**Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease**

Naoki Tani, Ryoma Morigaki, Ryuji Kaji and Satoshi Goto

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57105

## **1. Introduction**

[181] Tong Y., Giaime E., Yamaguchi H., Ichimura T., Liu Y., Si H., Cai H., Bonventre J.V., and Shen J. (2012). Loss of leucine-rich repeat kinase 2 causes age-dependent bi-pha‐

[182] Berger Z., Smith K.A., and LaVoie M.J. (2010). Membrane localization of LRRK2 is as‐ sociated with increased formation of the highly active LRRK2 dimer and changes in

sic alterations of the autophagy pathway. Mol. Neurodegener. 7: 2.

its phosphorylation. Biochemistry 49: 5511-5523.

192 A Synopsis of Parkinson's Disease

Recent advances in neuroimaging and neurosurgical techniques provide a growing body of evidence suggesting that deep brain stimulation (DBS) is a powerful and safe therapeu‐ tic option for medically intractable Parkinson's disease (PD). For more than half a centu‐ ry, the thalamic ventrolateral (VL) nucleus has been an anatomical target for stereotaxy in treating movement disorders that include PD. It plays a pivotal role in the basal gangliathalamo-cortical circuit that is associated with motor brain functions. The entire output of the basal ganglia is directed to the motor cortex via the VL nucleus where the cerebellar and pallidal afferents terminate predominantly in the ventralis intermedius (Vim) nucleus and ventralis oralis (Vo) nucleus, respectively. In accordance with the general concept that the cerebellothalamic fiber connections participate in tremor genesis, thalamic Vim DBS is now used in the treatment of a wide variety of tremor subtypes with different etiologies. Indeed, thalamic Vim DBS can exert a striking therapeutic impact on tremor-dominant PD that exhibits better clinical prognoses and slower disease progression with less cognitive decline as compared to akinesia/rigidity-dominant PD. In patients with tremor-dominant PD, tremor suppression can be achieved irrespective of age, disease duration, or baseline disease severity. Based on recent advances in the understanding of the pathophysiology of tremor-dominant PD, this review introduces the current use of thalamic Vim stimulation in treating patients with PD.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. Surgical anatomy**

The thalamic VL nucleus comprises 2 major functional territories [1-3]. Neurons in the VL thalamus that respond to voluntary movements are located largely within the Vo [4-6], and neurons that respond to kinesthetic/passive movements about a joint are mainly contained within the Vim [5, 7]. The pallidothalamic inhibitory afferents terminate preferentially in the ipsilateral Vo nucleus, with an anterior-to-posterior gradient of terminal densities through the VL nucleus. In contrast, the cerebellothalamic excitatory afferents terminate predominantly in the contralateral Vim nucleus, creating a posterior-to-anterior gradient of terminal densities through the VL nucleus [8-10]. Moreover, a somatotopic arrangement, i.e., a medial-to-lateral distribution of facial-, forelimb-, and hindlimb-receptive fields, also exists in the VL thalamic nucleus [11-14].

with tremor-dominant PD have less dopaminergic dysfunction than do patients with nontremor PD. On the other hand, patients with tremor-dominant PD have considerably more cell loss in the retrorubral area of the midbrain [21]. The retrorubral area could produce tremor via its dopaminergic projection to the pallidum. Further, Selikhova et al. [22] reported that patients with the non-tremor subtype had more severe cortical Lewy body pathology and were more

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

195

SPECT using Iodine-123 fluoropropyl-carbomethoxy-3 ( [123I]FP-CIT SPECT) targets the dopamine transporter and is used to determine ongoing loss of dopaminergic neurons in patients with PD [23-25]. [123I]FP-CIT SPECT shows that patients with tremor-dominant PD

The metabolic rate of glucose measured using (18F)fluoro-2-deoxy-D-glucose PET (FDG-PET) is known as a marker of integrated local synaptic activities and is sensitive to direct neuronal and synaptic damage and to the functional changes in synaptic activity distant from the primary site of pathology [29]. Using FDG-PET, Mure et al. [30] identified and validated that the PD tremor-related pattern is characterized by covarying metabolic increases in the cerebellum, motor cortex, and putamen. This network correlates specifically with clinical tremor ratings, but not with akinesia/rigidity. In patients with PD tremor, high-frequency stimulation of the Vim nucleus reduces regional metabolism and cerebral blood flow (CBF) in the ipsilateral sensorimotor cortex and contralateral dorsal cerebellar nucleus [30-33], and increases both measures in the Vim nucleus ipsilateral to the stimulation site [30, 34-37]. It should be noted that changes in CBF may not reflect the direct effects of DBS but rather may

**Figure 1.** Schematic representations of the stereotactic targets for Vim-DBS on the axial (A) and sagittal (B) planes.

**3.2. Positron emission tomography (PET) and single photon emission computed**

had less striatal dopamine depletion than do patients with non-tremor PD [26-28].

reflect sensory feedback from changes in motor activity [38].

