LABORATORY INVESTIGATION J Neurosurg 124:1406–1412, 2016 The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation Antonio Meola, MD,1,2 Ayhan Comert, MD,1,3 Fang-Cheng Yeh, MD, PhD,4 Sananthan Sivakanthan, BS,1 and Juan C. Fernandez-Miranda, MD1 1Department of Neurosurgery, University of Pittsburgh Medical Center; 4Department of Psychology, Carnegie Mellon University, Pittsburgh, Pennsylvania; 2Department of Neurosurgery, University of Pisa, Italy; and 3Department of Anatomy, Ankara University School of Medicine, Ankara, Turkey OBJECTIVE The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebel- lar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of this study was to clarify the anatomy of the dentatorubrothalamic connections in humans. METHODS The authors applied advanced deterministic fiber tractography to a template of 488 subjects from the Hu- man Connectome Project (Q1–Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dis- section of cadaveric brains prepared according to Klingler’s method. RESULTS The authors identified the “classic” decussating DRTT and a corresponding nondecussating path (the non- decussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentato- rubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle. CONCLUSIONS The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physi- ological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles. http://thejns.org/doi/abs/10.3171/2015.4.JNS142741 KEY WORDS dentate nucleus; red nucleus; fiber tractography; thalamus; fiber dissection; fiber tracts; anatomy HE dentatorubrothalamic tract (DRTT) is the major ous studies have shown that the DRTT is involved in cer- efferent pathway from the deep cerebellar nuclei to ebellar mutism after resection of posterior fossa tumors the brainstem and thalamus. Traditionally, its pre- and hemorrhage,24 schizophrenia,5 autism,23 and bipolar Tsumed role has been the motor coordination and timing of disorder.28 movement, but increasing evidence suggests an important Anatomically, the DRTT is classically described as a role in cognitive function such as planning, verbal fluency, bundle arising from the deep cerebellar nuclei, mainly the working memory, abstract thinking, and behavior.33 Vari- dentate nucleus (DN), running in the superior cerebellar ABBREVIATIONS DN = dentate nucleus; DRT = dentatorubro tract; DRTT = dentatorubrothalamic tract; 18FDG = 18-fluoro-deoxyglucose; fMRI = functional MRI; HCP = Human Connectome Project; HCP-488 = HCP 488-subject template; ICP = inferior cerebellar peduncle; LL = lateral lemniscus; MCP = middle cerebellar peduncle; nd-DRT = nondecussating DRT; nd-DRTT = nondecussating DRTT; RN = red nucleus; ROI = region of interest; rTMS = repetitive transcranial magnetic stimulation; SCP = superior cerebellar peduncle. SUBMITTED December 3, 2014. ACCEPTED April 7, 2015. INCLUDE WHEN CITING Published online October 9, 2015; DOI: 10.3171/2015.4.JNS142741. 1406 J Neurosurg Volume 124 • May 2016 ©AANS, 2016 Unauthenticated | Downloaded 10/07/21 04:18 AM UTC Anatomy of the dentatorubrothalamic connections in humans peduncle (SCP), and then completely decussating to the Fiber Tractography contralateral red nucleus (RN) to ascend to the thalamus The DN was easily identified in the axial T2-weighted and finally to the cortex.26 Because the corticospinal fi- sequences of the template (Montreal Neurological Insti- bers decussate once again, motor deficits related to uni- tute) as a crescent-shaped, medially concave, hypointense lateral hemispheric cerebellar lesions, such as strokes, area, immediately lateral to the fourth ventricle, at the lev- hemorrhages, and tumors, would be expected to influence el of the middle cerebellar peduncle (MCP). The seeding only the ipsilateral limbs.13,30 Surprisingly, each cerebellar region was tailored to enclose the DN. Since the DRTT hemisphere clearly influences bilateral limb movements, runs completely inside the SCP, a region of interest (ROI) as demonstrated by human functional magnetic resonance was created to enclose it. The SCP can be identified on imaging (fMRI) studies,12,14,22,25 human transcranial mag- sagittal sections