Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects. METHODS: The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects. RESULTS: The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks. CONCLUSIONS: This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.

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.

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.

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 indirect subthalamic nucleus targeting with validated 3-tesla magnetic resonance imaging.

BACKGROUND/OBJECTIVES: Indirect targeting of the subthalamic nucleus (STN) is commonly utilized at deep brain stimulation (DBS) centers around the world. The superiority of either midcommissural point (MCP)-based or red nucleus (RN)-based indirect targeting remains to be established. METHODS: The location of the STN was determined and statistically compared to MCP- and RN-based predictions in 58 STN DBS patients, using a validated 3-tesla MRI protocol. The influence of additional neuroanatomical parameters on STN midpoint location was evaluated. Linear regression analysis was utilized to produce an optimized MCP/RN targeting model. Targeting coordinates at 1.5 T were compared to results at 3 T. RESULTS: Accuracy and precision for RN-based targeting was superior to MCP-based targeting to predict STN midpoint location for each coordinate dimension (p < 0.01 and p < 0.05, respectively). RN-based targeting was statistically equivalent to an optimized regression-based targeting strategy incorporating multiple neuroanatomical parameters, including third-ventricle width and overall brain size. RN-based targeting at 1.5 T yielded equivalent coordinates to targeting at 3 T. CONCLUSIONS: RN-based targeting is statistically superior to MCP-based STN targeting and accommodates broad variations in neuroanatomical parameters. Neurosurgeons utilizing indirect targeting of the STN may consider favoring RN-based over MCP-based indirect targeting methods.

Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration.

BACKGROUND: Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft. RESULTS: When neurons of the thalamic reticular nucleus (TRN) and red nucleus were induced to regenerate axons along peripheral nerve grafts, a marked microglial response was found around their cell bodies, including the partial enwrapping of some regenerating neurons. T-cells were found amongst regenerating TRN neurons but not rubrospinal neurons. Axotomy alone or insertion of freeze-killed nerve grafts did not induce a similar perineuronal inflammation. Nerve grafts in the corticospinal tracts did not induce axonal regeneration or a microglial or T-cell response in the motor cortex. CONCLUSIONS: These results strengthen the evidence that perineuronal microglial accumulation (but not T-cell accumulation) is involved in axonal regeneration by intrinsic CNS and other neurons.

Direct validation of atlas-based red nucleus identification for functional radiosurgery.

Treatment targets in functional neurosurgery usually consist of selected structures within the thalamus and basal ganglia, which can be stimulated in order to affect specific brain pathways. Chronic electrical stimulation of these structures is a widely used approach for selected patients with advanced movement disorders. An alternative therapeutic solution consists of producing a lesion in the target nucleus, for example by means of radiosurgery, a noninvasive procedure, and this prevents the use of intraoperative microelectrode recording as a method for accurate target definition. The need to have accurate noninvasive localization of the target motivated our previous work on atlas-based identification; the aim of this present work is to provide additional validation of this approach based on the identification of the red nuclei (RN), which are located near the subthalamic nucleus (STN). Coordinates of RN were obtained from the Talairach and Tournoux (TT) atlas and transformed into the coordinates of the Montreal Neurological Institute (MNI) atlas, creating a mask representation of RN. The MNI atlas volume was nonrigidly registered onto the patient magnetic resonance imaging (MRI). This deformation field was then applied to the RN mask, providing its location on the patient MRI. Because RN are easily identifiable on 1.5 T T2-MRI images, they were manually delineated; the coordinates of the centers of mass of the manually and automatically identified structures were compared. Additionally, volumetric overlapping indices were calculated. Ten patients were examined by this technique. All indices indicated a high level of agreement between manually and automatically identified structures. These results not only confirm the accuracy of the method but also allow fine tuning of the automatic identification method to be performed.

Effects of red nucleus ablation and exogenous neurotrophin-3 on corticospinal axon terminal distribution in the adult rat.

Collateral sprouting of undamaged descending axons is one potential mechanism for recovery of function after incomplete spinal cord injury. In this study, we have investigated whether terminals of the intact corticospinal tract in the rat would sprout following ablation of a parallel descending pathway, the rubrospinal tract. No sprouting was detected after this injury alone. However, the combination of rubrospinal tract ablation with administration of 100ng neurotrophin-3 to neurons of the corticospinal tract resulted in marked increased density of corticospinal innervation in the superficial dorsal horn. There was no effect of administration of neurotrophin-3 alone and increase in axon density was not detected in the deep dorsal horn. These results imply that spontaneous sprouting of undamaged corticospinal axons does not occur following ablation of a parallel tract system, although collateral sprouting can be induced through a combination of the lesion plus exogenous growth factor. Induced change in corticospinal terminal density is detected in the superficial dorsal horn only, supporting the hypothesis that this is an area particularly supportive of circuit reorganisation.

