Article Text

Download PDFPDF

Bilateral stimulation of the caudal zona incerta nucleus for tremor control
  1. P Plaha,
  2. S Khan,
  3. S S Gill
  1. Institute of Neurosciences, Frenchay Hospital, Bristol, UK
  1. Professor Steven S Gill, Consultant Neurosurgeon, Frenchay Hospital, Bristol BS16 1LE, UK; steven.gill{at}nbt.nhs.uk

Abstract

Introduction: The ventrolateral (VL) nucleus of the thalamus is the commonly chosen target for deep brain stimulation (DBS) to alleviate tremor. However, it has a poor efficacy in alleviating proximal tremor and patients may develop tolerance to the action component of tremor. We performed bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) to determine its safety and efficacy in alleviating tremor.

Methods: 5 patients with parkinsonian tremor and 13 with a range of tremors (Holmes (HT), cerebellar (CT), essential (ET), multiple sclerosis (MS) and dystonic tremor (DT)) affecting both the proximal and distal body parts underwent MRI guided, bilateral cZI DBS. Tremor was assessed by the Fahn–Tolosa–Marin (FTM) tremor scale at baseline and at a mean follow-up of 12 months.

Results: Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET. HT improved by 70.2%, proximal CT by 60.4% and proximal MS tremor by 57.2% in the total tremor rating score. In the single patient with DT, there was improvement in both the dystonia and the tremor. Patients required low voltages of high-frequency stimulation and did not develop tolerance to it. Stimulation-related side effects were transient.

Conclusion This prospective study shows that the cZI may be an alternative target for the treatment of tremor with DBS. In contrast to bilateral DBS of the VL nucleus, it improves all components of tremor affecting both the distal and proximal limbs as well as the axial musculature.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Tremor is defined as a rhythmic, involuntary oscillation of a body part. It is classified according to the body part that it affects (eg, the axis, proximal or distal limbs), and the circumstances under which it occurs (eg, at rest (resting tremor) or during active muscle contraction (kinetic tremor)). Kinetic tremor is subclassified into tremor that occurs when maintaining limb position or posture (postural tremor), during active limb movement (action tremor) or when a limb is approaching a target (intention tremor). Parkinsonian tremor is classically described as a resting and postural tremor. Essential tremor (ET) and tremor associated with multiple sclerosis (MS) are usually postural but can manifest an action component. Cerebellar tremor (CT) classically manifests as an intention tremor, dystonic tremor (DT) is either a postural or task-specific tremor,1 and Holmes tremor (HT) is both a resting and kinetic tremor.

The aetiology of tremor is multifactorial and drug therapy is usually the first line of management. Functional neurosurgery is offered when tremor is functionally disabling and medically refractory. A number of subcortical nuclei and white matter tracts have been defined, which, when lesioned or stimulated, control different aspects of tremor.

Typically, the ventrolateral (VL) nucleus of the thalamus (Hasslers ventralis intermedius) is the target of choice to effectively suppress distal limb tremor having a resting or postural component. However, proximal tremor and the action component of distal tremor respond poorly to DBS,2 with only a third of the patients showing any significant improvement.3 4 Nguyen et al have, however, reported that stimulating the dorsal part of the VL nucleus could suppress proximal action tremor.5 Perhaps the key limiting factor in effectively suppressing tremor by DBS of this nucleus is the high incidence (30–50%) of bilateral stimulation-related dysarthria and disequilibrium.3 6 7 Therefore, in order to avoid the above complications, most centres lesion or implant the DBS lead only unilaterally, contralateral to the tremor-dominant side.

The other subcortical area that has been explored to suppress tremor is the subthalamic region, which includes the subthalamic nucleus (STN), the zona incerta nucleus (ZI) and the white matter fibre tracts surrounding them.8

The STN is an effective target to suppress resting tremor with DBS in patients with Parkinson’s disease (PD).9 In addition, stimulation of this nucleus improves rigidity and bradykinesia.10 11 Large lesions involving the ZI and the surrounding white matter tracts, including the prelemniscal radiation, have been shown to be effective in suppressing distal tremor in patients with PD12 and ET.13 This area has also been unilaterally stimulated to suppress resting tremor in PD,14 proximal action tremor in ET15 16 and MS tremor.17 The white matter prelemniscal radiation has also been exclusively stimulated unilaterally to alleviate resting tremor in PD18 and distal tremor in ET.19

In this prospective study, we present our results of bilateral stimulation of the caudal or motor component of the zona incerta (cZI) nucleus in 18 patients with a range of tremor types.