as a structure superior and medial to the netic stimulation (rTMS) studies,10,32 and human motor MCP, with an oblique orientation from the cerebellum to performance studies,17,20,34 as well as neurophysiological the midbrain. Finally, the RN and thalami were identified studies19,35,36 and experimental lesioning studies in mon- to verify the course of the DRTT after fiber tracking. In keys.4,7 Although the neuroanatomical basis of this phe- particular, the RN is seen as a paramedian round hypoin- nomenon is not clear,36 uncrossed projections from the DN tense area in the rostral midbrain, just behind the substan- to the ipsilateral RN and thalamus were demonstrated in tia nigra and the cerebral peduncles. After fiber tracking, monkeys,9,40 a finding that provides a simple and elegant only the fibers running from the DN to the RN and the explanation of the bilateral motor influence of each cer- thalamus were selected, according to the definition of the ebellar hemisphere. Still, the existence of a direct, nonde- DRTT. Each of the resulting bundles was measured by cussating DRTT (nd-DRTT) in the monkey brain is not assessing the number of tracts, tract volume, mean quan- generally accepted, and such a structure has never been titative anisotropy, and quantitative anisotropy standard demonstrated in humans. deviation. Thus, in an attempt to clarify the anatomy of the denta- torubrothalamic connections in humans we have applied Fiber Dissection Technique advanced deterministic fiber tractography to a template of Five normal brains obtained at routine autopsy were 488 subjects from the Human Connectome Project (Q1– fixed in 10% formalin aqueous solution for 4 weeks. Then, Q3 release, WU-Minn HCP consortium) (HCP-488) and the specimens were frozen for 2 weeks at −16°C, accord- validated our results with microsurgical postmortem dis- ing to Klingler’s method.31 Progressive dissection of the section of human brains. white matter tracts was performed by peeling off the gray Methods matter and isolating the fiber bundles in their glial sheets. We undertook the fiber dissection studies in the Surgical The HCP-488 Neuroanatomy Laboratory at the University of Pittsburgh, The WU-Minn HCP consortium is an ongoing NIH- with the aid of microsurgical instrumentation and a sur- funded, institutional review board–approved project led gical microscope (6–40 magnification; Carl Zeiss, OPMI by Washington University, the University of Minnesota, CS-NC), as previously reported.16 and Oxford University, which aims to define in detail a We removed the cerebral hemispheres, leaving in place “map” of human brain connectivity and function. Re- the thalami. Then, the tentorial surface of the cerebellar sults of this project will allow analysis and comparison hemispheres was dissected from the cerebello-mesence- of brain circuits, behavioral features, and genetic tracts phalic fissure anteriorly to the horizontal fissure posteri- within the same subject and between subjects.39 Data ac- orly. This exposed the inner core of the cerebellar hemi- cumulated from 500 subjects were released for the first sphere. Because the fibers of the MCP wrap around the three quarters (Q1–Q3, June 2014), and 488 healthy sub- DN passing above and below it, the nuclei were exposed jects (289 females, 199 males; average age 29.15 years, by removing the paravermian portion of the most superfi- SD 3.47 years) underwent diffusion scanning. The diffu- cial fibers of the MCP1 (Fig. 1). sion data were acquired in a Siemens 3-T Skyra scanner From the DN, the ascending course of the fibers of the using a 2D spin-echo single-shot multiband echo planar DRTT was clear. The fibers of the inferior cerebellar pe- imaging sequence with a multiband factor of 3 and mon- duncle (ICP) that crossed above the DRTT and in front opolar gradient pulse.38 The spatial resolution was 1.25 of the DN were left in place. The ependyma covering the mm isotropic, TR was 5500 msec, and TE was 89 msec. A SCP was removed, exposing the underlying portion of the multishell diffusion scheme was used. The b values were DRTT. At the level of the midbrain, the fibers of the lat- 1000, 2000,