Human pallidothalamic and cerebellothalamic tracts: anatomical basis for functional stereotactic neurosurgery
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Anatomical knowledge of the structures to be targeted and of the circuitry involved is crucial in stereotactic functional neurosurgery. The present study was undertaken in the context of surgical treatment of motor disorders such as essential tremor (ET) and Parkinson’s disease (PD) to precisely determine the course and three-dimensional stereotactic localisation of the cerebellothalamic and pallidothalamic tracts in the human brain. The course of the fibre tracts to the thalamus was traced in the subthalamic region using multiple staining procedures and their entrance into the thalamus determined according to our atlas of the human thalamus and basal ganglia [Morel (2007) Stereotactic atlas of the human thalamus and basal ganglia. Informa Healthcare Inc., New York]. Stereotactic three-dimensional coordinates were determined by sectioning thalamic and basal ganglia blocks parallel to stereotactic planes and, in two cases, by correlation with magnetic resonance images (MRI) from the same brains prior to sectioning. The major contributions of this study are to provide: (1) evidence that the bulks of the cerebellothalamic and pallidothalamic tracts are clearly separated up to their thalamic entrance, (2) stereotactic maps of the two tracts in the subthalamic region, (3) the possibility to discriminate between different subthalamic fibre tracts on the basis of immunohistochemical stainings, (4) correlations of histologically identified fibre tracts with high-resolution MRI, and (5) evaluation of the interindividual variability of the fibre systems in the subthalamic region. This study should provide an important basis for accurate stereotactic neurosurgical targeting of the subthalamic region in motor disorders such as PD and ET.
KeywordsBasal ganglia Thalamus Motor disorders Essential tremor Parkinson’s disease
Basal nucleus of Meynert
Brachium of the inferior colliculus
Central medial nucleus
Central lateral nucleus
Centre médian nucleus (or centromedian)
Globus pallidus, internal segment
Globus pallidus, external segment
Internal medullary lamina
Lateral dorsal nucleus
Lateral geniculate nucleus
Lateral posterior nucleus
Primary motor cortex
- MD (pc, mc, pl)
Mediodorsal nucleus (parvocellular, magnocellular, and paralamellar divisions)
Medial geniculate nucleus
Premotor cortex, caudal part
Premotor cortex, rostral part
Pre-supplementary motor area
Reticular thalamic nucleus
Supplementary motor area
Substantia nigra, pars compacta
Substantia nigra, pars reticulata
- VA (pc, mc)
Ventral anterior nucleus (parvocellular and magnocellular divisions)
Ventral lateral anterior nucleus
- VLp (d, v, pl)
Ventral lateral posterior nucleus (dorsal, ventral, and paralamellar divisions)
Ventral medial nucleus
Ventral posterior inferior nucleus
- VPL (p)
Ventral posterior lateral nucleus (posterior division)
Ventral posterior medial nucleus
Ventral posterior medial nucleus, parvocellular division
The current knowledge on the pallidothalamic and cerebellothalamic connections is dominantly derived from data in monkeys. Degeneration studies and the use of modern tracing techniques with multiple anterograde and retrograde tracers provided much information about the origin of these fibre tracts and their projections to the thalamus and thalamocortical circuits (Nauta and Mehler 1966; Carpenter et al. 1976; Asanuma et al. 1983a, b; Parent and De Bellefeuille 1983; Ilinsky et al. 1985; Percheron et al. 1993, 1996; Rouiller et al. 1994; Inase and Tanji 1995; Parent and Hazrati 1995a; Matelli and Luppino 1996; Sakai et al. 1996, 2000; Shink et al. 1997; Sidibe et al. 1997; Middleton and Strick 2000; Baron et al. 2001, 2006; Francois et al. 2002; Haber 2003; Parent and Parent 2004; Calzavara et al. 2005). Thus, more is known about the origin and terminations than the exact pathway of those fibres, particularly in the subthalamic region. In the human brain, the course of the pallidothalamic and cerebellothalamic fibre tracts is still unclear. Indeed the description of the subthalamic fibre pathways in the human brain dates from the late ninteenth and early twentieth centuries (Forel 1877; Von Monakow 1895; Vogt 1909; Vogt and Vogt 1920). The reference to Forel’s work (“fields of Forel”) is still used to describe the pallidothalamic fibre system.