[The dynamic behavioral changes and the compensatory-restorative processes in rats following the destruction of the red nucleus and the ventrolateral thalamic nucleus]. / Dinamika izmenenii povedeniia i kompensatorno-vosstanovitel'nye protsessy u krys posle razrusheniia krasnogo iadra i ventrolateral'nogo iadra talamusa.

In white non-strain rats with elaborated instrumental responses preliminary section of the rubro-spinal tract was shown to promote the compensatory restorative processes after the destruction of the red nucleus and the ventrolateral thalamic nucleus. Facilitation observed is considered to be a result of transfer of the motor activity to the cortico-spinal system due to activation of the inferior olive and the cerebellum.

Effects of red nucleus lesions on forelimb movements in the cat.

The effects of uni- and bilateral lesions of the red nucleus on the ability to retrieve food with a forepaw from food wells of different shape were analyzed. Movements which required the use of distal muscles, e.g. retrieving food from narrow horizontal and vertical tubes, were more affected than movements primarily involving more proximal muscles. A decrease in the digital skill occurred during at least 4 months after the surgery, even in the case of subtotal lesions of the red nucleus. The effects of uni- and bilateral rubral lesions appeared to be essentially similar.

[Neurosurgical anatomy of Forel's field H as applied to campotomy]. / Neirokhirurgicheskaia anatomiia polia Forelia H primenitel'no k campotomii.

Based on a study of 100 specimens of the brain of adult humans, data are presented on the variability of the shape and size of Forel's H field and its position in relation to intercerebral orienting points depending on the length of the intercommissural line and the breadth of the cerebral hemisphere and third ventricle. The stereotaxic coordinates, the shape and size of the foci of destruction for campotomy are given with due consideration for the individual anatomical features of the H field.

[A case of total hemipherectomy]. / A propos d'un cas d'hémisphérectomie totale.

The author described a case of extensive total hemispherectomy extending to the red nucleus, gave a review of the literature of such conditions together with a brief historical review. He analysed in detail the secondary degenerative changes of the nervous tracts within the brainstem. The histological study of the remaining hemisphere, the cerebellum and the membranes revealed the following: 1) a false sub-dural membrane within the surgical space, proliferation of the arachnoidal cells and a granular ependymitis, changes which were interpreted as an attempt to fill the empty space resulting from the operation; 2) an inflammatory meningo-encephalitis with rare intra-nuclear inclusions quite suggestive of a reaction due to a slow virus or of a slow resorptive process. From a clinico-pathological point of view, this case, an almost experimental model, illustrated the possibility that only one hypothalamus would be sufficient to maintain a good hormonal equilibrium.

On the absence of a rubrothalamic projection in the monkey with observations on some ascending mesencephalic projections.

In order to determine whether there is a rubrothalamic projection in the rhesus monkey, the ascending degeneration resulting from electrolytic lesions made in the red nucleus and adjacent mesencephalon in animals surviving at least one year after bilateral interruption of the superior cerebellar peduncles (PCS) was studied by means of the Fink-Heimer technique. In a necessary preliminary step it was shown that virtually all of the degeneration disappeared from the thalamus within twelve months after PCS interruption so that degeneration resulting from the subsequent electrolytic mesencephalic lesions could be attributed to interruption of non-cerebellar ascending fibres. The results show that degeneration was present in the thalamus following the electrolyte mesencephalic-diencephalic lesions but it could be accounted for on the basis of damage either to residual PCS fibres, to somatosensory pathways, to intrathalamic connections or to cell groups or projection fibres of the reticular formation, substantia nigra or globus pallidus. It is concluded that there is no direct rubrothalamic projection in the monkey and, in particular, no evidence of a projection from the red nucleus to the ventral lateral or ventral anterior thalamic nuclei. The results also indicate that the mesencephalic reticular formation is the main source of ascending afferents to the nucelus reticularis thalami. Some observations were made concerning nigrostriatal and nigrothalamic projections. Retrograde cell changes resulting from unilateral lesions made caudal to the red nucleus were studied in three animals. The observed cell changes are interpreted as being consistent with the conclusion that there is no rubrothalamic projection.