The DBS lead implanted into the Vim nucleus is also shown in (B).

likely to develop dementia.

**tomography (SPECT)**

The cerebellothalamic pathway plays a role in the fine spatial and temporal tuning of coordinated movements, as well as in the learning and retention of new motor skills. Thus, functional interference might also be achieved in deep cerebellar nuclei and affect activi‐ ties in the striatum and cerebral cortices via the VL nucleus, thereby affecting ongoing and intended movements [15-17].

## **3. Pathophysiology of parkinsonian tremor**

The clinical heterogeneity of PD is well recognized, and patients can often be divided into tremor-dominant and akinesia/rigidity-dominant subgroups. Accumulating evidence sug‐ gests that akinesia/rigidity and tremor may be associated with functional impairments of different motor circuits. Striatal dopamine depletion and dysfunction of the basal ganglia seem to be more important in akinesia/rigidity than in tremor. It is generally thought that tremor is primarily related to the cerebello-thalamo-cortical pathway, while akinesia/rigidity is rooted in the basal ganglia-thalamo-cortical pathway. Recent results from clinicopathological, electrophysiological, and neuroimaging studies on patients with PD are discussed in the following sections.

#### **3.1. Clinicopathological study**

Although post-mortem studies are limited, patients with tremor-dominant PD appear to progress slowly despite a poorer therapeutic response to levodopa. A statistical analysis performed using the Unified Parkinson's Disease Rating Scale (UPDRS) showed that the motor score for tremor is independent of the scores for other motor symptoms in patients with PD [18]. Rajput et al. [19] reported that patients with tremor-dominant PD showed slower disease progression and lower incidence of dementia than did patients with akinesia/rigiditydominant PD.

Patients with tremor-dominant PD have milder cell loss in the substantia nigra pars compacta and in the locus coeruleus than do patients with non-tremor PD [20]. This suggests that patients with tremor-dominant PD have less dopaminergic dysfunction than do patients with nontremor PD. On the other hand, patients with tremor-dominant PD have considerably more cell loss in the retrorubral area of the midbrain [21]. The retrorubral area could produce tremor via its dopaminergic projection to the pallidum. Further, Selikhova et al. [22] reported that patients with the non-tremor subtype had more severe cortical Lewy body pathology and were more likely to develop dementia.

#### **3.2. Positron emission tomography (PET) and single photon emission computed tomography (SPECT)**

**2. Surgical anatomy**

194 A Synopsis of Parkinson's Disease

nucleus [11-14].

following sections.

dominant PD.

**3.1. Clinicopathological study**

intended movements [15-17].

**3. Pathophysiology of parkinsonian tremor**

The thalamic VL nucleus comprises 2 major functional territories [1-3]. Neurons in the VL thalamus that respond to voluntary movements are located largely within the Vo [4-6], and neurons that respond to kinesthetic/passive movements about a joint are mainly contained within the Vim [5, 7]. The pallidothalamic inhibitory afferents terminate preferentially in the ipsilateral Vo nucleus, with an anterior-to-posterior gradient of terminal densities through the VL nucleus. In contrast, the cerebellothalamic excitatory afferents terminate predominantly in the contralateral Vim nucleus, creating a posterior-to-anterior gradient of terminal densities through the VL nucleus [8-10]. Moreover, a somatotopic arrangement, i.e., a medial-to-lateral distribution of facial-, forelimb-, and hindlimb-receptive fields, also exists in the VL thalamic

The cerebellothalamic pathway plays a role in the fine spatial and temporal tuning of coordinated movements, as well as in the learning and retention of new motor skills. Thus, functional interference might also be achieved in deep cerebellar nuclei and affect activi‐ ties in the striatum and cerebral cortices via the VL nucleus, thereby affecting ongoing and

The clinical heterogeneity of PD is well recognized, and patients can often be divided into tremor-dominant and akinesia/rigidity-dominant subgroups. Accumulating evidence sug‐ gests that akinesia/rigidity and tremor may be associated with functional impairments of different motor circuits. Striatal dopamine depletion and dysfunction of the basal ganglia seem to be more important in akinesia/rigidity than in tremor. It is generally thought that tremor is primarily related to the cerebello-thalamo-cortical pathway, while akinesia/rigidity is rooted in the basal ganglia-thalamo-cortical pathway. Recent results from clinicopathological, electrophysiological, and neuroimaging studies on patients with PD are discussed in the

Although post-mortem studies are limited, patients with tremor-dominant PD appear to progress slowly despite a poorer therapeutic response to levodopa. A statistical analysis performed using the Unified Parkinson's Disease Rating Scale (UPDRS) showed that the motor score for tremor is independent of the scores for other motor symptoms in patients with PD [18]. Rajput et al. [19] reported that patients with tremor-dominant PD showed slower disease progression and lower incidence of dementia than did patients with akinesia/rigidity-

Patients with tremor-dominant PD have milder cell loss in the substantia nigra pars compacta and in the locus coeruleus than do patients with non-tremor PD [20]. This suggests that patients

SPECT using Iodine-123 fluoropropyl-carbomethoxy-3 ( [123I]FP-CIT SPECT) targets the dopamine transporter and is used to determine ongoing loss of dopaminergic neurons in patients with PD [23-25]. [123I]FP-CIT SPECT shows that patients with tremor-dominant PD had less striatal dopamine depletion than do patients with non-tremor PD [26-28].

