Neurosurgical treatment of spasticity: a potential return to the cerebellum.

OBJECTIVE: Neurosurgical targeting of the cerebellar dentate nucleus via ablative dentatotomy and stimulation of the dentate nucleus was historically used for effective treatment of spasticity. Yet for decades, neurosurgical treatment of spasticity targeting the cerebellum was bypassed in favor of alternative treatments such as intrathecal baclofen pumps and selective dorsal rhizotomies. Cerebellar neuromodulation has recently reemerged as a promising and effective therapy for spasticity and related movement disorders. METHODS: In this narrative review, the authors contextualize the historical literature of cerebellar neuromodulation, comparing it with modern approaches and exploring future directions with regard to cerebellar neuromodulation for spasticity. RESULTS: Neurosurgical intervention on the cerebellum dates to the use of dentatotomy in the 1960s, which had progressed to electrical stimulation of the cerebellar cortex and dentate nucleus by the 1980s. By 2024, modern neurosurgical approaches such as tractography-based targeting of the dentate nucleus and transcranial magnetic stimulation of cerebellar cortex have demonstrated promise for treating spasticity. CONCLUSIONS: Cerebellar neuromodulation of the dentate nucleus and cerebellar cortex are promising therapies for severe cases of spasticity. Open areas for exploration in the field include the following: tractography-based targeting, adaptive cerebellar stimulation, and investigations into the network dynamics between the cerebellar cortex, deep cerebellar nuclei, and the subcortical and cortical structures of the cerebrum.

Dentate nucleus: a review and implications for dentatotomy.

PURPOSE: The dentate nucleus (DN) is the largest, most lateral, and phylogenetically most recent of the deep cerebellar nuclei. Its pivotal role encompasses the planning, initiation, and modification of voluntary movement but also spans non-motor functions like executive functioning, visuospatial processing, and linguistic abilities. This review aims to offer a comprehensive description of the DN, detailing its embryology, anatomy, physiology, and clinical relevance, alongside an analysis of dentatotomy. METHODS AND RESULTS: We delve into the history, embryology, anatomy, vascular supply, imaging characteristics, and clinical significance of the DN. Furthermore, we thoroughly review the dentatotomy, emphasizing its role in treating spasticity. CONCLUSIONS: Understanding the intricacies of the anatomy, physiology, vasculature, and projections of the DN has taken on increased importance in current neurosurgical practice. Advances in technology have unveiled previously unknown functions of the deep cerebellar nuclei, predominantly related to non-motor domains. Such discoveries are revitalizing older techniques, like dentatotomy, and applying them to newer, more localized targets.

Retrosigmoid transhorizontal fissure approach to lateral pontine cavernous malformation: comparison to transpetrosal presigmoid retrolabyrinthine approach.

OBJECTIVE: The retrosigmoid (RS) approach is a classic route used to access deep-seated brainstem cavernous malformation (CM). The angle of access is limited, so alternatives such as the transpetrosal presigmoid retrolabyrinthine (TPPR) approach have been used to overcome this limitation. Here, the authors evaluated a modification to the RS approach, horizontal fissure dissection by using the RS transhorizontal (RSTH) approach. METHODS: Relevant clinical parameters were evaluated in 9 patients who underwent resection of lateral pontine CM. Cadaveric dissection was performed to compare the TPPR approach and the RSTH approach. RESULTS: Five patients underwent the TPPR approach, and 4 underwent the RSTH approach. Dissection of the horizontal fissure allowed for access to the infratrigeminal safe entry zone, with a direct trajectory to the middle cerebellar peduncle similar to that used in TPPR exposure. Operative time was longer in the TPPR group. All patients had a modified Rankin Scale score ≤ 2 at the last follow-up. Cadaveric dissection confirmed increased anteroposterior working angle and middle cerebellar peduncle exposure with the addition of horizontal fissure dissection. CONCLUSIONS: The RSTH approach leads to a direct lateral path to lateral pontine CM, with similar efficacy and shorter operative time compared with more extensive skull base exposure. The RSTH approach could be considered a valid alternative for resection of selected pontine CM.

A Case of Dentatotomy for Pain and Spasticity and Systematic Review.