Targeting the pallidothalamic and cerebellothalamic tracts for surgical treatment of PD and ET was already explored with some success in the 1950s–1970s (Spiegel and Wycis 1954; Spiegel et al. 1963; Mundinger 1965; Velasco et al. 1972; Bertrand et al. 1973) but with a limited precision due to poor technical support at the time. This surgical approach was reappraised in the last 10 years based on pathophysiological evidence of dysfunctional thalamocortical system (thalamocortical dysrhythmia, TCD) following thalamic cells deactivation, in case of ET, or cell overinhibition, in case of PD (Magnin et al. 2001a, 2001b; Aufenberg et al. 2005). This pre-thalamic approach maximizes the disinhibition of the thalamus with a lesion of the pallidothalamic fibers, that is, at least three times smaller than the size of a pallidal lesion that would include the sensorimotor and the associative territories (Francois et al. 1994; Parent and Hazrati 1995a; Gross et al. 1999; Karachi et al. 2002; Morel et al. 2002). The relevance of the motor fiber tracts in the subthalamic area in surgical approach for motor disorders is also supported by recent reports on DBS [or in rare cases, of radiofrequency lesions (RFL)] of the subthalamic nucleus (STh) in PD, where the best clinical effect is obtained when the lesion or DBS electrode contact is dorsal to STh and involves at least part of the pallidothalamic fibres (H2 or fl) (Voges et al. 2002; Hamel et al. 2003; Zonenshayn et al. 2004; Alvarez et al. 2005; Breit et al. 2006; Godinho et al. 2006; Herzog et al. 2007a). Furthermore, direct targeting of the posterior subthalamic area has also recently been reported to be clearly more efficient than thalamic DBS in ET (Hamel et al. 2007; Herzog et al. 2007b).
In order to gain more knowledge about the course of the pallido- and cerebellothalamic tracts and their stereotactical positions in the subthalamic region, we conducted an anatomical study in human post-mortem brain using myelin staining techniques, immunohistochemical procedures and the Morel’s atlas of the human thalamus and basal ganglia (Morel et al. 1997; Morel 2007). The histological demonstration of the fibre tracts was also correlated with high-resolution post-mortem MRI and the variability of their trajectory and position in different brains was evaluated.
Materials and methods
List of brains and histological procedures
PM delay (h)
Cause of death
Hemisphere/plane of section
The procedures follow those described previously (Morel et al. 1997, 2002; Morel 2007). Prior to be exposed to antibodies, some series were pre-treated for 10 min by exposure to microwave in a 4% aluminium chloride solution (Evers and Uylings 1994) to improve antigen retrieval in formalin stored sections. All series for immunocytochemistry were preincubated 10 min in 1.5% H2O2 to remove endogenous peroxidase activity. After several rinses in phosphate buffered saline (pH 7.4), sections were incubated 48 h at 4°C or 24 h at room temperature in primary antibodies (dilutions 1:1,000–1:5,000; depending on the antibody and tissue fixation), 2% normal horse or goat serum; and 0.2% triton-X-100. The antibodies used were mouse monoclonal antibodies directed against parvalbumin (PV) or calbindin (CB) (SWant, Bellinzona, Switzerland or Sigma, St Louis, MO, USA), rabbit polyclonal against calretinin (CR) (SWant), mouse monoclonal against the nonphosphorylated neurofilament protein (SMI-32; Sternberger Monoclonals Inc., Covance Research Products Inc., Princeton, USA). After several rinses, sections were incubated 30–60 min at room temperature in biotinylated secondary antibodies (1:200, Vector Laboratories, Burlingame, CA, USA) and stained with the avidin–biotin complex (ABC) immunoperoxidase method (Vectastain Elite kits, Vector Laboratories). The reaction was visualized with 3,3′-diaminobenzidine tetrahydrochloride as chromogen, diluted 0.05% in 0.05 M Tris–saline (pH 7.7) and 0.001% H2O2. As controls, the primary antibody was omitted while the rest of the procedure remained the same.