The metabolic rate of glucose measured using (18F)fluoro-2-deoxy-D-glucose PET (FDG-PET) is known as a marker of integrated local synaptic activities and is sensitive to direct neuronal and synaptic damage and to the functional changes in synaptic activity distant from the primary site of pathology [29]. Using FDG-PET, Mure et al. [30] identified and validated that the PD tremor-related pattern is characterized by covarying metabolic increases in the cerebellum, motor cortex, and putamen. This network correlates specifically with clinical tremor ratings, but not with akinesia/rigidity. In patients with PD tremor, high-frequency stimulation of the Vim nucleus reduces regional metabolism and cerebral blood flow (CBF) in the ipsilateral sensorimotor cortex and contralateral dorsal cerebellar nucleus [30-33], and increases both measures in the Vim nucleus ipsilateral to the stimulation site [30, 34-37]. It should be noted that changes in CBF may not reflect the direct effects of DBS but rather may reflect sensory feedback from changes in motor activity [38].

**Figure 1.** Schematic representations of the stereotactic targets for Vim-DBS on the axial (A) and sagittal (B) planes. The DBS lead implanted into the Vim nucleus is also shown in (B).

#### **3.3. Functional magnetic resonance imaging (fMRI)**

Intrinsic blood oxygen consumption detected by fMRI is correlated with low-frequency electrical amplitude fluctuations [64]. Patients with PD show increased overall activity in networks coupled to the primary motor cortex and cerebellum, and reduced functional connections in the supplementary motor area, dorsolateral prefrontal area, and putamen [65]. A recent study with simultaneous fMRI and EMG recording shows that the basal ganglia are transiently activated at the onset of tremor episodes, whereas tremor amplitude-related activity correlates with the cerebello-thalamo-cortical circuit [26]. The patients with tremordominant PD had increased functional connectivity between the basal ganglia and the cerebello-thalamo-cortical circuit.

hypothesis that the tremor cells may represent a central pacemaker for generating tremor, independent of sensory feedback [46, 48]. Tremor cells are reportedly located in the Vim nucleus and Vo complex [43, 49, 50]. The distribution of tremor cells is important for thalamic surgery, because tremor has been successfully treated when the radiofrequency lesion was centered within the cluster of tremor cells [39, 51, 52]. However, recent studies show that tremor cells are widely distributed in the Vim, Vo, and VC nuclei, and that they show no apparent differences in proportion within each nucleus [50]. These findings suggest that the ideal surgical target might not be determined by microelectrode recordings of tremor cells alone [49, 53]. The number of tremor cells in patients with PD is much higher than that in patients with other movement disorders, such as essential tremor (ET) and multiple sclerosis. This may play a role in the better surgical outcomes seen in patients with PD [50]. Based on their experiences, Katayama et al. [53] postulated that tremor cells might play a predominant role in the lateral portion of the Vim nucleus, an area that provides the most significant control of PD-associated

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

197

DBS procedures enable intraoperative micro-/macrorecordings and postoperative macrore‐ cordings. Local field potentials (LFPs) can be recorded via macro- as well as microrecordings [66]. The oscillatory activity in the β frequency range has clinical relevance to movement disorders. It is widely distributed throughout the motor system and is desynchronized by voluntary movement in both the Vim and subthalamic nucleus (STN) [67-69]. Levodopa and high-frequency STN stimulation reduce β band LFP oscillations. This reduction positively correlates with an improvement of akinesia and rigidity, but not with a decrease of tremor [70-72], and the β range STN stimulation causes further impairment of movement in patients with PD [73-76]. The α range oscillations in patients with tremor-dominant PD show finely segregated muscle-specific subloops that strongly correlate with the tremor-affected muscles, and tremor suppression can be achieved using STN-DBS in areas with pronounced α oscilla‐ tions [77, 78]. Given that basal ganglia β oscillation correlates with rigidity and akinesia and α oscillation correlates with tremor, these findings further suggest a differential pathophysi‐

In summary, the pathophysiological studies on parkinsonian tremor indicate that resting tremor may result from a pathological interaction between the basal ganglia and the cerebellothalamo-cortical circuit. Tremor generation in the cerebello-thalamo-cortical circuit is likely

The Vim DBS procedure is divided into the following five stages: (i) stereotactic imaging; (ii) thalamic mapping; (iii) electrode implantation; (iv) receiver of pulse generator implantation; and (v) programming. We perform the two successive steps of the procedure in the same operative session. The first step involves fixation of the stereotactic frame, stereotactic imaging,

tremor, in accordance with previous reports [54, 55].

ology between akinesia-rigidity and tremor.

triggered by activity in the basal ganglia.

