Revisiting Forel Field Surgery.

BACKGROUND: Lesioning the Forel field or the subthalamic region is considered a possible treatment for tremoric patients with Parkinson disease, essential tremor, and other diseases. This surgical treatment was performed in the 1960s to 1970s and was an alternative to thalamotomy. Recently, there has been increasing interest in the reappraisal of stimulating and/or lesioning these targets, partly as a result of innovations in imaging and noninvasive ablative technologies, such as magnetic resonance-guided focused ultrasonography. OBJECTIVE: We wanted to perform a thorough review of the subthalamic region, both from an anatomic and a surgical standpoint, to offer a comprehensive and updated analysis of the techniques and results reported for patients with tremor treated with different techniques. METHODS: We performed a systematic review of the literature, gathering articles that included patients who underwent ablative or stimulation surgical techniques, targeting the pallidothalamic pathways (pallidothalamic tractotomy), cerebellothalamic pathway (cerebellothalamic tractotomy), or subthalamic area. RESULTS: Pallidothalamic tractotomy consists of a reduced area that includes pallidofugal pathways. It may be considered an interesting target, given the benefit/risk ratio and the clinical effect, which, compared with pallidotomy, involves a lower risk of injury or involvement of vital structures such as the internal capsule or optic tract. Cerebellothalamic tractotomy and/or posterior subthalamic area are other alternative targets to thalamic stimulation or ablative surgery. CONCLUSIONS: Based on the significant breakthrough that magnetic resonance-guided focused ultrasonography has meant in the neurosurgical world, some classic targets such as the pallidothalamic tract, Forel field, and posterior subthalamic area may be reconsidered as surgical alternatives for patients with movement disorders.

Whole course of pallidothalamic tracts identified on the sectioned images and surface models.

The anatomy of the pallidothalamic tracts, including the ansa lenticularis, lenticular fasciculus, and thalamic fasciculus (field H1 of Forel), should be elucidated by neurosurgeons and neuroscientists who study deep brain stimulation. In this study, serially sectioned images of a human cadaver head were employed to overcome the limitations of existing methods to observe the pallidothalamic tracts. Owing to the high resolution and real color of the sectioned images, 28 structures, including the pallidothalamic tracts and mammillothalamic fasciculus, were identified. The structures were segmented and made into surface models, which are helpful in improving the stereoscopic understanding. Observing the sectioned images and surface models may help in understanding the detailed anatomy of the pallidothalamic tracts. The new findings, such as the spatial relationship of the tracts, were summarized in a schematic figure. Moreover, to elucidate the anatomical structures along the course of deep brain stimulation, virtual electrodes were inserted into the surface models. The sectioned images and surface models of this study are expected to enhance the understanding of the pallidothalamic tract anatomy. A portable document format file containing the surface models and the sectioned images can be freely downloaded from the authors' homepage. Clin. Anat. 32:66-76, 2019. © 2019 Wiley Periodicals, Inc.

Neuroanatomical background and functional considerations for stereotactic interventions in the H fields of Forel.

The H fields of Forel constitute an intricate neuroanatomical structure that occupies a central position within the posterior subthalamus. Anatomically, it features a dense concentration of fiber bundles including corticofugal, pallidothalamic, cerebellothalamic and other projections that connect functionally relevant areas of the brain. Functionally, the fields of Forel are embedded within the cortico-striato-thalamo-cortical circuit and constitute the main link between the striatopallidal system and the thalamocortical network. Given the current understanding of basal ganglia involvement in movement disorders and neuropsychiatric disease we sought to investigate the H fields of Forel as a potential target in stereotactic functional neurosurgery. Although historically recognized in the treatment of movement disorders, behavioral disorders and epilepsy, the significance of the H fields is considerably diminished today receiving only little attention. Owing to the current lack of reviews addressing the anatomical and functional organization of Forel's fields, we aim to deliver an up-to-date overview of the H fields in this paper. We investigate the complex neuroanatomy and describe the passage of the various fiber systems that course through the posterior subthalamus. We revise the role of Forel's fields in the current context of our understanding of cortico-basal ganglia circuitry and discuss the historic relevance of Forel's fields during the lesional era. Finally, we provide an outlook regarding the potential of deep brain stimulation in close proximity and within the H fields of Forel.

The anatomy of the caudal zona incerta in rodents and primates.

