» See the corresponding retraction notice, DOI: 10.3171/2015.10.JNS145r, for full details. «

laboratory investigation

Anatomy of the , with correlation of deep stimulation

Akın Akakın, MD,1 Baran Yılmaz, MD,1 Türker Kılıç, MD,1 PhD, and Albert L. Rhoton Jr., MD2

1Department of Neurosurgery, School of Medicine, Bahcesehir University, Istanbul, Turkey; and 2Department of Neurosurgery, School of Medicine, University of Florida, Gainesville, Florida

O bject The goal in this study was to examine the cadaveric anatomy of the subthalamic nucleus (STN) and to analyze the implications of the findings for deep brain stimulation (DBS) surgery. Methods Five formalin-fixed human cerebrums were dissected using the Klingler fiber dissection technique. Digital photographs of the dissections were fused to obtain an anaglyphic image. Results The STN was located posteroinferior to the anterior corticospinal fibers, posterosuperior to the , and anteromedial to the , lenticular fasciculus, and thalamic fasciculus. The subthalamic region is ven- tral to the , medial to the internal capsule, and lateral and caudal to the . The nuclei found within the subthalamic region include the STN. The relationship between the STN and surrounding structures, which are not delineated sharply, is described. Conclusions The fiber dissection technique supports the presence of the subthalamic region as an integrative net- work in humans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with Parkinson disease. Further research is needed to define the exact role of the STN in the integrative process. http://thejns.org/doi/abs/10.3171/2014.10.JNS145 Key Words ; subthalamic nucleus; fiber dissection; anatomy

he subthalamic nucleus (STN) is an important part of the STN and movement. In this study we describe the of the brain related to Parkinson disease (PD) and anatomical relationship between the STN and surrounding other involuntary movements. The STN contains structures. someT fibers that travel to the cortical area and basal gan- glia.2 The STN is located just superomedial to the red Methods nucleus and substantia nigra. Widely acknowledged as an important modulator of output, the STN re- Anatomical Study ceives its major afferents from the , thala- The cerebral hemispheres and cerebrums of 5 human mus, externus (GPe), and . The cadavers were fixed in a 10% formalin solution for at least STN projects mainly to both segments of the GP, sub- 3 weeks. The first step in the preparation of the specimens stantia nigra, , and brainstem and is essentially was the removal of the arachnoidal and vascular structures composed of glutamatergic . Lesions of the STN with the aid of a surgical microscope (magnification range induce choreiform abnormal movements and ballism on ×6 to ×40). The hemispheres were frozen at -16°C for 2–4 the contralateral side of the body.2,3 Despite current inter- weeks. Twenty-four hours after completion of the freezing est, little is knownRetracted about the relation between function process, the white fiber dissection was done with fine and Abbreviations DBS = deep brain stimulation; GPe, GPi = globus pallidus externus, globus pallidus internus; PD = Parkinson disease; STN = subthalamic nucleus. submitted January 16, 2014. accepted October 15, 2014. include when citing Published online April 24, 2015; DOI: 10.3171/2014.10.JNS145. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