**4. Thalamic Vim DBS**

**4.1. Surgical procedures**

**3.6. Local field potentials (LFPs)**

#### **3.4. Magnetoencephalography (MEG)**

PD symptoms are related to alterations of oscillatory activity within the basal ganglia. Such pathologically increased oscillations have been demonstrated at several frequencies [56, 57]. In particular, those below 70 Hz have been shown to be antikinetic [56]. More specifically, oscillations at 4 to 12 Hz have been related to the origin of tremor symptoms in patients with PD [58]. Double tremor oscillations in the β range are not coherent with simultaneously recorded tremors [59-61]. However, a strong coherence in the β range is observed in the primary motor cortex, supplementary motor cortex, premotor cortex, diencephalon, and contralateral cerebellum [58]. Interestingly, this coupling can be successfully reduced by dopamine replacement therapy [62, 63]. These data indicate that PD resting tremor is associ‐ ated with synchronous oscillatory coupling in a cerebello-thalamo-cortical loop and cortical motor and sensory areas contralateral to the tremor hand [58].

#### **3.5. Cell recordings**

So-called "kinesthetic" cells receive afferent inputs from muscle spindles and respond to passive joint movements. These cells are located just anterior to the nucleus ventralis caudalis (VC), which receives tactile sensory inputs [39, 40]. Percheron et al. [8] postulated that the kinesthetic zone is located in the latero-ventral part of the Vim nucleus, a region that sends a majority of its axons to the motor cortex. Vitek et al. [13] reported that in a monkey model of PD produced using 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP), the kinesthetic zone expands anteriorly into regions that contain the active movement-related neurons. Kiss et al. [41] reported that in patients with tremor, there is an anterior expansion in the represen‐ tation of the kinesthetic neurons without a change in their receptive field sizes. They suggested that tremor activates receptors responsive to deep sensations and, to a lesser degree, superficial sensations. Thus, repetitive tremor activities could result in a gradual increase in the synaptic efficacy of somatosensory inputs to kinesthetic neurons. Cells that respond to both somato‐ sensory inputs and active movements are referred to as "combined" cells [42, 43] and have been identified only in patients with movement disorders.

Cells in the VL thalamic nucleus that demonstrate a discharge pattern with burst frequencies similar to that of tremor are called "tremor cells" [44, 45]. In a monkey model of resting tremor produced by a lesion of the ventral tegmentum, thalamic activity related to tremor frequency is unchanged following the interruption of sensory inputs [46, 47]. This finding has led to the hypothesis that the tremor cells may represent a central pacemaker for generating tremor, independent of sensory feedback [46, 48]. Tremor cells are reportedly located in the Vim nucleus and Vo complex [43, 49, 50]. The distribution of tremor cells is important for thalamic surgery, because tremor has been successfully treated when the radiofrequency lesion was centered within the cluster of tremor cells [39, 51, 52]. However, recent studies show that tremor cells are widely distributed in the Vim, Vo, and VC nuclei, and that they show no apparent differences in proportion within each nucleus [50]. These findings suggest that the ideal surgical target might not be determined by microelectrode recordings of tremor cells alone [49, 53]. The number of tremor cells in patients with PD is much higher than that in patients with other movement disorders, such as essential tremor (ET) and multiple sclerosis. This may play a role in the better surgical outcomes seen in patients with PD [50]. Based on their experiences, Katayama et al. [53] postulated that tremor cells might play a predominant role in the lateral portion of the Vim nucleus, an area that provides the most significant control of PD-associated tremor, in accordance with previous reports [54, 55].

#### **3.6. Local field potentials (LFPs)**

**3.3. Functional magnetic resonance imaging (fMRI)**

motor and sensory areas contralateral to the tremor hand [58].

been identified only in patients with movement disorders.

cerebello-thalamo-cortical circuit.

196 A Synopsis of Parkinson's Disease

**3.5. Cell recordings**

**3.4. Magnetoencephalography (MEG)**

Intrinsic blood oxygen consumption detected by fMRI is correlated with low-frequency electrical amplitude fluctuations [64]. Patients with PD show increased overall activity in networks coupled to the primary motor cortex and cerebellum, and reduced functional connections in the supplementary motor area, dorsolateral prefrontal area, and putamen [65]. A recent study with simultaneous fMRI and EMG recording shows that the basal ganglia are transiently activated at the onset of tremor episodes, whereas tremor amplitude-related activity correlates with the cerebello-thalamo-cortical circuit [26]. The patients with tremordominant PD had increased functional connectivity between the basal ganglia and the

PD symptoms are related to alterations of oscillatory activity within the basal ganglia. Such pathologically increased oscillations have been demonstrated at several frequencies [56, 57]. In particular, those below 70 Hz have been shown to be antikinetic [56]. More specifically, oscillations at 4 to 12 Hz have been related to the origin of tremor symptoms in patients with PD [58]. Double tremor oscillations in the β range are not coherent with simultaneously recorded tremors [59-61]. However, a strong coherence in the β range is observed in the primary motor cortex, supplementary motor cortex, premotor cortex, diencephalon, and contralateral cerebellum [58]. Interestingly, this coupling can be successfully reduced by dopamine replacement therapy [62, 63]. These data indicate that PD resting tremor is associ‐ ated with synchronous oscillatory coupling in a cerebello-thalamo-cortical loop and cortical