Magnetic resonance images
In two autopsy brains (Table 1, Hb4 and Hb5), MR images were acquired with a 3-Tesla scanner (Philips). Whole brains were placed in a plastic bag filled with 4% PAF or neutral formalin and maintained in the scanner with foam pieces. For the first case (Hb4), T1-weighted MRI in the three stereotactic planes were acquired with the following parameters: FOV 220 mm; 400 × 400; TSE factor 15; TR 3,000 ms; TE 80; thickness 2 mm/0 gap; acquisition voxel: 0.55/0.56/2.0 mm; and total scan time: 3 h. For the second case (Hb5), a protocol for high-resolution proton density (PD) MRI was used: 2D multislice acquisition; FOV: 160 mm; matrix: 528 × 528; 52 coronal and 32 axial slices; thickness 1.25 mm/0 gap; TR 3,000 ms; TE 24; acquisition voxel size: 0.30 × 0.30 mm (coronal) and 0.31 × 0.31 (axial); and scan time 5 h for each series (coronal and horizontal).
The cerebellothalamic tract, or brachium conjuntivum, originates in the dentate, interposed and fastigial cerebellar nuclei. The cerebellothalamic tract ascends through the superior cerebellar peduncle, crosses (most of the fibres) over its decussation, passes through and anteriorly to the red nucleus and then rises into the thalamus. To ease the description, we adopted a Latin nomenclature for the subthalamic fibre systems, i.e. the cerebellothalamic fibre bulk is called “fasciculus cerebellothalamicus” (fct) from the level of the red nucleus (RN) to its entrance into the thalamus.
In adjacent sections stained for AChE or immunoreacted for CaBP, the fct appears generally negative, except for PV-immunoreactivity (PV-ir), which also characterizes the RN and STh, as described below.
In relation to the classic nomenclature, Forel field H2 corresponds to the emergence of fl fibres from the internal capsule. The field H1, on the other hand, is more difficult to relate with the al or fl because it contains both fibre bundles. The most medial component of the ft seems to arise from al more than fl (Fig. 5, L4.5, L5.4, and L6.3), which in turn joins the ft more laterally (Fig. 5, L7.2 and L8.1). Whether this apparent mediolateral gradient persists at the entrance of the tract into the thalamus cannot be determined at this point. At most posterior and medial levels (e.g. Fig. 5, L7.2), the pallidothalamic fibres form the so-called “H1 + H2” field of Forel. At this level, the ft is not yet joined by all of the fl fibres. The transition between this part of ft and the ansa, as well as with ft proper containing both fl and al fibres, is unclear and cannot be identified on the basis of the present data. As best seen in the horizontal plane, the ft tract comes close to the mammillothalamic (mtt) tract which courses toward the anteroventral (AV) nucleus. This close vicinity of the two tracts occurs near midcommissural level (mcl; Fig. 5, sagittal planes L4.5 and L5.4; Fig. 6).
Striatonigral and pallidosubthalamic fibres
The large fibre bundles characterized by high CB-ir and AChE staining reaching the substantia nigra (SN) correspond to the striatonigral fibres described previously (Morel et al. 2002). In the subthalamic area, these fibres run ventral to the STh and to the fasciculus subthalamicus to continue posteriorly toward the SN, as shown in Fig. 11b. Through not illustrated in the present report, these fibres can be followed from their origin in the striatum (mostly from the posterior two-third of the putamen), through the two pallidal segments and the internal capsule, to their entry in the pars reticulata (SNr). The striatonigral fibres are also enhanced in SMI-32-ir, while only moderately for PV- and CR-ir (Figs. 4c, e; 11d). They appear largely unstained in myelin (Fig. 11a), which is presumably related to their smaller size.