©AANS, 2015 J Neurosurg April 24, 2015 1 A. Akakın et al. self-shaped wooden spatulas. We took numerous digital tween the claustrum and the . By removing the photographs during dissections and, using a specific soft- fibers of the dorsal extreme capsule, we can see the fibers ware program (Anamaker 3D; available free from www. of the dorsal external capsule at the periphery of the dorsal stereoeye.com), we fused the images to obtain an ana- claustrum. At the level of the limen insula, the uncinate glyphic image. fasciculus and inferior frontooccipital fasciculus can be observed (Fig. 1). Results After dissection of the crus cerebri, we first observe the Anatomical Dissection substantia nigra, which is located superolateral to the red nucleus. When the red nucleus is dissected, fibers of the The dissection of the brain is started from the gray mat- ansa lenticularis can be observed. The STN is located pos- ter of the cortex, and U-fibers are observed under the gray teroinferior to the anterior corticospinal fibers, posterosu- matter. After the removal of U-fibers, the cortical fibers perior to the substantia nigra, and anteromedial to the red are seen. To expose the superior longitudinal fasciculus, nucleus, lenticular fasciculus, and thalamic fasciculus. The we remove the cortical gray matter; adjacent superficial STN had a café-au-lait color in cadaver sections (Fig. 2). short fibers of the frontal, temporal, and parietal oper- cula; the middle, frontal, superior, and middle temporal Identification of the STN gyri; and the inferior parietal lobule. The first identified fasciculus in dissection, which begins on the lateral hemi- The STN is a small, lens-shaped nucleus in the brain. spheric surface, is the superior longitudinal (arcuate) fas- The STN is a part of the basal ganglia system and is lo- ciculus. Traditionally, this fasciculus can be described as cated ventral to the thalamus, dorsal to the substantia nig- a reversed C-shaped structure, which surrounds the insula ra, and medial to the internal capsule (Fig. 3). Anterior and interconnects the frontal and temporal lobes (Fig. 1). and lateral borders of the STN are enveloped by fibers of At a deeper level in the temporoparietal area, a group the internal capsule, which separates this nucleus laterally of fibers arching around the posterosuperior insular bor- from the GP. Posteromedially, the STN is very close to der is seen to be traveling between the posterior temporal the red nucleus. The ventral borders of the STN are the region and the prefrontal area. These fibers form the fron- cerebral peduncle and the substantia nigra. Dorsally, the totemporal or arcuate segment of the superior longitudi- STN has a border with the fasciculus lenticularis, which nal fasciculus. By dissecting the inferolateral hemispheric separates the STN from the ventral thalamus. surface, we can see a group of fibers deep to the tempo- Several fiber tracts course near the borders of the STN. roparietal segment of the superior longitudinal fasciculus The subthalamic fasciculus consists of fibers that inter- (Fig. 1). connect the STN and GP. This fiber bundle arises from Progressive dissection of the fibers of the superior lon- the inferolateral border of the STN (Fig. 2). gitudinal fasciculus reveals the insular cortex. After re- The ansa lenticularis consists of fibers from the globus moval of the insular subcortex, we can see the white fibers pallidus internus (GPi) that project toward the thalamus. of the extreme capsule; and at the level of the limen in- It originates mainly from the lateral portion of the GPi, sula, the fibers of the uncinate and inferior occipitofrontal coursing in a medial, ventral, and rostral direction and fascicles can be distinguished. The extreme capsule is a sweeping anteriorly around the posterior limb of the in- group of fibers situated between the insular cortex and the ternal capsule. This tract arises from the medial aspect claustrum (Fig. 1). of the GPi, perforates the internal capsule, and forms a The external capsule is composed of fibers situated be- bundle ventral to the . Although some fibers

FIG. 1. A: Gray matter has been dissected, and fibers have been uncovered. The gyri and sulci have been identified. B: Fibers haveRetracted been dissected; the claustrum can be seen. Internal capsules have been dissected. The inferior frontal fasciculus and uncinate fasciculus are identified. The optic radiation can be followed inferiorly. C: The claustrum has been dissected, and the putamen is identified. The sagittal stratum can be followed, radiating posteriorly. Fasc. = fasciculus; Front. = frontal; gyr. = gyrus; i.c. = internal capsule; Inf. = inferior; Int. = internal; Lat. Gen. bod = lateral geniculate body; long. = longitudinal; Midd. = middle; Occ. = occipital; rad. = radiation; Sup. = superior; Temp. = temporal. Figure is available in color online only.