MATERIALS AND METHODS

Demographics

Included in this consecutive study were 5 patients with tremor-predominant PD, 6 with ET, 4 with MS tremor, 1 with CT, 1 with HT and 1 with DT (table 1).

Table 1 Patient demographics and clinical history

All patients underwent bilateral implantation of DBS leads, having given fully informed consent. The Frenchay Hospital local ethical committee gave approval to perform the stereotactic procedures under general anaesthesia using implantable guide tubes to deliver the DBS leads.

Clinical evaluation

PD tremor was evaluated by applying the tremor subscores of the motor component (Part-III) of the Unified Parkinson’s Disease Rating Scale (UPDRS).20 All patents with non-parkinsonian tremor were assessed using the FTM Tremor Rating scale.21 The severity of dystonia in the patient with dystonic tremor and the functional disability caused by it was evaluated by applying the Burke–Fahn–Marsden Dystonia (BFMD) rating scale.22

Preoperative assessments were performed with patients who were off all anti-tremor or anti-parkinsonian medications for 12 hours overnight. Post-operatively, they were assessed 12 hours after stopping anti-parkinsonian and anti-tremor medications and switching off the stimulation (off medication/off stimulation); and then after switching on the DBS (off medication/on stimulation). Patients who were not on any anti-tremor medications (4 MS and 1 CT patient) were assessed after switching off the DBS for 12 hours. A Specialist Movement disorder nurse performed all evaluations preoperatively and at follow-up. All pre- and post-operative tremor scores were evaluated independently from videos, which were scored independently by a blinded neurosurgeon.

Outcome measures

The primary outcome measure in patients with PD tremor was the percentage change in tremor subscores of the motor UPDRS from baseline (off medication) to follow-up at 12 months (off medication/on stimulation). The secondary outcome measure was the percentage improvement in the subscores of rigidity and bradykinesia between baseline and follow-up.

In all patients with non-parkinsonian tremor, our primary outcome measure was the percentage change of each of the subscores of the tremor rating scale (parts A–C) between baseline and follow-up (off medication versus off medication/on stimulation score). In the single patient with dystonic tremor, the secondary outcome measure was the percentage change in the BFMD movement and disability score from baseline to follow-up. We also recorded complications related to the surgical procedure, stimulation-related complications and the stimulation parameters required for optimal symptom control.

Surgery

Surgery was performed under general anaesthesia using high-resolution long-acquisition MRI scans acquired under stereotactic conditions to identify the cZI target that is located posterior-medial to the posterior-dorsal STN (fig 1). A transfrontal trajectory to the target, 45° to the AC-PC plane was planned and the anatomical position of each contact on the DBS lead was defined such that the second contact from its distal end (contacts 1 or 5) was placed at the target site. A frontal burr hole was made and a rigid probe inserted into the target and over which a plastic guide tube (Electrode Introducer Kit; Renishaw, UK) was advanced so that its distal end was short of the target by 12 mm. A hub on the proximal end of the guide tube was bonded in the burr hole with acrylic cement. The probe was then withdrawn and replaced with a plastic stylette to the planned position in the cZI. An intraoperative MRI was performed to verify the position of the plastic stylette in relation to the planned target. On confirmation of satisfactory placement, the stylette was removed and replaced with a DBS lead (model 3389; Medtronic, Minneapolis, MN, USA). The procedure was performed bilaterally and the leads connected to a DBS pulse generator (Kinetra), which was implanted in the infra-clavicular location.19 23 24

Figure 1 (A) An intraoperative axial MRI scan with bilateral stylettes in the caudal zona incerta. (B) A matching slice from the Schaltenbrand atlas with the red dot defining the target location in the caudal zona incerta. (C) An intraoperative sagittal MRI scan with the stylette passing dorsal and posterior to the subthalamic nucleus (STN) via a transfrontal trajectory. The tip of the stylette is in the caudal zona incerta. (D) A matching sagittal slice from the Schaltenbrand atlas. RN, red nucleus.