So-called "kinesthetic" cells receive afferent inputs from muscle spindles and respond to passive joint movements. These cells are located just anterior to the nucleus ventralis caudalis (VC), which receives tactile sensory inputs [39, 40]. Percheron et al. [8] postulated that the kinesthetic zone is located in the latero-ventral part of the Vim nucleus, a region that sends a majority of its axons to the motor cortex. Vitek et al. [13] reported that in a monkey model of PD produced using 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP), the kinesthetic zone expands anteriorly into regions that contain the active movement-related neurons. Kiss et al. [41] reported that in patients with tremor, there is an anterior expansion in the represen‐ tation of the kinesthetic neurons without a change in their receptive field sizes. They suggested that tremor activates receptors responsive to deep sensations and, to a lesser degree, superficial sensations. Thus, repetitive tremor activities could result in a gradual increase in the synaptic efficacy of somatosensory inputs to kinesthetic neurons. Cells that respond to both somato‐ sensory inputs and active movements are referred to as "combined" cells [42, 43] and have

Cells in the VL thalamic nucleus that demonstrate a discharge pattern with burst frequencies similar to that of tremor are called "tremor cells" [44, 45]. In a monkey model of resting tremor produced by a lesion of the ventral tegmentum, thalamic activity related to tremor frequency is unchanged following the interruption of sensory inputs [46, 47]. This finding has led to the

DBS procedures enable intraoperative micro-/macrorecordings and postoperative macrore‐ cordings. Local field potentials (LFPs) can be recorded via macro- as well as microrecordings [66]. The oscillatory activity in the β frequency range has clinical relevance to movement disorders. It is widely distributed throughout the motor system and is desynchronized by voluntary movement in both the Vim and subthalamic nucleus (STN) [67-69]. Levodopa and high-frequency STN stimulation reduce β band LFP oscillations. This reduction positively correlates with an improvement of akinesia and rigidity, but not with a decrease of tremor [70-72], and the β range STN stimulation causes further impairment of movement in patients with PD [73-76]. The α range oscillations in patients with tremor-dominant PD show finely segregated muscle-specific subloops that strongly correlate with the tremor-affected muscles, and tremor suppression can be achieved using STN-DBS in areas with pronounced α oscilla‐ tions [77, 78]. Given that basal ganglia β oscillation correlates with rigidity and akinesia and α oscillation correlates with tremor, these findings further suggest a differential pathophysi‐ ology between akinesia-rigidity and tremor.

In summary, the pathophysiological studies on parkinsonian tremor indicate that resting tremor may result from a pathological interaction between the basal ganglia and the cerebellothalamo-cortical circuit. Tremor generation in the cerebello-thalamo-cortical circuit is likely triggered by activity in the basal ganglia.

## **4. Thalamic Vim DBS**

#### **4.1. Surgical procedures**

The Vim DBS procedure is divided into the following five stages: (i) stereotactic imaging; (ii) thalamic mapping; (iii) electrode implantation; (iv) receiver of pulse generator implantation; and (v) programming. We perform the two successive steps of the procedure in the same operative session. The first step involves fixation of the stereotactic frame, stereotactic imaging, and placement of the thalamic electrode after application of local anesthesia. In the second step, the thalamic electrode is connected to the pulse generator while the patient is under general anesthesia. The intercommissural line-based coordinates for the tentative target in the thalamic Vim are determined 12 mm lateral to the midline, 5 mm anterior to the posterior commissure, and on the intercommissural line. In the operating room, a precoronal burr hole is placed 3 cm lateral to the midline, and a guiding cannula is inserted stereotactically. A quadripolar DBS electrode (Model 3387; Medtronic) is advanced directly through the guiding cannula. The characteristics of the tremor are assessed before, during, and immediately after the insertion of the electrode. Improvement of tremor at the time of insertion of the lead (the "microthalamotomy-like effect") is considered to indicate good positioning of the electrode. Thresholds for both intrinsic and extrinsic evoked responses are analyzed directly via the implanted electrode with a screening device (Model 3625; Medtronic). When a satisfactory electrode position has been achieved, the stylet of the lead and the guiding cannula are carefully removed. The lead is fixed to the cranium with the burr hole ring and cap. General anesthesia is induced while the stereotactic head frame is removed. The pulse generator is implanted in a subcutaneous infraclavicular pouch after being connected to the DBS electrode with a subcutaneous extension wire. In most patients, an Activa SC implantable pulse generator (Medtronic) is used.

stop tremor. If these measures are still not helpful, the position of the electrode can be checked