2 J Neurosurg April 24, 2015 Subthalamic nucleus anatomy

FIG. 2. Left: View from the medial aspect of the cerebrum. The red nucleus can be viewed medial to the substantia nigra. The thalamus is located posterolateral to the substantia nigra. The optic and the stalk can be observed medially. Right: Subtha- lamic nucleus and ansa lenticularis fibers are seen. Association fibers between basal ganglia and the STN can be viewed. The red nucleus is located medially and inferiorly. The ansa lenticularis and substantia nigra can be seen on the inferior and lateral side of the STN, respectively. Pit. = pituitary. Figure is available in color online only. from the lenticular fasciculus are dorsal to the STN, most nuclei found within the subthalamic region include the of this tract courses rostral to the nucleus. Fiber tracts ly- STN and zona incerta. The STN has a very close relation- ing posterior to the STN include the medial lemniscus, ship with the substantia nigra and the red nucleus (Fig. 5). spinothalamic tract, and trigeminothalamic tract (Fig. 2). In particular, the dorsal aspects of the lateral portion of Discussion the rostral two-thirds and the caudal one-third of the nu- cleus are anatomically related to the motor circuits. Sub- The STN is a small, lens-shaped nucleus in the brain. thalamic afferent fibers, corticosubthalamic projections, The STN is part of the basal ganglia system and is located and most of the cortical afferents to the STN arise from ventral to the thalamus, dorsal to the substantia nigra, and the primary , supplementary motor area, pre– medial to the internal capsule. It was first described by supplementary motor area, and premotor area (Fig. 4). Jules Bernard Luys in 1865, and the terms corpus luysi The fibers traveling between the red nucleus and STN and Luys body are still sometimes used. The STN is sur- are known as the habenular commissure at midline sec- rounded by dense bundles of myelinated fibers.2 Dorsally tions of the brain. The mammillary body is located anteri- the STN is bordered by a portion of the fasciculus len- or to the STN. The mammillothalamic pathway is located ticularis and the zona incerta, which separate this nucleus anterosuperior to the STN (Fig. 4). from the ventral thalamus.2–7,10,12 As a consequence, the STN does not have sharp borders with the surrounding Atlas-Based Localization of the Subthalamic Region structures. Hence, the dissection is very difficult in this Using the 3 spatial MRI planes and applying the ana- intricate region because of the challenge involved in cal- tomical knowledge acquired from the cadaveric dissec- culating any anatomical measurement. tions, we can localize the subthalamic region. This region The volume of the STN is 40 mm3 in humans. The rela- is located ventral to the thalamus, medial to the internal tionship between the volume of the STN and the total vol- capsule, and lateral and caudal to the hypothalamus. The ume of the brain is proportionally similar in all humans.6 Retracted FIG. 3. Left: Cortical fibers, GPi, and GPe have been dissected. The STN, substantia nigra, and crus cerebri are displayed, and the thalamus can also be seen. Right: has been completely dissected. The STN can be seen inferior to the red nucleus. The substantia nigra and red nucleus can be observed. The optic nerve has been sectioned. Figure is available in color online only.

J Neurosurg April 24, 2015 3 A. Akakın et al.

FIG. 4. Lateral appearance of the anterior commissure posteriorly and dentate rubrothalamic tract anteriorly. A: The STN is inferior to the crus cerebri. The substantia nigra and the red nucleus can be seen at the anterior part of the corticospinal tract fibers. B: The midbrain, , and have been dissected. The substantia nigra and the red nucleus are clearly visible. The superior and inferior colliculus are posterior to the STN. The superior cerebellar peduncle is lateral to the substantia nigra and inferolateral to the STN. C: The STN, the primary motor cortex, and the premotor cortex are shown, which illustrates the relationship between these structures in a wide anatomical dissection. The optic nerve has been cut so that the lateral geniculate body can be seen. D: Medial appearance of the cerebrum. The mammillothalamic tract and the STN can be seen close to the thalamus. The habenular commissure, which includes the posterior commissure and the habenular nucleus, can be observed. Subthalamic-cortical fibers can be followed. Ant = anterior; cer. Ped. = cerebellar peduncle. Figure is available in color online only.

Chronic stimulation of the STN, called deep brain stimulation (DBS), is used to treat patients with PD. The first cells to be stimulated are the terminal arborizations of afferent ; the stimulation modifies the activity of subthalamic neurons.11 The function of the STN is unknown, but current theo- ries present it as a component of the basal ganglia control system, which may perform action selection. Dysfunction of the STN has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli. The STN is populated mainly by projection neurons. The first intracellular electrical recordings of subtha- lamic neurons were performed using sharp electrodes in a rat slice preparation.1 Several recent studies have focused on the autonomous pace-making ability of the subthalam- ic neurons. These neurons are often referred to as “fast- spiking pacemakers.” The connection of the lateral pallidum with the STN is part of the basal ganglia. The activity of the medial pal- lidum is influencedRetracted by afferent signals from the lateral pallidum and the STN. The STN sends axons to anoth- er regulator region: the pedunculopontine complex. The FIG. 5. Three spatial MRI planes and atlas-based localization of the lateropallido-subthalamic system is thought to have a key subthalamic region. Figure is available in color online only.