High-resolution proton density MRI was obtained from one brain (Hb5, Table 1; see also MRI acquisition protocole in “Materials and methods”) prior to guillotine sectioning and histological processing. After MRI acquisition, one hemisphere was cut in the frontal plane and the other in the horizontal plane. The MRI slices (1.3-mm thick) were correlated with the closest myelin stained sections and drawings of the same brain. Examples of these correlations are shown on frontal sections in Figs. 7 and 8, at different anteroposterior levels of the thalamus. On these high-resolution MRI, several thalamic and basal ganglia subdivisions can be well recognized: the striatum (PuT, Cd), both segments of the pallidum (GPe/GPi) separated by the internal medullary lamina (Fig. 8, A20–A15), medial, lateral, and anterior thalamic nuclei (AV, LD, MD, LP, and the intralaminar CM and CL nuclei). The reticular nucleus (R) is also distinguishable between the internal capsule and the lateral nuclei (Fig. 7, A5–A7.5). The fct tract is illustrated in Fig. 7 at three anteroposterior levels (A7.5, A5.0, and A2.5), highlighting its entrance into the thalamus. The course of the pallidothalamic fibres is shown in Fig. 8, from their emergence from the internal part of the pallidum (A20.0 and A17.5 for the al and A17.5 and A15.0 for the fl) up to their entry in the thalamus (A12.25). At levels A17.5 and A15.0, the course of the tract in the subthalamic area and the most medial extension of the al just before merging with the fl to form the ft are also clearly recognized. Other fibre tracts such as the fornix (fx), the mtt and the optic tract (ot) are strongly contrasted.
Stereotactic localization and interindividual variability
The smallest anteroposterior distance between fct and ft centers is similar (2.4 mm) in both Hb1 and Hb4, when considering the three dorsoventral planes. At V2 level, the median anteroposterior value of ft is 11 mm in Hb1 and 12.7 mm in Hb4. In terms of mediolateral extension, there is a significant difference between the two cases with an extension from L4.5 to L9 for Hb1, and from L2 to L5 for Hb4. The position of the fl is more anterior to ft in both cases (median values of 15.6 and 15.2 mm anterior to pc for Hb1 and Hb4, respectively), and the mediolateral extension varies from 6.3 to 8.1 mm in case Hb1, and from 3 to 6 mm in case Hb4. For the fct, anteroposterior median value is 6.8 mm in Hb1 and 6.7 mm in Hb4. The mediolateral extension is from L4.5 to L14 in Hb1, and from L2 to L10 in Hb4. As already shown in Fig. 12, the variations of the tracts in the different cases are not homogeneous in the three planes, with smallest variations in anteroposterior and dorsoventral axes, and largest variations in mediolateral axis.