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

199

Similarities in the effectiveness of thalamic DBS and thalamotomy have led investigators to suggest that DBS acts as a reversible lesion of the thalamus, but the mechanism of action of thalamic DBS is yet unclear. With respect to tremor suppression, 4 different hypotheses of Vim DBS have been proposed: (1) conduction block—this hypothesis is supported by the fact that Vim thalamotomy has similar effects to Vim DBS [83]; (2) activation of inhibitory axon terminals that synapse onto and inhibit projection neurons [93]; (3) superimposition of continuous stimuli onto rhythmically oscillating subcortical-cortical loops [94]; and (4) inhibition of neuronal activity near the stimulation site while activating axonal elements that leave the target structure [95]. Recent reports have shown that during high-frequency stimu‐ lation, glutamate and adenosine are increased [96-99], and this elevated glutamate release could excite local interneurons, thereby increasing the production of inhibitory neurotrans‐ mitters (e.g., GABA and glycine) and resulting in a decrease in the firing rates of projection

Before the levodopa era, severe tremor was a main indication for surgery [79]. In the 1960s, thousands of patients with PD throughout the world received a thalamotomy [80] or other procedures such as pallidotomy, campotomy, or pedunculotomy [81]. During this period, it was observed that the high-frequency stimulation used for targeting during lesioning of the thalamus significantly reduced tremor [82]. In the 1980s, Benabid et al. demonstrated that DBS of the Vim significantly reduced tremor, and they have treated more than 100 patients with thalamic DBS [83-85]. Several studies have demonstrated that DBS of the thalamus has comparable control of tremor with fewer side effects than does thalamotomy. Vim DBS is highly beneficial for tremor control, but ineffective for the other disabling features of PD, including akinesia, rigidity, and gait and postural disturbances. Benabid et al. [85] showed that chronic Vim stimulation is highly effective for tremor in a group of 117 tremor patients; over 85% of patients had a very good or excellent response with little or no tremor evident in the contralateral arm. With a double-blind multicenter study to assess the efficacy of unilateral Vim DBS against placebo, Koller et al. [86] have shown an 80% reduction in contralateral arm tremor in 24 patients with PD tremor and 29 patients with ET with Vim DBS at the 1-year

With respect to the long-term efficacy of Vim DBS, Schuurman et al. [87] reported that 88% of patients showed complete or nearly complete tremor suppression after a mean follow-up period of 5 years. Hariz et al. [88] reported 38 patients with PD who received Vim DBS with a follow-up period of 6 years. The long-term follow-up of Vim DBS revealed effective control of tremor 6 years postoperatively, while axial symptoms worsened. The initial improvement in activities of daily living (ADL) scores at the 1-year follow-up disappeared after 6 years. Hariz et al. [89] showed significant increases in stimulation parameters for up to 1 year; however,

using MRI or CT, and re-implantation can be discussed if necessary.

**4.3. Mechanism of action**

neurons [99].

follow-up.

**4.4. Therapeutic impacts**

The pulse generator can be programmed immediately after surgery. If a prolonged microtha‐ lamotomy-like effect is present, the pulse generator is programmed at the time of reappearance of the tremor. Routine postoperative CT scans are performed to rule out hemorrhage. Patients are instructed on how to switch their device on and off using a handheld magnet, and told to turn their device off at night when possible to maximize battery life. Some teams do not connect the pulse generator immediately and use this period to repeat some external stimulation to confirm that the stimulation improves tremor without side effects. This period can also be used to perform a brain MRI to check the electrode location and possible lesion. Many radiologists prefer this to be done before pulse generator implantation for safety reasons.

#### **4.2. Programming challenges**

The optimal stimulating parameters are determined using monopolar or bipolar stimulation. The easiest way to screen the parameters is to study each contact one after the other: the contact studied is programmed as the cathode, and the case is programmed as the anode. For example, first a constant pulse width of 90 µs and a constant frequency of 160 Hz are selected. Then the voltage is progressively increased to find the threshold for symptom suppression without adverse effects, using the contact(s) that gives the best effect. Best results are usually obtained at a pulse frequency of 130–185 Hz (no lower than 100 Hz), pulse width of 60–90 µs, and amplitude of 1.5–3.6 V.

If this screening does not reveal parameters to control tremor, other combinations can be tried. The pulse width and frequency can be increased. Stimulating more than one contact at the same time and using bipolar stimulation can also be tried. Bipolar stimulation is particularly useful if limiting side effects are obtained with a low voltage before reaching the threshold to stop tremor. If these measures are still not helpful, the position of the electrode can be checked using MRI or CT, and re-implantation can be discussed if necessary.