BACKGROUND: Surgical interventions for spasticity aim to improve motor function and pain in cases that are refractory to medical treatment. Ablation of the cerebellar dentate nucleus (dentatotomy) may be a useful alternative. CASE REPORT: A 55-year-old male patient with spasticity, secondary to a traumatic cervical spinal cord injury with quadriparesis, had bilateral lumbar DREZotomy with an improvement that lasted for 6 years. Ten years after the DREZotomy, a progressive increased spasticity manifested as spastic diplegia (Ashworth 4) and spontaneous muscle painful spasms (Penn 4), as well as spasticity in the upper extremities, predominantly on the right side (Ashworth 3). A right radio frequency dentatotomy was performed with intraoperative electrophysiological monitoring. Spasticity scales were applied at the following times: preoperative and at 1 and 8 months after surgery. During the first month, the patient presented a clear decrease in spasticity ipsilateral to the side of lesioning (Ashworth 1) and of painful spasms in the lower extremities (Penn 1). After 8 months, spasticity ipsilateral to the injury decreased even more to Ashworth (0), but a progressive increase in muscle spasms of lower extremities was observed (Penn 2). CONCLUSION: Stereotactic dentatotomy may be an effective surgical alternative for management of spasticity associated with painful spasms in selected patients.

Advanced Imaging and Direct Targeting of the Motor Thalamus and Dentato-Rubro-Thalamic Tract for Tremor: A Systematic Review.

Direct targeting methods for stereotactic neurosurgery in the treatment of essential tremor have been the subject of active research over the past decade but have not yet been systematically reviewed. We present a clinically oriented topic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses Group guidelines. Our focus is studies using advanced magnetic resonance imaging (MRI) techniques (ultrahigh-field structural MRI, diffusion-weighted imaging, diffusion-tensor tractography, and functional MRI) for patient specific, in vivo identification of the ventral intermediate nucleus and the dentato-rubro-thalamic tract.

Frameless Stereotactic Targeting of the Cerebellar Dentate Nucleus in Nonhuman Primates: Translatable Model for the Surgical Delivery of Gene Therapy.

BACKGROUND: Stereotactic targeting techniques in nonhuman primate (NHP) models are often utilized in the preclinical investigation of new drug therapies with the goal of demonstrating accurate and reliable delivery of a therapy to the target tissue. However, targeting certain neuroanatomical structures can be challenging. The deep cerebellar nuclei, specifically the dentate nucleus, are potential stereotactic targets for the treatment of certain ataxias. Currently, there are no detailed techniques describing frameless targeting of these structures in a NHP model. A well-defined, accurate, and reliable stereotactic surgical approach to the dentate in these animal models is critical to prove the feasibility and safety of drug delivery in order to develop clinical protocols. METHODS: Frameless stereotactic neuronavigation was employed to target the bilateral dentate nuclei of the cerebellum in four healthy juvenile Cynomolgus monkeys via a suboccipital, transcerebellar approach. The precision and accuracy of the targeting were evaluated radiologically and histologically. RESULTS: Using the described surgical methodology, we were successful in hitting the target deep cerebellar nuclei seven out of eight times. CONCLUSION: Frameless stereotactic targeting of the cerebellar dentate nuclei in NHPs for future investigational drug delivery is feasible, safe, and accurate as described by this report. Potential areas for improving the technique are discussed.

Deep brain stimulation of the cerebellum for poststroke motor rehabilitation: from laboratory to clinical trial.