The caudal zona incerta is the target of a recent modification of established procedures for deep brain stimulation (DBS) for Parkinson's disease and tremor. The caudal zona incerta contains a number of neuronal populations that are distinct in terms of their cytoarchitecture, connections, and pattern of immunomarkers and is located at a position where a number of major tracts converge before turning toward their final destination in the forebrain. However, it is not clear which of the anatomical features of the region are related to its value as a target for DBS. This paper has tried to identify features that distinguish the caudal zona incerta of rodents (mouse and rat) and primates (marmoset, rhesus monkey, and human) from the remainder of the zona incerta. We studied cytoarchitecture, anatomical relationships, the pattern of immunomarkers, and gene expression in both of these areas. We found that the caudal zona incerta has a number of histological and gene expression characteristics that distinguish it from the other subdivisions of the zona incerta. Of particular note are the sparse population of GABA neurons and the small but distinctive population of calbindin neurons. We hope that a clearer appreciation of the anatomy of the region will in the end assist the interpretation of cases in which DBS is used in human patients.

Evolution and rebirth of functional stereotaxy in the subthalamus.

The first human stereotactic surgery based on intracerebral landmarks and Cartesian coordinates was performed in 1947. With this followed the publication of a number of stereotactic frames and atlases. The intercommissural line joining the anterior and posterior commissures was to define stereotactic coordinate systems used in movement disorders and other functional neurosurgical procedures. Initially the target for Parkinson disease was the globus pallidus internus (GPi), but many investigators soon turned to the thalamus or parts of the subthalamus, but not the subthalamic nucleus. Microelectrode recording was introduced in 1961. With the apparent clinical efficacy of L-DOPA in 1965 interest in stereotactic surgery for Parkinson disease declined. The failure of prolonged, consistent pharmacologic management of bradykinesia and tremor, the side effects of dyskinesias, and the fading therapeutic success of medical treatment of movement disorders led to a resurgence of interest in the surgical management of movement disorders. With advances in understanding of the functional anatomy of the corticobasal ganglia circuit, advances in brain imaging, more sophisticated electrophysiologic recordings, and the use of deep brain stimulation as a reversible lesion, stereotactic surgery returned as a viable option for the treatment of movement disorders. The posterior medial part of the globus pallidus, ventral intermediate nucleus of the thalamus, and the subthalamus, its nuclei and pathways, are sites for interrupting pathophysiologic circuits. Not only has this been applied to movement disorders, but to epilepsy, chronic pain, and behavioral disorders.

Unilateral caudal zona incerta deep brain stimulation for Parkinsonian tremor.

BACKGROUND: The subthalamic nucleus is currently the target of choice in deep brain stimulation (DBS) for Parkinson's disease (PD), while thalamic DBS is used in some cases of tremor-dominant PD. Recently, a number of studies have presented promising results from DBS in the posterior subthalamic area, including the caudal zona incerta (cZi). The aim of the current study was to evaluate cZi DBS in tremor-dominant Parkinson's disease. METHODS: 14 patients with predominately unilateral tremor-dominant PD and insufficient relief from pharmacologic therapy were included and evaluated according to the motor part of the Unified Parkinson Disease Rating Scale (UPDRS). The mean age was 65 ± 6.1 years and the disease duration 7 ± 5.7 years. Thirteen patients were operated on with unilateral cZi DBS and 1 patient with a bilateral staged procedure. Five patients had non-L-dopa responsive symptoms. The patients were evaluated on/off medication before surgery and on/off medication and stimulation after a minimum of 12 months after surgery. RESULTS: At the follow-up after a mean of 18.1 months stimulation in the off-medication state improved the contralateral UPDRS III score by 47.7%. Contralateral tremor, rigidity, and bradykinesia were improved by 82.2%, 34.3%, and 26.7%, respectively. Stimulation alone abolished tremor at rest in 10 (66.7%) and action tremor in 8 (53.3%) of the patients. CONCLUSION: Unilateral cZi DBS seems to be safe and effective for patients with severe Parkinsonian tremor. The effects on rigidity and bradykinesia were, however, not as profound as in previous reports of DBS in this area.

Visualisation of the zona incerta for deep brain stimulation at 3.0 Tesla.

