pallidus as they navigated their routes. However, presumably because of his anomia (Boston Naming Test score, 42; maximum score, 60, mean of four control Dietmar Plenz* & Stephen T. Kital subjects, 54.5)7, E.P. omitted street names more frequently than did the control Department of Anatomy and Neurobiology, University of Tennessee, subjects (0.5 omissions per question compared with 0.3 omissions for controls; College of Medicine, Memphis, Tennessee 38163, USA range, 0.1±0.5). Accordingly, we also used another scoring method, which ......................................................................................................................... required both a correct sequence of turns and correct street names. An The subthalamic nucleus of the basal ganglia (STN) is important independent scorer who was blind to subject identity scored all transcripts for normal movement1,2 as well as in movement disorders3±5. using both scoring criteria. Average inter-scorer reliability across both scoring Lesioning6 or deep-brain stimulation7,8 of the STN can alleviate criteria was 0.91. resting tremor in Parkinson's disease. The STN5 and its target The ®ve verbal navigation questions for current neighbourhoods were nuclei9,10 display synchronized oscillatory burst discharge at low administered in the same way as the `familiar navigation' task. Across subjects, frequencies, some of which correlate with tremor, but the the questions were similar with respect to the distance travelled and the number mechanism underlying this synchronized bursting is unknown. of turns needed to reach location (mean, 6.5 miles and 5.5 turns, respectively). Here we show that the excitatory STN and inhibitory, external globus pallidus (GPe) form a feedback system that engages in Received 29 April; accepted 9 June 1999. synchronized bursting. In mature organotypic cortex±striatum± 1. Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. STN±GPe cultures, neurons in the STN and GPe spontaneously Neurosurg. Psychiat. 20, 11±21 (1957). produce synchronized oscillating bursts at 0.4, 0.8 and 1.8 Hz. 2. Mishkin, M. Memory in monkeys severely impaired by combined but not separate removal of the amygdala and hippocampus. Nature 273, 297±298 (1978). Pallidal lesion abolishes this bursting, whereas cortical lesion 3. Squire, L. R. Memory and the hippocampus: a synthesis from ®ndings with rats, monkeys, and favours bursting at 0.8 Hz. Pallidal bursts, although weaker than humans. Psychol. Rev. 99, 195±231 (1992). STN bursts, were required for synchronized oscillatory burst 4. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Clarendon, Oxford, 1978). 5. Jarrard, L. E. What does the hippocampus really do? Behav. Brain Res. 71, 1±10 (1995). generation by recruitment of subthalmic rebound excitation. 6. Cohen, N. J. & Eichenbaum, H. Memory, Amnesia, and the Hippocampal System (MIT Press, We propose that the STN and GPe constitute a central pacemaker Cambridge, Massachusetts, 1993). 7. Reed, J. M. & Squire, L. R. Retrograde amnesia for facts and events: Findings from four new cases. J. modulated by striatal inhibition of GPe neurons. This pacemaker Neurosci. 18, 3943±3954 (1998). could be responsible for synchronized oscillatory activity in the 8. Hamann, S. B. & Squire, L. R. Intact perceptual memory in the absence of conscious memory. Behav. normal and pathological basal ganglia. Neurosci. 111, 850±854 (1997). 9. Reed, J. M., Hamann, S. B., Stefanacci, L. & Squire, L. R. When amnesic patients perform well on To test our proposal that the STN and GPe produce synchronized recognition memory tasks. Behav. Neurosci. 111, 1163±1170 (1997). oscillatory bursts, we developed an in vitro model11 in which both 10. Batschelet, E. Statistical Methods for the Analysis of Problems in Animal Orientation and Certain Biological Rhythms (American Institute of Biological Sciences, Washington DC, 1965). nuclei were co-cultured with the cortex and striatum, their main 11. O'Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map: Preliminary evidence from unit extrinsic input sources, to ensure proper maturation. The STN and activity in the freely-moving rat. Brain Res. 34, 171±175 (1971). GPe were obtained from rats at postnatal day 0±2 and cultured with 12. Smith, M. L. & Milner, B. The role of the right hippocampus in the recall of spatial location. Neuropsychologia 19, 781±793 (1981). frontomedial cortex and dorsolateral striatum. After 38 6 1 days in 13. Cave, C. B. & Squire, L. R. Equivalent impairment of spatial and nonspatial memory following vitro (n 58 cultures), spontaneous single- and multi-unit activi- damage to the human hippocampus. Hippocampus 1, 329±340 (1991). 