The Pallidosubthalamic Projection: An Anatomical Substrate for Nonmotor Functions of the Subthalamic Nucleus in Primates Carine Karachi, MD, * Je ´ro ˆme Yelnik, MD, Dominique Tande ´, BT, Le ´on Tremblay, PhD, Etienne C. Hirsch, PhD, and Chantal Franc ¸ois, PhD INSERM U289, Neurologie et The ´rapeutique Expe ´rimentale, Ho ˆpital de la Salpe ˆtrie `re, Paris, France Abstract: The subthalamic nucleus (STN) is the best target for correcting motor disability in parkinsonian patients with high- frequency stimulation. However, STN stimulation has also been reported to modify cognitive, emotional, and motivational functions. The aim of this study was to analyze the topographic organization of the STN according to its inputs coming from the sensorimotor, associative, and limbic territories of the ex- ternal globus pallidus (GPe) in monkeys, with special reference to the limbic projection. Axonal tracers were injected into the different functional territories of the GPe. Injection performed in the limbic GPe resulted in labeling of cell bodies in the dorsal nucleus accumbens and in a dense labeling of axons in the anterior and medioventral portion of the STN. In compar- ison, injections in the associative and sensorimotor GPe led to labeling in the central and dorsolateral parts of the STN, re- spectively. Individual pallidosubthalamic axons ramified into numerous varicose branches, which were restricted to a given territory in the STN. These data provide a functional cartogra- phy of this structure in primates and suggest that behavioral disorders observed in stimulated parkinsonian patients could result from a dysfunction of the limbic part of the STN. © 2004 Movement Disorder Society Key words: monkeys; axonal tracing; basal ganglia; globus pallidus The subthalamic nucleus (STN) has proved to be the most efficient target to improve advanced forms of Par- kinson’s disease by chronic high-frequency stimula- tion. 1,2 In addition to these motor effects, STN stimula- tion can also improve or trigger psychiatric symptoms. 3,4 Experimental data have demonstrated that lesion of the STN induces deficits in attentional and emotional func- tions in rats 5–7 and that microinjections of the GABA agonist muscimol in the anterior part of the STN induce transitory atypical behavior in monkeys. 8 These data support the notion that the STN is involved not only in motor control but also in cognitive, emotional, and mo- tivational processes. The anatomical basis of such a subdivision into motor and nonmotor regions in the basal ganglia has largely been based upon axonal tracing studies. On the basis of the topography of the cortical information that it re- ceives, the monkey striatum has been subdivided into three different regions—sensorimotor, associative, and limbic—treating, respectively, sensorial and motor, cog- nitive, and emotional and motivational information, even though zones of overlap exist between adjacent re- gions. 9 –11 It has also been reported that these anatomo- functional subdivisions are preserved at the pallidal level, namely that the sensorimotor pallidum is located ventrolaterally, the associative pallidum is located dor- somedially, and the limbic pallidum is located anteriorly and ventromedially. 12–15 In parallel with axonal tracing techniques, calbindin immunoreactivity revealed that three distinct areas, identified by a poorly-, intermediate-, and strongly labeled calbindin immunoreactivity, corre- sponded to the sensorimotor, associative, and limbic territories of the striatopallidal complex, respectively, in primates. 16 –18 An important issue was to determine whether the same compartmentation exists in the STN of monkeys, and in particular whether a limbic subpart could be anatomi- cally identified, as demonstrated in rats. 19,20 The basic network underlying the interconnections between the *Correspondence to: Dr. Carine Karachi, INSERM U289, Neurologie et The ´rapeutique Expe ´rimentale, Ho ˆpital de la Salpe ˆtrie `re, 47 Boulevard de l’Ho ˆpital, 75013 Paris, France. E-mail: Karachi@ccr.jussieu.fr Received 16 March 2004; Revised 17 May 2004; Accepted 8 June 2004 Published online 20 September 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20302 Movement Disorders Vol. 20, No. 2, 2005, pp. 172–180 © 2004 Movement Disorder Society 172