Postoperative management

The Kinetra generator was switched on immediately following surgery. The movement disorder nurse programmed the patients. Anti-parkinsonian and anti-tremor medications were reduced as appropriate by the neurologist.

Anatomical location of active contacts

To compare the mean location of the active contacts in our patient cohort with those defined by other groups, we plotted the location of each individual’s active contacts at their known position from the tip of the plastic stylette visualised on their perioperative scans (fig 2). The spatial location of each active contact with respect to the boundary of the STN, defined by MRI, was then transposed to a standardised STN, as defined on the Schaltenbrand and Warren atlas.8

Figure 2 Anatomical location of active contacts. (A) Shows the spatial location of the active contacts as transposed onto the Schaltenbrand atlas. The subthalamic nucleus (STN) and zona incerta from axial slice H.v –1.5 (drawn in red) are superimposed onto axial slice H.v –3.5 (shown in black) and the STN on H.v –2.5 is drawn out in between the two (dotted green). Active contacts (shown as crosses) positioned at/or within 1 mm dorsal to a defined axial plane are shown in the same colour. (B) Shows the active contacts in the STN in the sagittal plane between slice S.l 12.0 (black colour) and the STN from slice S.l 13 (grey colour). (C) Shows the mean location of our active contact in the caudal ZI in comparison with that of other groups that have targeted the subthalamic region for tremor.

Statistical analysis

The primary efficacy was analysed using the paired Wilcoxon signed-rank and sign test. The test of significance was applied to the subscores of the motor UPDRS and the tremor rating score. The test of significance was not applied to the four patients with MS tremor, single patients with HT, DT or CT.

RESULTS

Parkinsonian tremor

In the 5 patients with tremor-dominant PD, the resting tremor score improved by 94.8% (preoperative mean score of 11.6±4.72 to 0.6±0.55 post-surgery, p = 0.006); and postural tremor by 88.2% (preoperative mean score of 3.4±1.67 to 0.4±0.54 post-surgery, p = 0.028) (fig 3). Other cardinal signs of PD, such as bradykinesia and rigidity, also improved by 62.1% (preoperative mean score of 14.8±7.91 to 5.6±4.21 post-surgery, p = 0.008) and 77.4% (preoperative mean score of 10.6±5.36 to 2.4±1.4 post-surgery, p = 0.014), respectively.

Figure 3 Parkinsonian tremor. (A) The improvement in the resting and postural/action component of Parkinson’s disease (PD) tremor. (B) The improvement in rigidity and bradykinesia in PD. Baseline-off, baseline off medication score; postop-off/on, postoperative off medication/on stimulation score.

ET, CT and MS tremor

Clinical improvement is detailed in table 2. Following surgery, there was complete suppression of a grade 4 head and neck tremor in two ET patients, whereas one patient had a residual grade 1 tremor.

Table 2 Improvement in essential tremor, multiple sclerosis tremor, Holmes tremor and cerebellar tremor

Along with an improvement in the severe proximal upper limb tremor, two MS patients noticed an improvement in truncal ataxia and, having been wheelchair-bound preoperatively, could now mobilise with the help of a rollator frame. One patient had a grade 4 head and neck tremor, which was completely suppressed. This patient also noted an improvement in her scanning cerebellar speech.

Dystonic tremor

The BFM Dystonia movement score improved by 65% from a preoperative score of 63 to 22 at 12 months. The Fahn–Marsden disability score improved by 61.5% (preoperative score 13 and follow-up score of 5). There was a 70.5% improvement in the FTM Tremor Rating scale (baseline score 68 to 20 and at the 12-month follow-up).

Stimulation parameters

The mean stimulation parameters are shown in table 3. High-frequency stimulation controlled tremor in all patients except in one patient with MS tremor in whom a 40 Hz bilateral stimulation was required to suppress her proximal action and intention tremor. All patients were on continuous 24-hour stimulation and no patient developed tolerance to stimulation (no significant change in the stimulation parameters on serial follow-ups during the 12-month period).