Ischemic stroke is a leading cause of disability worldwide, with profound economic costs. Poststroke motor impairment is the most commonly encountered deficit resulting in significant disability and is the primary driver of stroke-associated healthcare expenditures. Although many patients derive some degree of benefit from physical rehabilitation, a significant proportion continue to suffer from persistent motor impairment. Noninvasive brain stimulation, vagal nerve stimulation, epidural cortical stimulation, and deep brain stimulation (DBS) have all been studied as potential modalities to improve upon the benefits derived from physical therapy alone. These neuromodulatory therapies aim primarily to augment neuroplasticity and drive functional reorganization of the surviving perilesional cortex. The authors have proposed a novel and emerging therapeutic approach based on cerebellar DBS targeted at the dentate nucleus. Their rationale is based on the extensive reciprocal connectivity between the dentate nucleus and wide swaths of cerebral cortex via the dentatothalamocortical and corticopontocerebellar tracts, as well as the known limitations to motor rehabilitation imposed by crossed cerebellar diaschisis. Preclinical studies in rodent models of ischemic stroke have shown that cerebellar DBS promotes functional recovery in a frequency-dependent manner, with the most substantial benefits of the therapy noted at 30-Hz stimulation. The improvements in motor function are paralleled by increased expression of markers of synaptic plasticity, synaptogenesis, and neurogenesis in the perilesional cortex. Given the findings of preclinical studies, a first-in-human trial, Electrical Stimulation of the Dentate Nucleus Area (EDEN) for Improvement of Upper Extremity Hemiparesis Due to Ischemic Stroke: A Safety and Feasibility Study, commenced in 2016. Although the existing preclinical evidence is promising, the results of this Phase I trial and subsequent clinical trials will be necessary to determine the future applicability of this therapy.

Deep Brain Stimulation of the Dentato-Rubro-Thalamic Tract: Outcomes of Direct Targeting for Tremor.

OBJECTIVES: Targeting the dentato-rubro-thalamic tract (DRTt) has been suggested to be efficacious in deep brain stimulation (DBS) for tremor suppression, both in case reports and post-hoc analyses. This prospective observational study sought to analyze outcomes after directly targeting the DRTt in tremor patients. METHODS: 20 consecutively enrolled intention tremor patients obtained pre-operative MRI with diffusion tensor (dTi) sequences. Mean baseline tremor amplitude based on The Essential Tremor Rating Assessment Scale was recorded. The DRTt was drawn for each individual on StealthViz software (Medtronic) using the dentate nucleus as the seed region and the ipsilateral pre-central gyrus as the end region and then directly targeted during surgery. Intraoperative testing confirmed successful tremor control. Post-operative analysis of electrode position relative to the DRTt was performed, as was post-operative assessment of tremor improvement. RESULTS: The mean age of patients was 66.8 years; mean duration of tremor was 16 years. Mean voltage for the L electrode = 3.4 V; R = 2.6 V. Mean distance from the center of the active electrode contact to the DRTt was 0.9 mm on the L, and 0.8 mm on the R. Improvement in arm tremor amplitude from baseline after DBS was significant (P < 0.001). CONCLUSION: Direct targeting of the DRTt in DBS is an effective strategy for tremor suppression. Accounting for hardware, software, and model limitations, depiction of the DRTt allows for placement of electrode contacts directly within the fiber tract for modulation despite any anatomical variation, which reproducibly resulted in good tremor control.

Distance between Active Electrode Contacts and Dentatorubrothalamic Tract in Patients with Habituation of Stimulation Effect of Deep Brain Stimulation in Essential Tremor.

Background Some patients under thalamic deep brain stimulation (DBS) for essential tremor (ET) experience habituation of tremor reduction. The nucleus ventralis intermedius (Vim) is the current main target side for ET in DBS. However, the dentatorubrothalamic tract (DRTT) is considered the relevant structure to stimulate. We investigated the distance between the active contact of the DBS electrode and the DRTT and compared this distance in patients with habituation of tremor reduction and good responders. Material and Methods In this retrospective study, we performed deterministic fiber tracking of the DRTT in 6 patients (12 hemispheres) with ET who underwent DBS in the Vim. We subsequently measured the distance between the active contact of the electrode and the ipsilateral DRTT in both hemispheres. The clinical tremor response of those 6 patients was analyzed accordingly. Results The distance between the active contact and the DRTT in patients with better and constant clinical tremor reduction was shorter (mean distance: 2.9 ± 2.2 mm standard deviation [SD]) than in patients who showed habituation of their response (mean distance: 6.1 ± 3.9 mm SD). After re-placement of a thalamic electrode inside the DRTT in one patient who experienced unsatisfying tremor reduction due to habituation of stimulation, the tremor alleviation was significant and persistent at a 13-month follow-up. Conclusion This retrospective analysis suggests that recurrence of ET tremor under chronic DBS might be associated with a larger distance between the DRTT and the active lead contact, in comparison with the smaller distances in patients with persistently good tremor control.