4 J Neurosurg April 24, 2015 Subthalamic nucleus anatomy role in the generation of the patterns of activity seen in nucleus neurons in the monkey. J Comp Neurol 197:579– PD.9 603, 1981 In clinical practice, DBS of the STN is a promising 6. Coubes P, Cif L, El Fertit H, Hemm S, Vayssiere N, Serrat S, new surgical option for the treatment of advanced PD. et al: Electrical stimulation of the globus pallidus internus The marked clinical benefits obtained in these severely in patients with primary generalized dystonia: long-term 4 results. J Neurosurg 101:189–194, 2004 disabled patients outweigh the adverse effects. Accurate 7. Kita H, Chang HT, Kitai ST: Pallidal inputs to subthalamus: positioning of the electrodes allows the effects of stimula- intracellular analysis. Brain Res 264:255–265, 1983 8 tion to be confined to sensorimotor circuits. 8. Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, et al: Double-blind evaluation of subthalamic Conclusions nucleus deep brain stimulation in advanced Parkinson’s dis- ease. Neurology 51:850–855, 1998 The fiber dissection technique supports the presence of 9. Nakanishi H, Kita H, Kitai ST: Electrical membrane proper- the subthalamic region as an integrative network in hu- ties of rat subthalamic neurons in an in vitro slice prepara- mans and offers the potential to aid in understanding the tion. Brain Res 437:35–44, 1987 impacts of DBS surgery of the STN in patients with PD. 10. Nowinski WL: Anatomical targeting in functional neuro- Further research is needed to delineate definitively the surgery by the simultaneous use of multiple Schaltenbrand- role of the STN in the integrative process. Fiber dissec- Wahren brain atlas microseries. Stereotact Funct Neuro- tions, done in conjunction with electrophysiological visu- surg 71:103–116, 1998 11. Parent A, Hazrati LN: Functional anatomy of the basal gan- alization or other techniques, offer confirmatory evidence glia. II. The place of subthalamic nucleus and external pal- that can lead to improvements in atlas-based localization lidum in basal ganglia circuitry. Brain Res Brain Res Rev of the subthalamic region. 20:128–154, 1995 12. Sarma SV, Eden UT, Cheng ML, Williams ZM, Hu R, Es- References kandar E, et al: Using point process models to compare neu- ral spiking activity in the subthalamic nucleus of Parkinson’s . 1 Afsharpour S: Topographical projections of the cerebral cor- patients and a healthy primate. IEEE Trans Biomed Eng tex to the subthalamic nucleus. J Comp Neurol 236:14–28, 57:1297–1305, 2010 1985 2. Alvarez L, Macias R, Guridi J, Lopez G, Alvarez E, Marago- to C, et al: Dorsal subthalamotomy for Parkinson’s disease. Author Contributions Mov Disord 16:72–78, 2001 3. Ashby P, Kim YJ, Kumar R, Lang AE, Lozano AM: Neuro- Conception and design: Akakın, Rhoton. Acquisition of data: Yıl­ physiological effects of stimulation through electrodes in the maz, Rhoton. Analysis and interpretation of data: Kılıç, Rhoton. human subthalamic nucleus. Brain 122:1919–1931, 1999 4. Baron MS, Sidibé M, DeLong MR, Smith Y: Course of mo- Correspondence tor and associative pallidothalamic projections in monkeys. J Akın Akakın, Department of Neurosurgery, Bahcesehir Univer- Comp Neurol 429:490–501, 2001 sity School of Medicine, Cıragan Caddesi Osmanpasa Mektebi 5. Carpenter MB, Baton RR III, Carleton SC, Keller JT: Inter- Sokak No: 4-6, 34353 Besiktas, Istanbul 81156, Turkey. email: connections and organization of pallidal and subthalamic [email protected].

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