14. Maguire, E. A., Burke, T., Phillips, J. & Staunton, H. Topographical disorientation following unilateral ties were recorded from the STN and GPe with one or two temporal lobe lesions in humans. Neuropsychologia 34, 993±1001 (1996). extracellular electrodes. 15. Morris, R. G. M., Garrud, P., Rawlins, J. N. P. & O'Keefe, J. Place navigation in rats with hippocampal Spontaneous activity in the STN showed distinctive, stereotypic lesions. Nature 297, 681±683 (1982). 16. Aguirre, G. K., Detre, J. A., Alsop, D. C. & D'Esposito, M. D. The parahippocampus subserves periods of oscillatory burst discharge that lasted for 10±15 s topographical learning in man. Cereb. Cort. 6, 823±829 (1996). (Fig. 1a). Intraburst ®ring rates reached several hundred spikes 17. Maguire, E. A., Frackowiak, R. S. J. & Frith, C. D. Learning to ®nd your way: A role for the human hippocampal formation. Proc. R. Soc. Lond. 263, 1745±1750 (1996). per second, and the bursts oscillated at low frequencies. Between 18. Maguire, E. A., Frackowiak, R. S. J. & Frith, C. D. Recalling routes around London: Activation of the bursts, STN units were either silent or ®red irregularly at low rates. right hippocampus in taxi drivers. J. Neurosci. 17, 7103±7110 (1997). The burst activity of STN units was phase-locked and synchronized 19. Maguire, E. A. et al. Knowing where and getting there: A human navigation network. Science 280, 921±924 (1998). with other STN and GPe units (Fig. 1b, c), showing that it re¯ects 20. Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal population activity across both nuclei. Spontaneous synchronized complex. Curr. Opin. Neurobiol. 7, 217±227 (1997). 21. De Renzi, E., Faglioni, P.& Villa, P.Topographicalamnesia. J. Neurol. Neurosurg. Psychiat. 40, 498±505 bursting occurred regularly every 1±2 min and with occasional (1977). shifts in main frequency (Fig. 1d). 22. Paterson, A. & Zangwill, O. L. A case of topographical disorientation associated with a unilateral Based on correlation analysis and frequency plots using contin- cerebral lesion. Brain 68, 188±211 (1945). 23. Levine, D. N., Warach, J. & Farah, M. Two visual systems in imagery: Dissociation of ``what'' and uous periods of spontaneous spiking (324 6 135 s per neuron), ``where'' in imagery disorders due to bilateral posterior cerebral lesions. Neurology 35, 1010±1018 about half of STN (83/181) and a third of GPe units (31/102) (1985). 24. Bottini, G., Cappa, S., Geminiani, G. & Sterzi, R. Topographic disorientationÐa case report. ®red in oscillatory bursts with frequencies between 0.1 and 4 Hz Neuropsychologia 28, 309±312 (1990). (20 ms time resolution). Similarly, 61% of STN±STN (46/76), 44% 25. Incisa della Rochetta, A., Cipolotti, L. & Warrington, E K. Topographical disorientation: Selective of STN±GPe (33/75), and 23% of GP±GPe (4/17) neuronal pairs impairment of locomotor space? Cortex 32, 727±735 (1996). 26. Pai, M.-C. Topographic disorientation: Two cases. J. Formos. Med. Assoc. 96, 660±663 (1997). displayed synchronized oscillatory bursts in that frequency range. 27. Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N. & Hirayama, K. Pure topographic disorienta- The STN±GPe system showed clear preferences for particular tion due to right retrosplenial lesion. Neurology 49, 464±469 (1997). 28. Wechsler, D. Wechsler Memory Scale-III. Administration and Scoring Manual (Psychological Corpora- frequencies during synchronized bursts. The relative power spec- tion, San Antonio, Texas, 1997). trum analysis revealed two main population frequencies at f 0:44 Hz and f 0:79 Hz, respectively (Fig. 2a). A third Acknowledgements. We thank J. Zouzounis, L. Stefanacci, J. Frascino and the Hayward Area Historical 01 02 Society for assistance. This work was supported by the Medical Research Service of the Department of Veterans Affairs, NIMH, and the McDonnell-Pew Center for Cognitive Neuroscience. * Present address: Unit of Neural Network Physiology, Laboratory of Systems Neuroscience, National Correspondence and requests for materials should be addressed to L.R.S. (e-mail: [email protected]). Institute of Mental Health, Bldg 36 2D-30, Bethesda, Maryland 20892, USA. NATURE | VOL 400 | 12 AUGUST 1999 | www.nature.com © 1999 Macmillan Magazines Ltd 677 letters to nature Figure 1 STN units display periods of oscillatory bursting, synchronized with STN or GPe units at 08, close to 08 (b, arrowheads), or 1808 (c, arrowheads). other STN and GPe units. a, Oscillatory bursting periods with basic frequencies of Simultaneous extracellular multi-unit recording with two electrodes. d, Synchro- 1.7, 0.8 and 0.4 Hz. Upper traces: instantaneous ®ring rates (t 0:1 s).
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