Table 3 Stimulation parameters (mean (SD)) for all the patients

Complications

There was one surgery-related complication. The single patient with HT developed dysphagia for a period of about 3 months post-surgery. This was secondary to an error in frame relocation, which resulted in both guide tube stylettes being implanted into the Vim nucleus. Both the stylettes were subsequently relocated to the cZI. Two patients developed transient stimulation-related disequilibrium, with one lasting for 8 weeks and the other for 8–10 weeks post-surgery. In both cases, oedema was seen in the target region, extending into the prelemniscal radiation on the intraoperative MRI scan. One patient with MS complained of prolonged lethargy and reduced mobility following the procedure. Examination of this patient by the neurologist responsible for his care found no new neurological deficit and excluded a relapse of MS. The patient’s mobility returned to baseline within 3 months.

DISCUSSION

This study shows that stimulation of the cZI is effective in suppressing both resting and kinetic tremor, whether affecting the proximal, distal or the axial musculature.

Localisation of active contacts

The location of the active contacts in our patients transposed onto the Schaltenbrand Warren atlas shows that they lie within the cZI postero-medial to the postero-dorsal STN (fig 2). Velasco et al have implanted unilateral DBS electrodes into the posterior subthalamic region in the prelemniscal radiation, which is more medial and deeper than our cZI target.18 The prelemniscal radiation lies between the medial border of the STN and the lateral border of the red nucleus, with its posterior extent limited by the cZI and the postero-medially placed medial lemniscus.8 Kitagawa et al define an effective target for treating ET and tremulous PD that lies in the region of ZI and the prelemniscal radiation1416—that is, between our target and the target defined by Velasco et al18 (see fig 2). Nandi et al have targeted the rostral ZI ventral to the Ventral oralis posterior (Vop) nucleus of the thalamus, to treat MS tremor.17

Patient outcomes

The conventional targets for the surgical treatment of PD tremor are the VL nucleus of the thalamus and the STN. Although the number of patients in our series with PD tremor is small, we have seen an 94.8% improvement in resting tremor and an 88.2% improvement in postural and action tremor. This is consistent with our previous results in a larger cohort of patients with PD in which we saw a 93% improvement in tremor scores contralateral to 27 electrodes implanted into the cZI.23 Stimulation of the VL nucleus and the STN typically achieve an improvement in tremor scores in the region of 80%.2 29

In patients with ET, we have seen an improvement in both distal (79.5%) and proximal (71.2%) action tremor. DBS of the VL nucleus has been shown to improve distal action tremor by 50–65% following unilateral or bilateral stimulation30 31 but, as discussed previously, it is not effective in suppressing proximal limb tremor. Unilateral stimulation of the cerebellothalamic fibres in the prelemniscal radiation, which may also have included the ZI region, has been found to be effective in suppressing proximal and distal ET, achieving an 81% reduction (8 patients) in the total tremor rating scale.15 16 We have previously reported an 84% improvement in distal and axial ET control (4 patients) from stimulating this region bilaterally.19

In our small series of MS tremor patients, the postural component improved by 87% and the intention component by 75%. Nandi and Aziz performed bilateral stimulation ventral to the Vop nucleus in a region encompassing the prelemniscal radiation and the rostral ZI, with moderate improvement in both the postural (63.7%) and intention component (36%) of complex MS tremor.32 Foote et al33 reported on a single MS tremor patient in whom improvement was seen following dual stimulation of the Vim and ventral oralis anterior and ventral oralis posterior (Voa/Vop) nuclei of the thalamus.

In our single case of HT, there was no anatomical abnormality identified on the MRI scan but the patient expressed all three components of tremor—that is, resting, postural and intention—which improved with cZI DBS. This condition has been previously treated by stereotactic lesions34 35 or DBS of the Vim nucleus of the thalamus with variable outcome. Romanelli et al36 have performed unilateral stimulation of both the Vim nucleus and the STN in a single patient with HT with a 55% reduction in tremor. Foote and Okun37 implanted unilateral twin VL/VA thalamic DBS leads to suppress tremor in this condition, overriding the abnormality in both the pallidothalamic and cerebellothalamic circuit.