Case Study of Image-Guided Deep Brain Stimulation: Magnetic Resonance Imaging-Based White Matter Tractography Shows Differences in Responders and Nonresponders.

BACKGROUND: The caudal zona incerta (cZI) is an increasingly popular deep brain stimulation (DBS) target for the treatment of tremor-predominant disease. The dentatorubrothalamic tract (DRTT) is a white matter fiber bundle that traverses the cZI and can be identified using diffusion-weighted magnetic resonance imaging fiber tractography to ascertain its precise course. In this report, we compare 2 patient cases of cZI DBS, a responder and a nonresponder. CASE DESCRIPTION: Patient 1 (responder) is a 65-year-old man with medically refractory Parkinson disease who underwent bilateral DBS lead placement in the cZI. Postoperatively he demonstrated >90% reduction in baseline tremor and was not limited by stimulation side effects. Postoperative imaging showed correct lead placement in the cZI. Tractography revealed a DRTT within the field of stimulation, bilaterally. Patient 2 (nonresponder) is a 61-year-old man with medically refractory Parkinson disease who also underwent bilateral DBS lead placement in the cZI. He initially demonstrated >90% reduction in baseline tremor but developed disabling dystonia of his left leg and significant slurring of his speech in the months after surgery. Postoperative imaging showed bilateral lead placement in the cZI. Right-sided electrode revision was recommended and resulted in relief of tremor and reduced dystonic side effects. Tractography analysis of the original leads revealed a DRTT with an atypical anterior trajectory and a location outside the field of stimulation. Tractography analysis of the revised lead showed a DRTT within the field of stimulation. CONCLUSIONS: Preoperative diffusion-weighted magnetic resonance imaging fiber tractography imaging of the DRTT has the potential to improve and individualize DBS planning.

The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation.

OBJECT 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 cerebellar 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 Human Connectome Project (Q1-Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler's method. RESULTS The authors identified the "classic" decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro 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 physiological 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.

Evaluating cerebellar dentatotomy for the treatment of spasticity with or without dystonia.

Spasticity represents a common and very often incapacitating neurologic condition, for which a limited number of treatment options are available. Stereotactic ablation of the dentate cerebellar nuclei (dentatotomy) was widely used in the past with variable results. In the present study, we reviewed 12 consecutive cases operated on at the Midland Centre for Neurosurgery and Neurology at Birmingham University (Smetwick, UK) in the 1980s. The following clinical aspects were analyzed: severity of spasticity, occurrence of abnormal movements (dystonia/athetosis), language fluency, gait, and overall clinical condition. Follow-up ranged from 0.5 to 94 (mean: 31.6) months. Immediate improvement was noted in 10 patients, and five of them had sustained this improvement at the time of the last assessment. A more pronounced improvement was observed for gait, relative to speech and abnormal movements. No significant morbidity related to the procedure was observed. We conclude that dentatotomy is a safe procedure that should still be considered in specific cases. Here, we review the cases reported in the literature, and present a mechanistic hypothesis about how dentatotomy influences motor tonus, in light of the current knowledge about cerebellar physiology. We believe that this issue is critical for the development of alternative surgical approaches targeting the cerebellum, such as chronic electric stimulation.

Three-dimensional microsurgical anatomy of cerebellar peduncles.