Implications for stereotactic surgery
This study was designed to provide an anatomical basis for stereotactic targeting of the pallido- and cerebellothalamic fibre tracts in motor disorders, particularly in PD and ET. Indeed, there is an increasing evidence that RFL or DBS partially or completely involving subthalamic fibre tracts from the pallidum (in case of PD) or from the cerebellar nuclei (in case of ET or other types of kinetic tremors) to the thalamus are more efficient for relieving PD or ET symptoms than targets placed in the thalamus or STh (Voges et al. 2002; Zonenshayn et al. 2004; Breit et al. 2006; Godinho et al. 2006; Plaha et al. 2006; Hamel et al. 2007; Herzog et al. 2007a, b). Our surgical approach, which aims at directly interrupting the fibre tracts in subthalamic area with a RFL (Magnin et al. 2001a, b; Aufenberg et al. 2005), is a re-actualisation of earlier surgical experiences (Spiegel and Wycis 1954; Spiegel et al. 1963; Mundinger 1965; Bertrand et al. 1973), although with limited technical support at the time. This approach offers the advantage over thalamic RFL (as used principally for tremor) to spare thalamic cells and related thalamocortical loops. Furthermore, with a relatively small lesion (∼4 mm diameter), the efferents from a large pallidal territory (in case of the PTT in PD) and afferents to relatively large thalamic territory (in case of the CTT in ET) can be interrupted and efficacy of the surgery significantly improved. Risks associated with thalamic (e.g. encroachment onto internal capsule when the lateral part of the nucleus is targeted) or pallidal (with the vicinity of the optic tract and internal capsule) surgery are also prevented by accurate targeting of the subthalamic area.
Our results are based on histologically processed sections of the human thalamus and basal ganglia and on correlations with post-mortem MRI. The myelin staining served as first basis for the identification of the fibre tracts, though with the following limitations: since the origin and terminal of the fibre tracts cannot be assessed in the present material (myelin stain, in normal brains), our identification relies on previous studies in humans, particularly those based on Marchi retrograde degeneration methods after lesions in the pallidum or cerebellar nuclei (Martinez 1961; Beck and Bignami 1968). These studies provide very valuable anatomical information and link to the clinic but cannot be used for stereotactic targeting. On the other hand, the most commonly used atlases of the human thalamus (Schaltenbrand and Bailey 1959; Schaltenbrand and Wahren 1977; Mai et al. 2004) provide a basis for coordinate determination of the tracts, though with low-spatial resolution and insufficient 3D stereotactic precision. In spite of these limitations, the reproducibility of our results in many cases and comparison with the existing data in human allow us to identify the main bulks of the fibre tracts with a certain confidence. Furthermore, the use of immunohistochemical staining procedures in addition to myelin and Nissl stainings, provide further criteria to ascertain the delimitations and discriminate between the different tracts. This was particularly the case for the passage of fibres through the internal capsule and cerebral peduncle, where identification of tracts can only be inferred, but not firmly assessed, on myelin stained sections. One critical problem with myelin stain, i.e. deformation and shrinkage due to alcohol pre-treatment in the myelin staining procedure could be partly corrected in a most recent case (Table 1, Hb5) by applying a protocol on mounted, instead of free-floating sections (Burgel et al. 1997). The delineations of the fibre bulks were also superposed on Nissl sections (where they appear negatively stained), which undergo minimal deformations and served as primary basis for map drawings in the Morel atlas. Moreover, high-resolution post-mortem MRI scans prior to guillotine section and histological processing, were very helpful not only to visualize the subthalamic fibre tracts and thalamic structures with no additional deformation (except that caused by removing the brain from the skull), but also to better assess the positions of the reference stereotactic intercommissural plane and estimate the mediolateral extent of thalamic and subthalamic areas.
The nomenclature of the subthalamic fibres was revised and adapted in an effort to combine old terminology with more recent studies in primates. Since Forel’s seminal morphological studies of the pallidothalamic fibres (without knowing their origin) that were described as fields (or “Campi”) (Forel 1877), the terms H, H1, and H2 fields of Forel have been consecutively used by different neuroanatomists. Initially, field H1 designated the dorsal extension of the fibres from H en route to the thalamus, and H2 the ventral continuity of H to the substantia innominata and the Pes Pedunculi. The origin of H field was supposed to be the red nucleus. Forel described those fibres with the idea of the logical sequence of H, H1, and H2, but not knowing the relationship between the fibres coursing in his fields and the thalamus or the pallidum. He was not able to differentiate between cerebellothalamic fibres running in his H field (the so-called prerubral field of Forel) and the pallidothalamic (ft) fibres more anteriorly. By close examination of the illustrations in Forel’s original paper (Forel 1877) and according to our data, we consider field H as comprising the posterior extension of the ft containing fibres from both the ansa lenticularis and the fasciculus lenticularis, and a part of the dorsal extension of the fct near its entry into the thalamus. Nevertheless, the definition of the H field as part of the pallidothalamic pathways is still used in the literature and often misleading. A continuity of the fibres from H2, to H2 + H1, and H1 was first described by Cécile Vogt and Oskar Vogt (1920) and corresponds to the fl, fl/al mergence and the ft in our study. Other fibre degeneration studies in monkeys adopted this nomenclature (Vogt 1909; Ranson 1939; Nauta and Mehler 1966), changing also the names of the components of the ansa lenticularis of von Monakow (Von Monakow 1895; Nauta and Mehler 1966) to take into account their different projections, such as the STh for the middle component.