PURPOSE: Deep-brain stimulation (DBS) of the zona incerta (ZI) has shown promising results for medication-refractory neurological disorders including Parkinson's disease (PD) and essential tremor (ET). The success of the intervention is indispensably dependent on the reliable visualisation of the ZI. The aim of the study was to evaluate different promising new magnetic resonance imaging (MRI) methods at 3.0 Tesla for pre-stereotactic visualisation of the ZI using a standard installation the protocol. METHODS: MRI of nine healthy volunteers was acquired (T1-MPRAGE, T2-FLAIR, T2*-FLASH2D, T2-SPACE and susceptibility-weighted imaging (SWI). Image quality and visualisation of the ZI for each sequence were analysed independently by two neuroradiologists using a 6-point scale. For T2*-FLASH2D the axial, coronal and sagittal planes were compared. The delineation of the ZI versus the internal capsule, the subthalamic nucleus and the pallidofugal fibres was evaluated in all sequences and compared to T2-FLAIR using a paired t-test. Inter-rater reliability, contrast-to-noise ratios (CNR), and signal-to-noise ratios (SNR) for the ZI were computed. For illustration, coronal T2*-FLASH2D images were co-registered with the corresponding section schema of the Schaltenbrand-Wahren stereotactic atlas. RESULTS: Only the rostral part of the ZI (rZI) could be identified. The rZI was best and reliably visualised in T2*-FLASH2D (particularly coronal orientation; p < 0.05). No major artifacts in the rZI were observed in any of the sequences. SWI, T2-SPACE, and T2*-FLASH imaging offered significant higher CNR values for the rZI compared to T2-FLAIR imaging using standard parameters. The co-registration of the coronal T2*-FLASH2D images projected the ZI clearly into the boundaries of the anatomical sections. CONCLUSIONS: The delineation of the rZI is best possible in T2*-FLASH2D (particularly coronal view) using a standard installation protocol at 3.0 T. The caudal ZI could not be discerned in any of the sequences.

Quality of life following DBS in the caudal zona incerta in patients with essential tremor.

BACKGROUND: Essential tremor (ET) is the most common movement disorder and often affects the quality of life. There are only a few studies evaluating the quality of life after deep brain stimulation (DBS). FINDINGS: This is a prospective study of 16 patients undergoing deep brain stimulation in the caudal Zona incerta (cZi). The quality of life was assessed with Quality of Life in Essential Tremor Questionnaire (QUEST) and SF-36 scores, and the tremor was evaluated using the essential tremor rating scale (ETRS). RESULTS: In the tremor rating, hand tremor on the treated side improved by 95%, hand function by 78% and activities of daily living by 71%. The QUEST score showed statistically significant improvements in the psychosocial and activities of daily living subscores. The SF-36 score did not show any significant improvement. CONCLUSIONS: Although very good tremor reduction was achieved, the improvement in the quality of life scores was more modest. This could partly be explained by the quality of life being affected by other factors than the tremor itself.

Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor.

PURPOSE: The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS. METHODS: 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated. RESULTS: A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time. CONCLUSION: cZi DBS is a safe and effective treatment for the long term suppression of ET.

[Interconnections of the pallidum, pedunculopontine nucleus, zona incerta, and deep mesencephalic nucleus--the structures of the basal ganglia morpho-functional system].

Method of anterograde and retrograde axonal transport of horseradish peroxidase was used to study the organization of projections of different substructures of zona incerta (ZI), pedunculopontine nucleus (PPN), deep mesencephalic nucleus (DMN) complex, and functionally distinct structures of the pallidum of dog brain (n=20). It was found that pallidum and nucleus entope-duncularis are connected by reciprocal projections with dorsal, ventral and caudal sectors of ZI, as well as with DMN, lateral segment of the pars dissipata, and the pars compacta of PPN. The rostral sector of ZI, cuneiform and subcuneiform nuclei of DMN complex, the medial region of PPN pars dissipata are connected by ipsilateral projections with the same pallidal nuclei. Among all the structures studied, the presence of reciprocal connections with the ventral pallidum was found only in the lateral segment of the pars dissipata and pars compacta of PPN. The possible pathways of transfer of functionally different information and its integration in the investigated projection systems, are discussed.

Individual fiber anatomy of the subthalamic region revealed with diffusion tensor imaging: a concept to identify the deep brain stimulation target for tremor suppression.