#### **4.3. Mechanism of action**

and placement of the thalamic electrode after application of local anesthesia. In the second step, the thalamic electrode is connected to the pulse generator while the patient is under general anesthesia. The intercommissural line-based coordinates for the tentative target in the thalamic Vim are determined 12 mm lateral to the midline, 5 mm anterior to the posterior commissure, and on the intercommissural line. In the operating room, a precoronal burr hole is placed 3 cm lateral to the midline, and a guiding cannula is inserted stereotactically. A quadripolar DBS electrode (Model 3387; Medtronic) is advanced directly through the guiding cannula. The characteristics of the tremor are assessed before, during, and immediately after the insertion of the electrode. Improvement of tremor at the time of insertion of the lead (the "microthalamotomy-like effect") is considered to indicate good positioning of the electrode. Thresholds for both intrinsic and extrinsic evoked responses are analyzed directly via the implanted electrode with a screening device (Model 3625; Medtronic). When a satisfactory electrode position has been achieved, the stylet of the lead and the guiding cannula are carefully removed. The lead is fixed to the cranium with the burr hole ring and cap. General anesthesia is induced while the stereotactic head frame is removed. The pulse generator is implanted in a subcutaneous infraclavicular pouch after being connected to the DBS electrode with a subcutaneous extension wire. In most patients, an Activa SC implantable pulse

The pulse generator can be programmed immediately after surgery. If a prolonged microtha‐ lamotomy-like effect is present, the pulse generator is programmed at the time of reappearance of the tremor. Routine postoperative CT scans are performed to rule out hemorrhage. Patients are instructed on how to switch their device on and off using a handheld magnet, and told to turn their device off at night when possible to maximize battery life. Some teams do not connect the pulse generator immediately and use this period to repeat some external stimulation to confirm that the stimulation improves tremor without side effects. This period can also be used to perform a brain MRI to check the electrode location and possible lesion. Many radiologists

The optimal stimulating parameters are determined using monopolar or bipolar stimulation. The easiest way to screen the parameters is to study each contact one after the other: the contact studied is programmed as the cathode, and the case is programmed as the anode. For example, first a constant pulse width of 90 µs and a constant frequency of 160 Hz are selected. Then the voltage is progressively increased to find the threshold for symptom suppression without adverse effects, using the contact(s) that gives the best effect. Best results are usually obtained at a pulse frequency of 130–185 Hz (no lower than 100 Hz), pulse width of 60–90 µs, and

If this screening does not reveal parameters to control tremor, other combinations can be tried. The pulse width and frequency can be increased. Stimulating more than one contact at the same time and using bipolar stimulation can also be tried. Bipolar stimulation is particularly useful if limiting side effects are obtained with a low voltage before reaching the threshold to

prefer this to be done before pulse generator implantation for safety reasons.

generator (Medtronic) is used.

198 A Synopsis of Parkinson's Disease

**4.2. Programming challenges**

amplitude of 1.5–3.6 V.

Similarities in the effectiveness of thalamic DBS and thalamotomy have led investigators to suggest that DBS acts as a reversible lesion of the thalamus, but the mechanism of action of thalamic DBS is yet unclear. With respect to tremor suppression, 4 different hypotheses of Vim DBS have been proposed: (1) conduction block—this hypothesis is supported by the fact that Vim thalamotomy has similar effects to Vim DBS [83]; (2) activation of inhibitory axon terminals that synapse onto and inhibit projection neurons [93]; (3) superimposition of continuous stimuli onto rhythmically oscillating subcortical-cortical loops [94]; and (4) inhibition of neuronal activity near the stimulation site while activating axonal elements that leave the target structure [95]. Recent reports have shown that during high-frequency stimu‐ lation, glutamate and adenosine are increased [96-99], and this elevated glutamate release could excite local interneurons, thereby increasing the production of inhibitory neurotrans‐ mitters (e.g., GABA and glycine) and resulting in a decrease in the firing rates of projection neurons [99].

#### **4.4. Therapeutic impacts**

Before the levodopa era, severe tremor was a main indication for surgery [79]. In the 1960s, thousands of patients with PD throughout the world received a thalamotomy [80] or other procedures such as pallidotomy, campotomy, or pedunculotomy [81]. During this period, it was observed that the high-frequency stimulation used for targeting during lesioning of the thalamus significantly reduced tremor [82]. In the 1980s, Benabid et al. demonstrated that DBS of the Vim significantly reduced tremor, and they have treated more than 100 patients with thalamic DBS [83-85]. Several studies have demonstrated that DBS of the thalamus has comparable control of tremor with fewer side effects than does thalamotomy. Vim DBS is highly beneficial for tremor control, but ineffective for the other disabling features of PD, including akinesia, rigidity, and gait and postural disturbances. Benabid et al. [85] showed that chronic Vim stimulation is highly effective for tremor in a group of 117 tremor patients; over 85% of patients had a very good or excellent response with little or no tremor evident in the contralateral arm. With a double-blind multicenter study to assess the efficacy of unilateral Vim DBS against placebo, Koller et al. [86] have shown an 80% reduction in contralateral arm tremor in 24 patients with PD tremor and 29 patients with ET with Vim DBS at the 1-year follow-up.