For the cerebellothalamic fibres, the choice of the term fasciculus cerebellothalamicus participates to the same effort to homogenize the nomenclature for subthalamic fibre tracts.
Pallidothalamic tract: origin of the al and fl
The origin of the pallidothalamic tract through al and fl from the internal segment of the globus pallidus has been confirmed by a number of studies in primates (Nauta and Mehler 1966; Kuo and Carpenter 1973; Inase and Tanji 1994; Parent and Hazrati 1995a; Sakai et al. 1996; Sidibe et al. 1997, 2002; Baron et al. 2001; Parent et al. 2001; Haber 2003; Parent and Parent 2004) but how the cells of origin of these two fibre systems distribute within the GPi is still controversial. On one hand, Parent and col. (Parent et al. 2001; Parent and Parent 2004), using single-axon tracing method propose a wide distribution of pallidofugal fibres through the al or fl, without particular anteroposterior or lateromedial segregation of their parent cells in GPi. Others using tracer injections or RFL lesions in GPi (Baron et al. 2001, 2006) put forward a different innervation by the al and fl, with the fl originating principally from posterior (motor-related) and the al from anterior (non-motor related) GPi, in line with earlier model (Kuo and Carpenter 1973). The origin of the al and fl within the human GPi cannot be assessed in the present study, but we infer from the anteroposterior extent of the medial and ventral components of the fibres emerging from GPi that al comprises fibres originating from more anterior portions of the nucleus than the fl, although the al can also be followed relatively far posteriorly at the ventral edge of the GPi.
Course of al and fl in the subthalamic region
The merging together of the al and fl (H2) to form the ft (H1) in subthalamic area was first described by Vogt (1909). The exact location where the fl and al meet together, becoming ft, could not be determined with our methods, but the data suggest that the two tracts merge in the dorsal part of the H1 + H2 field of Forel, about 2.5 mm ventral to the DV0 plane and about 2 mm posterior to mcl level.
The thalamic projections of the ft, based on studies in monkeys, distribute principally to VApc and VLa, but also VLp, VM and the centre médian-parafascicular (CM-Pf) complex (Nauta and Mehler 1966; Kuo and Carpenter 1973; Parent and De Bellefeuille 1983; Percheron et al. 1993; Inase and Tanji 1994, 1995; Rouiller et al. 1994; Parent and Hazrati 1995a; Sakai et al. 1996, 1999, 2000; Sidibe et al. 1997; Haber and McFarland 2001; Parent and Parent 2004). They overlap to some extent with terminals of the fct in VLp and VLa (Ilinsky and Kultas-Ilinsky 1987; Rouiller et al. 1994; Sakai et al. 1996), though direct convergence of the pallido- and cerebellothalamic pathways onto thalamocortical neurons appears very rare, as also demonstrated physiologically (Yamamoto et al. 1983; Anderson and Turner 1991). The VLa, Vapc, and VM are likely to be also primary targets of the ft in the human brain, as indicated by the course of the tract, particularly on sagittal sections (e.g. Fig. 5). Furthermore, in spite of the fact that the ft is negatively stained for CB (see Fig. 11b), the VLa and VApc show enhanced immunostaining (Figs. 4b, 11b; Morel 2007) and pallidothalamic terminals have been reported to be confined to the CB-positive territory of the motor thalamus in monkeys (see Percheron et al. 1996; Parent et al. 2001; also suggested by Calzavara et al. 2005). In terms of functional aspects related to the fibres coursing along al and fl in the human subthalamic area, our surgical experience revealed that in a PD patient, a partial PTT due to lateral shift of the electrode that left the medial part of the ft (most probably containing mainly fibres of the al) intact, resulted in only partial relief of the motor symptoms. A second, complementary surgical intervention with a medially placed RFL resulted in complete relief (unpublished observation). This clinical observation would agree with the scheme proposed by Parent and colleagues (Parent and Parent 2004), where motor fibres course through both fl and al, more than with that of Baron et al. (Baron et al. 2006), where those fibres are mainly restricted to the fl.