BACKGROUND: Deep brain stimulation (DBS) has been proven to alleviate tremor of various origins. Distinct regions have been targeted. One explanation for good clinical tremor control might be the involvement of the dentatorubrothalamic tract (DRT) as has been suggested in superficial (thalamic) and inferior (posterior subthalamic) target regions. Beyond a correlation with atlas data and the postmortem evaluation of patients treated with lesion surgery, proof for the involvement of DRT in tremor reduction in the living, the scope of this work, is elusive. OBJECTIVE: To report a case of unilateral refractory tremor in tremor-dominant Parkinson disease treated with thalamic DBS. METHODS: Preoperative diffusion tensor imaging (DTI) was performed. Correlation with individual DBS electrode contact locations was obtained through postoperative fusion of helical computed tomography (CT) data with DTI fiber tracking. RESULTS: Tremor was alleviated effectively. An evaluation of the active electrode contact position revealed clear involvement of the DRT in tremor control. A closer evaluation of clinical effects and side effects revealed a highly detailed individual fiber map of the subthalamic region with DTI fiber tracking. CONCLUSION: This is the first time the involvement of the DRT in tremor reduction through DBS has been shown in the living. The combination of DTI with postoperative CT and the evaluation of the electrophysiological environment of distinct electrode contacts led to an individual detailed fiber map and might be extrapolated to refined DTI-based targeting strategies in the future. Data acquisition for a larger study group is the topic of our ongoing research.

Organization of projections of the zona incerta of the diencephalon to pallidal structures in the dog brain.

Detailed studies of the organization of individual sectors in the zona incerta of the diencephalon to functionally diverse pallidal structures in the dog brain were performed by antero- and retrograde axon transport of horseradish peroxidase. The results showed that neurons in the caudal sector of the zona incerta innervate the globus pallidus and entopeduncular nucleus, which receive more extensive innervation from motor structures. The same pallidal structures receive projections from occasional neurons in the dorsal and causal sectors of the zona incerta. No connections of the zona incerta with the limbic ventral pallidum were found.

Deep brain stimulation of the posterior subthalamic area in the treatment of tremor.

BACKGROUND: Several studies have described lesional therapy in the posterior subthalamic area (PSA) in the treatment of various movement disorders. Recently, some publications have illustrated the effect of deep brain stimulation (DBS) in this area in patients with Parkinson's disease, essential tremor, MS-tremor, and other forms of tremor. Even though the clinical series is small, the reported benefits prompted us to explore DBS in this area in the treatment of tremor. METHOD: Five patients with tremor were operated using unilateral DBS of the PSA. Two patients had dystonic tremor, one primary writing tremor, one cerebellar tremor and the other neuropathic tremor. All patients were assessed before and 1 year after surgery using items 5 and 6 (tremor of the upper extremity), 11-14 (hand function), and when appropriate item 10 (handwriting) from the essential tremor rating scale. FINDINGS: The mean improvement on stimulation after 1 year was 87%. A pronounced and sustained microlesional effect was seen in several of the patients, and while the mean improvement off stimulation was 56% the reduction in the three patients with the most pronounced effect was 89%. The two patients with dystonic tremor did also become free of the dystonic symptoms and pain in the treated arm. No severe complication occurred. CONCLUSIONS: DBS of the PSA in this small group of patients had an excellent effect on the different forms of tremor, except for the neuropathic tremor where the effect was moderate. These preliminary results suggest PSA to be an effective target for the treatment of various forms of tremor. Further studies concerning indications, safety and efficacy of DBS in the posterior subthalamic area are required.

Structural organization of the zona incerta of the dog diencephalon.

Studies performed using the Nissl and Kluver-Barrera methods for analysis of the organization of fibers, morphological neuron types, and neuron density distribution were undertaken to map the zona incerta of the diencephalon of the dog brain; five individual sectors were identified, whose boundaries were further identified by histochemical detection of NADPH-diaphorase-positive neurons.

GABAergic and non-GABAergic thalamic, hypothalamic and basal forebrain projections to the ventral oral pontine reticular nucleus: their implication in REM sleep modulation.

The ventral part of the oral pontine reticular nucleus (vRPO) is a demonstrated site of brainstem REM-sleep generation and maintenance. The vRPO has reciprocal connections with structures that control other states of the sleep-wakefulness cycle, many situated in the basal forebrain and the diencephalon. Some of these connections utilize the inhibitory neurotransmitter GABA. The aim of the present work is to map the local origin of the basal forebrain and diencephalon projections to the vRPO whether GABAergic or non-GABAergic. A double-labelling technique combining vRPO injections of the neuronal tracer, cholera-toxin (CTB), with GAD-immunohistochemistry, was used for this purpose in adult cats. All of the numerous CTB-positive neurons in the reticular thalamic and dorsocaudal hypothalamic nuclei were double-labelled (CTB/GAD-positive) neurons. Approximately 15%, 14% and 16% of the CTB-positive neurons in the zona incerta and the dorsal and lateral hypothalamic areas are, respectively, CTB/GAD-positive neurons. However, only some double-labelled neurons were found in other hypothalamic nuclei with abundant CTB-positive neurons, such as the paraventricular nucleus, perifornical area and H1 Forel field. In addition, CTB-positive neurons were abundant in the central amygdaline nucleus, terminal stria bed nuclei, median preoptic nucleus, medial and lateral preoptic areas, dorsomedial and ventromedial hypothalamic nuclei, posterior hypothalamic area and periventricular thalamic nucleus. The GABAergic and non-GABAergic connections described here may be the morphological pillar through which these prosencephalic structures modulate, either by inhibiting or by exciting, the vRPO REM-sleep inducing neurons during the different sleep-wakefulness cycle states.