In the single patient with dystonic tremor, there was an improvement in both components of this syndrome—that is, dystonia by 65% on the dystonia movement scale and tremor by 70.5% on the tremor rating scale. Both dystonia and tremor components can be suppressed by stimulating separate subcortical nuclei, such as the GPi for dystonia and the Vim nucleus for tremor.38 39

Stimulation parameters and tolerance

Although there was no statistical difference between the stimulation parameters in patients with parkinsonian tremor in contrast to non-parkinsonian tremor, the non-parkinsonian group required a higher pulse width to suppress the tremor. The mean stimulation parameters are comparable to those in other series of DBS of the STN for PD11 40 and stimulation of the other areas in the subthalamic region for non-parkinsonian tremor (ET, CT and MS tremor).15 16 19 Interestingly, in one patient with MS tremor, improvement was seen at 40 Hz frequency in contrast to higher frequencies of 130 Hz and above. In the second patient with MS tremor, there was moderate improvement in tremor at 40 Hz, but stimulation at 130 Hz was found to be optimal. Tolerance to Vim stimulation has been reported, especially to the action component of tremor, in up to 18% of cases by 3–6 months.3 38 Some patients therefore switch off the stimulator at night for a variable period to postpone the appearance of tolerance. In our series, tolerance was not seen despite the fact that constant stimulation was maintained.

Interpretation of our findings

In this study, we have demonstrated that high-frequency DBS of the cZI is effective in suppressing all forms of tremor. Although a number of hypotheses have been put forward to explain the mechanisms underlying the generation of tremor and the pathways involved, none of these incorporate the cZI. Here, we describe the anatomy and putative physiological role of the cZI and proffer an explanation of the findings in our clinical study.

ZI nucleus and its function

The ZI, an embryological derivative of the ventral thalamus, is a distinct heterogenous nucleus that lies at the base of the dorsal thalamus and is an extension of the reticular thalamic nucleus.41 Its rostral component extends over the dorsal and medial surface of the STN, whereas its caudal or motor component lies posteromedial to the STN.42 43 Each of these components is divided into a dorsal and ventral part.

The ZI receives afferents from the globus pallidus internus (GPi) and the substantia nigra reticulate (SNr);42 44 45 the ascending reticular activating system;4446 the interpositus nucleus of the cerebellum; and also motor, associative and limbic areas of the cerebral cortex,44 47 which are known to facilitate and modulate motor behaviour.

The ZI sends efferents to the centromedian and parafascicular nuclei (CM/Pf),4850 the ventral anterior (VA) nucleus and the VL nucleus of the thalamus.51 It also sends efferents to the brainstem, including the midbrain extrapyramidal area (MEA)42 and the medial reticular formation (MRF), as well as to the GPi and SNr.42 The interpositus nucleus of the cerebellum, the inferior olive (IO) and cerebral cortex also receive ZI efferents.5254

ZI neurons are predominantly γ-aminobutyric acid (GABA)ergic and, as with other GABAergic systems such as the reticular thalamic nucleus, the basal ganglia neurons (striatum, GPi and SNr) and the universally distributed local circuit neurons, they probably play a role in synchronising firing between neuronal assemblies. Typically, GABAergic neurons synapse on the necks of dendrites of large assemblies of neurons, which are usually driven by glutamatergic afferents. The inhibitory GABAergic neurons control both the frequency and magnitude of the signal transmitted by the group.5557 Synchronisation of neuronal firing between assemblies of neurons is the means by which the brain facilitates and directs information processing in its otherwise noisy and complex network of 100 billion interconnected neurons, each with their own intrinsic rhythm. If neurons participating in information transfer oscillate at the same or a harmonic frequency (typically in the ranges 20, 40 and 80 Hz), they become hypopolarised and receptive at the same time, whereas non-co-operating neurons firing irregularly and out of phase will not be receptive.5861

The ZI provides a unique GABAergic link between the basal ganglia output nuclei and the cerebello-thalamo cortical loop (fig 5). This places it in a key position to transmit synchronised oscillations into this loop; these oscillations are generated in the basal ganglia during the preparation and execution of volitional movement plans. The loop carries detailed spatiotemporal movement instructions to the motor cortex and is powerfully influenced by visual guidance. ZI efferents to the VL neurons in the cerebello-thalamocortical loop synapse on the necks of their dendrites. Consequently, the volitionally led basal ganglia oscillations transmitted via ZI will dominate and facilitate coherent and integrated information processing during the planning and execution of the movement. Similarly, the efferents of ZI to the brainstem motor effectors, the MRF and MEA, which are involved in controlling axial and proximal limb muscles, will presumably help to synchronise their firing frequency with neurons in those areas of the motor cortex, controlling distal limb movements.