The microsurgical anatomy of cerebellar peduncles and their relationships with neighbouring fasciculi were investigated by using a fibre dissection technique. As the dissection progressed, photographs of each progressive layer were obtained and stereoscopic images were created using the 3D anaglyphic method. These findings provided the anatomical basis for a conceptual division of cerebellar peduncles into segments. The middle cerebellar peduncle (MCP) was divided into two segments: cisternal and intracerebellar segments. The inferior cerebellar peduncle (ICP) was divided into three segments: cisternal, ventricular and intracerebellar segments. The superior cerebellar peduncle (SCP) was divided into three segments: intracerebellar, intermediate and intrategmental segments. The fibre dissection technique disclosed a constant course of peduncular fibres inside the white core of the cerebellum. The pontocerebellar fibres of the MCP pass over and laterally to the bundles of the ICP and SCP. The centripetal fibres of the ICP wrap around the radiation of the SCP and the dentate nucleus, directed towards the cortex of the vermis. The centrifugal bundle of the SCP ascends towards the mesencephalon where it sinks passing below the fibres the lateral lemniscus. The knowledge gained by studying the intrinsic anatomy of the cerebellum is useful to accomplish appropriate surgical planning and, ultimately, to understand the repercussions of surgical procedures on the white matter tracts in this region.

Cerebellar anatomy as applied to cerebellar microsurgical resections.

OBJECTIVE: To define the anatomy of dentate nucleus and cerebellar peduncles, demonstrating the surgical application of anatomic landmarks in cerebellar resections. METHODS: Twenty cerebellar hemispheres were studied. RESULTS: The majority of dentate nucleus and cerebellar peduncles had demonstrated constant relationship to other cerebellar structures, which provided landmarks for surgical approaching. The lateral border is separated from the midline by 19.5 mm in both hemispheres. The posterior border of the cortex is separated 23.3 mm from the posterior segment of the dentate nucleus; the lateral one is separated 26 mm from the lateral border of the nucleus; and the posterior segment of the dentate nucleus is separated 25.4 mm from the posterolateral angle formed by the junction of lateral and posterior borders of cerebellar hemisphere. CONCLUSIONS: Microsurgical anatomy has provided important landmarks that could be applied to cerebellar surgical resections.

Cerebellar anatomy as applied to cerebellar microsurgical resections / Anatomia cerebelar aplicada à microcirurgia cerebelar ablativa

OBJECTIVE: To define the anatomy of dentate nucleus and cerebellar peduncles, demonstrating the surgical application of anatomic landmarks in cerebellar resections. METHODS: Twenty cerebellar hemispheres were studied. RESULTS: The majority of dentate nucleus and cerebellar peduncles had demonstrated constant relationship to other cerebellar structures, which provided landmarks for surgical approaching. The lateral border is separated from the midline by 19.5 mm in both hemispheres. The posterior border of the cortex is separated 23.3 mm from the posterior segment of the dentate nucleus; the lateral one is separated 26 mm from the lateral border of the nucleus; and the posterior segment of the dentate nucleus is separated 25.4 mm from the posterolateral angle formed by the junction of lateral and posterior borders of cerebellar hemisphere. CONCLUSIONS: Microsurgical anatomy has provided important landmarks that could be applied to cerebellar surgical resections.

OBJETIVO: Definir a anatomia do núcleo denteado e dos pedúnculos cerebelares, demonstrando a aplicação dos marcos anatômicos em cirurgias cerebelares. MÉTODOS: Foram estudados 20 hemisférios cerebelares. RESULTADOS: A maioria dos núcleos denteados e pedúnculos cerebelares demonstraram relação anatômica constante com outras estruturas cerebelares, fato que proporcionou o estabelecimento de marcos anatômicos específicos a serem utilizados em acessos cirúrgicos. O bordo lateral do núcleo denteado é separado da linha média em 19,5 mm em ambos os hemisférios cerebelares. O bordo posterior do córtex é separado do segmento posterior do núcleo denteado por 23,3 mm. O bordo lateral do córtex é separado do bordo lateral do núcleo por 26 mm e o segmento posterior do núcleo denteado é separado por 25,4 mm do ângulo posterolateral, que é formado pela junção dos bordos lateral e posterior do hemisfério cerebelar. CONCLUSÕES: O estudo da anatomia microcirúrgica proporcionou o estabelecimento de marcos anatômicos importantes que podem ser utilizados durante cirurgias cerebelares ablativas.

Lesions of the dentate and interposed nuclei are associated with impaired prehension in cerebellar patients.