Other subthalamic fibre tracts related to basal ganglia efferent pathways
Two fibre systems apart from the pallidothalamic tracts could be recognized on the basis of immunohistochemical stainings. The first is related to CB positive fibres running through the pallidal segments, the internal capsule and penetrating the cerebral peduncle on the ventral aspect of the STh “en route” to the substantia nigra, pars reticulata. The latter is also enhanced in CB-ir and is known to receive important projections from the striatum (putamen and caudate) (Lynd-Balta and Haber 1994; Haber et al. 1995; Parent and Hazrati 1995a; Levesque and Parent 2005). These striatonigral fibres were already described in terms of neurochemical characteristics in a previous report on the human basal ganglia (Morel et al. 2002). A second fibre tract could be recognized at the anterior, mid-dorsal, and lateral aspect of the STh nucleus, both characterized by enhanced PV-ir. Although the course of the fibres could not be followed back to the pallidum, their position between the fl and the al strongly suggests that they belong to the fasciculus subthalamicus, or middle division of von Monakow’s ansa lenticularis (Von Monakow 1895; Nauta and Mehler 1966) which connects the external globus pallidus (GPe) with the STh (Ranson 1939; Nauta and Mehler 1966; Parent and Hazrati 1995b; Shink et al. 1996). Indeed, dense degenerated fibres were observed in this part of the tract and in the STh after lesion of GPe in human (Morel et al. 2001). Some fibres coursing on the dorsal aspect of the STh and continuous with the fl tract (e.g. Fig. 4b) may correspond to efferents from the GPi to the pedonculopontine nucleus (PPN) (Nauta and Mehler 1966; Shink et al. 1997; Parent et al. 2001; Parent and Parent 2004). These pallido-pedunculopontine connections are supposed to be affected by medial pallidotomies in PD patients and could explain part of the beneficial results against akinesia. These would likely be also interrupted by the PTT and possibly, though only partially, by subthalamic DBS or RFL (targets too far anterior and lateral).
Previous experiments in monkey have shown that SNr projects to the thalamus, particularly to VAmc, VM, MDpl, and Pf nuclei (Carpenter et al. 1976; Parent and De Bellefeuille 1983; Francois et al. 1984, 2002; Ilinsky et al. 1993; Percheron et al. 1996). Thalamic projections of the SNr share some territories with those from the GPi (e.g. VM), but others are different (e.g. VAmc) (Ilinsky et al. 1993). Nigral projections to the thalamus were not described in humans but by comparison with data gathered in monkeys, we can infer that they probably course along the posterior part of the ft. These would also be interrupted by the PTT, in contrast to pallidotomies or subthalamic DBS or RFL, the latter affecting only the fl.