Figure 5 Shows how the ZI provides a unique GABAergic link between the basal ganglia output nuclei, the cerebello-thalamocortical loop and the brainstem nuclei, and synchronises the oscillatory firing of these subcortical nuclei. The GABAergic ZI output is shown as stippled blue to signify its synchronising function. MRF, medial reticular formation; PFC, prefrontal cortex; VA, ventralis anterior nucleus of thalamus; VL, ventro-lateral nucleus of thalamus; ZI, zona incerta.

ZI and tremor

Current hypotheses regarding the mechanisms of tremor generation point to abnormal synchronisation of neuronal firing in the basal ganglia-thalamo-cortical loop (in PD and DT) or the cerebello-thalamocortical loop (in ET, CT and MS tremor) or involving both loops (HT).

We believe that the cZI is an effective target for the surgical control of all forms of tremor because of its unique GABAergic connections with both the basal ganglia and cerebello-thalamocortical loops, in addition to the brain stem motor effectors through which tremor oscillation may be transmitted.

PD tremor

Evidence of synchronised tremor oscillations arising in the basal ganglia-thalamocortical loop in PD come from peri-operative electrophysiological recordings in which synchronised ∼10 and ∼20 Hz oscillations and 4–6 Hz tremor frequency oscillations have been recorded in the GPi and the STN, which are coherent with neuronal oscillations in the motor cortex.6264 Transmission of abnormal oscillations from the premotor cortex to the cerebellum and thence to thalamus and motor cortex seems possible, and MEG study data has demonstrated strong coherence between the cerebellum, diencephalon and motor cortex at tremor frequency (4–6 Hz), double tremor frequency (8–12 Hz) and at ∼20 Hz, suggesting that the propagation and maintenance of PD tremor is due to a central oscillator with oscillations entraining both the basal ganglia and cerebello-thalamocortical-loops.65 Nevertheless, although lesioning or DBS of GPi and STN can improve tremor,9 6669 lesioning of the VA nucleus of the thalamus (Hasslers Voi and Lpo), which transmits the basal ganglia output to the premotor cortex,70 does not.71 This implies that there must be an alternative pathway for conduction of tremor oscillations into the cerebello-thalamocortical loop. We propose that the key pathway involved is via the cZI, which receives direct afferents from the GPi and SNr and sends efferents to the VL thalamus, the cerebellar interpositus nucleus and the IO.

The VL thalamus has long been established as an effective surgical target for controlling distal limb tremor,4 including PD tremor. However, because it receives predominantly cerebellar afferents and no direct basal ganglia afferents,72 73 the reason why it is effective in controlling PD tremor has remained a paradox. The conduction of abnormal oscillations generated in the basal ganglia in PD to the VL nucleus via cZI would therefore explain this paradox and also explain why we observed such a potent anti-tremor effect from stimulating cZI in our patients with PD.

Essential tremor

In ET, synchronised oscillations at 4–12 Hz are thought to arise in the IO (IO) nucleus and are transmitted to the cerebellar cortex and then distributed along the ascending cerebellothalamic pathway and the descending brainstem medial reticular formation to manifest as tremor. The transmission of oscillations along both pathways is supported by clinical, imaging7478 and electrophysiology data.79 These oscillations probably result from excessive electrotonic coupling between dendrites of the IO neurons via GABA-mediated gap junctions.8082