In a recent study using voxel based lesion symptom mapping (VLSM) in cerebellar patients following stroke we found associations of prehensile deficits to lesions of the cerebellar cortex and dentate nucleus (DN). Associations to lesions of the interposed nucleus (IN), which has been shown to contribute to prehension in monkeys, could not be established. One possible reason was that the IN was largely unaffected in the stroke patients. To further address the question of IN involvement in prehension we performed VLSM in patients with surgical cerebellar lesions (n=20), exhibiting high lesion overlap in the medial and intermediate cerebellum including the IN. Prehensile deficits were quantified by analyses of movement kinematics and finger forces. In the patient population prehensile deficits comprised lower movement velocity in reaching and increased lift-off time in grasping. These were associated with lesions of the intermediate and lateral cerebellar cortex together with their output nuclei. Specifically, IN lesions were linked to increased lift-off time in grasping and not to slower reaching movements. Thus, our data support IN contribution particularly for the fluent production of grip forces during dexterous prehension in humans.

A role of diffusion tensor imaging fiber tracking in deep brain stimulation surgery: DBS of the dentato-rubro-thalamic tract (drt) for the treatment of therapy-refractory tremor.

INTRODUCTION: Deep brain stimulation (DBS) can alleviate tremor of various origins. A number of regions are targeted. In recent work our group was able to show the involvement of the dentato-rubro-thalamic tract (drt) in tremor control with fiber tracking techniques. Here we report for the first time the successful use of magnetic resonance tractography in combination with traditional landmark-based targeting techniques to perform the implantation of a bilateral DBS system in a patient with dystonic head tremor. METHODS: We report on a 37-year-old female with long-standing pure head tremor from myoclonus dystonia. She was identified as a candidate for thalamic DBS. The use of head fixation in a stereotactic frame would blur target symptoms (head tremor) during surgery and was therefore avoided. Her dentate-rubro-thalamic tracts were visualized with preoperative diffusion tensor imaging (DTI) and tractography, and then directly targeted stereotactically with DBS electrodes. RESULTS: Three months after implantation, tremor control was excellent (>90%). A close evaluation of the active electrode contact positions revealed clear involvement of the drt. CONCLUSION: This is the first time that direct visualization of fiber tracts has been employed for direct targeting and successful movement disorder tremor surgery. In the reported case, additional knowledge about the position of the drt, which previously has been shown to be a structure for modulation to achieve tremor control, led to a successful implantation of a DBS system, although there was a lack of intra-operatively testable tremor symptoms. In concordance with studies in optogenetic neuromodulation, fiber tracts are the emerging target structures for DBS. The routine integration of DTI tractography into surgical planning might be a leading path into the future of DBS surgery and will add to our understanding of the pathophysiology of movement disorders. Larger study populations will have to prove these concepts in future research.

Extracerebellar progenitors grafted to the neurogenic milieu of the postnatal rat cerebellum adapt to the host environment but fail to acquire cerebellar identities.

Stem or progenitor cells acquire specific regional identities during early ontogenesis. Nonetheless, there is evidence that cells heterotopically transplanted to neurogenic regions of the developing or mature central nervous system may switch their fate to adopt host-specific phenotypes. Here, we isolated progenitor cells from different germinative sites along the neuraxis where GABAergic interneurons are produced (telencephalic subventricular zone, medial ganglionic eminence, ventral mesencephalon and dorsal spinal cord), and grafted them to the prospective white matter of the postnatal rat cerebellum, at the time when local interneurons are generated. The phenotype acquired by transplanted cells was assessed by different criteria, including expression of region-specific transcription factors, acquisition of morphological and neurochemical traits, and integration in the cerebellar cytoarchitecture. Regardless of their origin, all the different types of donor cells engrafted in the cerebellar parenchyma and developed mature neurons that shared some morphological and neurochemical features with local inhibitory interneurons, particularly in the deep nuclei. Nevertheless, transplanted cells failed to activate cerebellar-specific regulatory genes. In addition, their major structural features, the expression profiles of type-specific markers and the laminar placement in the recipient cortex did not match those of endogenous interneurons generated during the same developmental period. Therefore, although exogenous cells are influenced by the cerebellar milieu and show remarkable capabilities for adapting to the foreign environment, they essentially fail to switch their fate, integrate in the host neurogenic mechanisms and adopt clear-cut cerebellar identities.