Auguste Forel already described fibres originating in the dentate nucleus and passing through and lateral to the red nucleus (“Bindearm”) before entering the thalamus. The first experimental anterograde study of the cerebellothalamic fibres after destruction of the dentate nucleus in monkey is due to Vogt (Vogt 1909). She described projections to the thalamus, in particular to its ventral lateral part. The origin of the cerebellothalamic fibres in the cerebellar nuclei (dentate, interposed, and fastigial nuclei) and its projections to the thalamus are now well established. Anterograde studies in monkeys have shown that after tracer injections in cerebellar nuclei, terminal labels are found primarily in VLp, in discrete zones of VLa and in the intralaminar CM/Pf and CL nuclei (Asanuma et al. 1983a, b; Jones 1990; Percheron et al. 1993; Rouiller et al. 1994; Sakai et al. 1996; Calzavara et al. 2005). Our observations that the bulk of the fct is mainly directed toward the VLp, which is enhanced in PV-ir (see also Fig. 3d), are consistent with reports in monkeys although with indirect demonstration (Calzavara et al. 2005). We cannot exclude however that the fct also innervates the VLa, as suggested in sagittal sections where some fibres ascend toward the VLa through a more anterior part of the VM. Although some overlap exists between the cerebello- and pallidothalamic terminals fields in the lateral thalamus, direct interaction between the two seems very limited, as discussed above. For the medial thalamus, we noticed that some fibres emerging from the RN and most probably associated with the fct, take a turn medially toward the CM and possibly CL nuclei. This may well correspond to the medial cerebellothalamic component directed to the intralaminar nuclei described by others (Asanuma et al. 1983a, b; Rouiller et al. 1994; Sakai et al. 1996; Calzavara et al. 2005).
Relations between cerebello- and pallidothalamic fibres in the subthalamic region: consequences for neurosurgical targeting
The present study demonstrates that the pallidothalamic and cerebellothalamic tracts do not to converge in the subthalamic region. We cannot exclude some fibre exchanges between the two tracts, but we can demonstrate that the main bulks are clearly separated. Immunohistochemical stainings, especially PV immunoreactivity and AChE, provided additional evidence for a separation between the two tracts. At thalamic level, evidence for a convergence of pallidal and cerebellar fibres onto the same nuclei, although with minor overlap, has been brought by experimental studies in monkeys (Rouiller et al. 1994; Sakai et al. 1996, 1999, 2000).
The demonstration at subthalamic level of a separation between cerebello- and pallidothalamic fibres is of major interest for functional neurosurgery. Being able to target a fibre bundle while sparing the other is particularly relevant for the surgical treatments of motor disorders with different underlying pathophysiology, such as PD and ET. The three-dimensional coordinates of the fct and ft determined in the present study allow placing RFL to selectively interrupt one or the other tract, as shown in Figs. 12 and 14. The most commonly used surgical approach for PD is to target the subthalamic nucleus with DBS. In the last few years, increasing evidence for more effectiveness of the stimulation sites at the dorsal border of the STh, rather than within the nucleus, has been reported (Voges et al. 2002; McIntyre et al. 2004; Zonenshayn et al. 2004; Breit et al. 2006; Godinho et al. 2006; Miocinovic et al. 2006; Butson et al. 2007). This indicates that the effect is at least partially due to involvement of the fibres from the fl (or H2 field of Forel) coursing over the dorsal border of the nucleus, on their way to join the al to finally form the ft. Similar evidence for the importance of the fibres in DBS efficacy was proposed by Benabid and col. (Benabid et al. 1996) using DBS of the VLp (or VIM) against tremor. They suggest that at the frequency most optimal for tremor suppression, the fibres (probably from the fct), rather than the thalamic cells, are affected. All these observations point to the fact that in the near future, the fibre tracts may well regain importance for the surgical treatment of motor disorders.
We thank V. Streit for her skilful histological work, S. Kolias and M. Wyss for post-mortem MR scanning; and A. Aguzzi and H.-P. Lipp for providing autopsy material. This study was supported by the Swiss National Science Foundation (grants No. 31-47238.96, 31-54179.98; 31-68248.02).
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