When outgoing and incoming signals meet: new insights from the zona incerta.

In the sense of touch, it is the motion of the sensory receptors themselves that leads to an afferent signal-whether these receptors are in our fingertips sliding along a surface or a rat's whiskers palpating an object. Afferent signals can be correctly interpreted only if the sensory system receives information about the brain's own motor output. In this issue of Neuron, Urbain and Deschênes provide new insights into the physiological and anatomical interplay between tactile and motor signals in rats.

Motor cortex gates vibrissal responses in a thalamocortical projection pathway.

Higher-order thalamic nuclei receive input from both the cerebral cortex and prethalamic sensory pathways. However, at rest these nuclei appear silent due to inhibitory input from extrathalamic regions, and it has therefore remained unclear how sensory gating of these nuclei takes place. In the rodent, the ventral division of the zona incerta (ZIv) serves as a relay station within the paralemniscal thalamocortical projection pathway for whisker-driven motor activity. Most, perhaps all, ZIv neurons are GABAergic, and recent studies have shown that these cells participate in a feedforward inhibitory circuit that blocks sensory transmission in the thalamus. The present study provides evidence that the stimulation of the vibrissa motor cortex suppresses vibrissal responses in ZIv via an intra-incertal GABAergic circuit. These results provide support for the proposal that sensory transmission operates via a top-down disinhibitory mechanism that is contingent on motor activity.

Connections of the zona incerta to the reticular nucleus of the thalamus in the rat.

This study demonstrated that there is a pathway from the zona incerta to the thalamic reticular nucleus. Injections of horseradish peroxidase or Fluorogold were made, using stereotaxic coordinates, into the rostral, intermediate or caudal regions of the thalamic reticular nucleus of adult Sprague-Dawley rats. The results show that the different regions of the thalamic reticular nucleus have distinct patterns of connections with the sectors of the zona incerta. In terms of the relative strength of the connections, injections made into the rostral regions of the thalamic reticular nucleus showed the highest number of labelled cells within the rostral and ventral sectors of the zona incerta; injections made into the intermediate regions of the thalamic reticular nucleus showed labelled cells in the dorsal and ventral sectors; while injections to the caudal regions of the thalamic reticular nucleus showed only a few labelled cells in the caudal sector of the zona incerta. Previous studies have shown that the zona incerta projects to the higher order thalamic nuclei but not first order thalamic nuclei. The labelling observed in the present study may represent collaterals of zona incerta to higher order thalamic nuclei projections.

State-dependent gating of sensory inputs by zona incerta.

We have previously shown that the GABAergic nucleus zona incerta (ZI) suppresses vibrissae-evoked responses in the posterior medial (POm) thalamus of the rodent somatosensory system. We proposed that this inhibitory incerto-thalamic pathway regulates POm responses during different behavioral states. Here we tested the hypothesis that the cholinergic reticular activating system, implicated in regulating states of arousal, modulates ZI activity. We show that stimulation of brain stem cholinergic nuclei (laterodorsal tegmental and pedunculopontine tegmental) results in suppression of spontaneous firing of ZI neurons. Iontophoretic application of the cholinergic agonist carbachol to ZI neurons suppresses both their spontaneous firing and their vibrissae-evoked responses. We also found that carbachol application to an in vitro slice preparation suppresses spontaneous firing of neurons in the ventral sector of ZI (ZIv). Finally, we demonstrate that the majority of ZIv neurons contain parvalbumin and project to POm. Based on these results, we present the state-dependent gating hypothesis, which states that differing behavioral states-regulated by the brain stem cholinergic system-modulate ZI activity, thereby regulating the response properties of higher-order nuclei such as POm.