Physiologically, the IO is thought to act as a “movement error detector”8387 (fig 4) in that it receives information regarding the movement plan via the cerebellum and parvocellular red nucleus (pRN),88 as well as the movement instruction from the motor cortex and can compare this with the proprioceptive feedback that it receives during movement.8991 On detecting a movement error, it modulates a correction via its efferent climbing fibres that synapse directly on purkinje cells in the cerebellar cortex and on the deep cerebellar nuclei (dentate and interpositus).92 93 The interpositus effects the ongoing movement correction assisted by visual and proprioceptive feedback.25 26 9496 Ascending efferents from interpositus pass to the VL nucleus and descending fibres to the MRF carrying information related to both distal limb movement correction and axial and proximal limb movement correction, respectively. En passant interpositus sends efferents to cZI.97

Figure 4 The interaction between various nuclei including zona incerta nucleus (ZI) in the control of limb movement. The general movement plan is conveyed from the pre-motor cortex to the parvocellular red nucleus (pRN), the microcomplex zone (MCZ) in the cerebellar cortex, the dentate (D), interpositus (I) nuclei and the medial reticular formation (MRF). The detailed plan from the cerebellum encompassing spatiotemporal coordination and timing of limb movement2528 is conveyed to the motor cortex via the ventro-lateral (VL) nucleus of the thalamus with a copy of the plan to the pRN and MRF and the inferior olive (IO). The pRN acts as a comparator of the general and detailed movement plan and, on detecting a “mismatch” between the two, fires to the IO nucleus via its efferents. The IO acts as a movement error detector by receiving input from various subcortical nuclei and modulates a correction via efferents to the cerebellum. Interpositus corrects distal limb movement via ascending efferents to VL thalamus and axial and proximal movement via descending fibres to the MRF. Blue stippled lines indicate GABAergic output. GABAergic ZI output synchronises neuronal firing in the brainstem, thalamus and cerebellum.

It is presumed that the consequence of the abnormal electronic coupling in the IO in ET will be excessive movement correction in response to limb displacement detection and then overcorrection of the now further displaced limb that is creating oscillations. This will be seen as postural tremor while trying to hold a limb in space; action tremor during limb movement and intention tremor as the limb approaches a target and proprioceptive feedback is maximal.

Other kinetic tremors

Tremor associated with MS and ET is kinetic but tends to have a greater postural element involving axial and proximal limb movements. The exact mechanisms of its generation are unclear but, typically, there is widespread demyelination involving the olivocerebellar circuit.98 In CT, a structural or functional abnormality in the interpositus nucleus is thought to cause the <5 Hz intention tremor that predominantly affects proximal limb movements.99102 HT is both a resting and kinetic tremor (<4.5 Hz) and results from lesions involving both the basal ganglia thalamocortical and the cerebello-thalamocortical loop.

In the kinetic tremors discussed, abnormal oscillations are carried in efferents from the interpositus to the VL nucleus and/or to the MRF to be expressed as distal and/or axial and proximal limb tremor, respectively. Interpositus will also transmit these oscillations to cZI, which sends GABAergic efferents to wide receptive fields in VL, MRF, IO, pRN and back to interpositus, which will help to sharpen and amplify the oscillations. Thus, DBS of the cZI is likely to suppress distal tremor by overriding oscillations in the VL nucleus, interpositus and IO nucleus, and proximal tremor by overriding oscillations in the interpositus, IO and MRF. In contrast, VL nucleus stimulation only affects the ascending cerebellothalamic fibres, resulting in an improvement in only distal resting, postural and sometimes action tremor. In addition, bilateral stimulation is associated with dysarthria and disequilibrium. The latter is not seen with bilateral cZI DBS, as this would only override tremor oscillations without interrupting patterns of information related to fine movements of vocal cords and proprioceptive sensation.

CONCLUSION

This prospective study suggests that the cZI nucleus is effective in suppressing all components of tremor affecting both the distal and proximal part of the body. These results, if replicated in larger randomised controlled studies, have important implications for our current surgical management of patients with tremor and point to a more promising target area than the VL nucleus of the thalamus.

Acknowledgments

We wish to thank our neurologist Dr Peter Heywood for his assistance in the management of our patients and our movement disorder nurse specialists Mrs Karen O’ Sullivan, Ms Deirdre O’Brien and Mrs Lucy Mooney for carrying out all the clinical assessments.

REFERENCES

Footnotes

  • Funding: PP was supported by a grant from the UK Medical Research Council (G9900797).

  • Competing interests: None.