With respect to the long-term efficacy of Vim DBS, Schuurman et al. [87] reported that 88% of patients showed complete or nearly complete tremor suppression after a mean follow-up period of 5 years. Hariz et al. [88] reported 38 patients with PD who received Vim DBS with a follow-up period of 6 years. The long-term follow-up of Vim DBS revealed effective control of tremor 6 years postoperatively, while axial symptoms worsened. The initial improvement in activities of daily living (ADL) scores at the 1-year follow-up disappeared after 6 years. Hariz et al. [89] showed significant increases in stimulation parameters for up to 1 year; however, after the 1-year stimulation, the parameters seemed to stabilize. By contrast, Kumar et al. [90] reported that it was necessary to increase the current intensity over time to control tremor. This increase in amplitude is undesirable, as it often causes paresthesia and cerebellar adverse effects [83, 91]. During the follow-up, some tolerance (necessity to gradually increase the voltage to control tremor) and a rebound effect (tremor much worse than before when the stimulator is switched off) can develop [86, 89]. This affects an action tremor more frequently. Switching off the stimulator at night can sometimes limit the tolerance effect. Recurrence of tremor is seen in ~5% of patients several weeks or years after surgery [83, 92].

**Author details**

, Ryoma Morigaki2

, Ryuji Kaji3

\*Address all correspondence to: sgoto@clin.med.tokushima-u.ac.jp

1 Department of Neurosurgery, Otemae Hospital, Osaka, Japan

Medical Sciences, University of Tokushima, Tokushima, Japan

of the monkey. Brain Res. 286 (3): 237-265.

and Satoshi Goto2

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

201

2 Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Bioscien‐ ces, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan

3 Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of

[1] Asanuma, C.; Thach, WT. & Jones EG. (1983). Distribution of cerebellar terminations and their relation to other afferent terminations in the ventral lateral thalamic region

[2] Kultas-Ilinsky, K. & Ilinsky IA. (1991). Fine structure of the ventral lateral nucleus (VL) of the Macaca mulatta thalamus: cell types and synaptology. J Comp Neurol.

[3] Ilinsky, IA. & Kultas-Ilinsky, K. (2002). Motor thalamic circuits in primates with em‐ phasis on the area targeted in treatment of movement disorders. Mov Disord. 17

[4] Hassler, R. Anatomy of the thalamus. In: Schaltenbrand G, Bailer, P., editor. An in‐ troduction to Stereotaxis With an Atlas of the Human Brain. Stuttgart: Thieme; 1959.

[5] Krack, P.; Dostrovsky, J.; Ilinsky, I.; Kultas-Ilinsky, K.; Lenz, F.; Lozano, A. & Vitek, J. (2002). Surgery of the motor thalamus: problems with the present nomenclatures.

[6] Lenz, FA.; Jaeger, CJ.; Seike, MS.; Lin, YC. & Reich, SG. (2002). Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cere‐

[7] Ohye, C.; Maeda, T. & Narabayashi, H. (1976). Physiologically defined VIM nucleus. Its special reference to control of tremor. Appl Neurophysiol. 39 (3-4): 285-295.

[8] Percheron, G.; Francois, C.; Talbi, B.; Yelnik, J. & Fenelon, G. (1996). The primate mo‐

tor thalamus. Brain research Brain research reviews. 22 (2): 93-181.

Naoki Tani1

**References**

314 (2): 319-349.

(Suppl 3): S9-14.

Mov Disord. 17 (Suppl 3): S2-S8.

bellar disease. J Neurophysiol. 87 (4): 2084-94.

p. 230-290.

#### **4.5. Adverse events**

The stimulation-induced side effects of Vim DBS are reversible, and usually mild and accept‐ able. Incidences of stimulation-related complications reported at long-term (greater than 5 years) follow-up include paresthesia (4–38%), dysarthria (3–36%), dystonia/hypertonia (3– 16%), gait disturbance (11–16%), balance disturbance (5%), and cognitive dysfunction (2%). Among these adverse effects, non-adjustable and long-lasting complications include dysarth‐ ria (10–27%), paresthesia (16%), gait disturbance (7%), dystonia (5%), upper limb ataxia (3– 4%), and disequilibrium (3–4%) [88, 100, 101]. Pahwa et al. [101] described occurrences of persistent complications, including dysarthria, disequilibrium, and gait disturbance, after bilateral stimulation, even when the stimulus parameters were optimized.

The incidence of infection appears to be 0–11% during the early follow-up periods and 0– 8% throughout the postoperative course [87, 88, 100]. Hardware failures are occasionally found in the stimulator (0–3%), the DBS lead (0–8%), or the cable (0–3%); skin erosion (0– 4%) and hematoma requiring evacuation of the stimulator (0–3%) have also been reported [87, 88, 100].

## **5. Conclusions**

Vim DBS is an appropriate first-line treatment for medically intractable tremor in patients with PD. Although its therapeutic effects on ADL outcome decreases gradually after the surgery, long-term tremor suppression remains stable. We suggest that Vim DBS is useful for patients with tremor-dominant PD, who manifest slow progression of disease and a good response of non-tremor PD symptoms to dopaminergic therapy.

## **Acknowledgements**

This work was supported in part by the Grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant-in-aid for Scientific Research, 23500428; 21390269; 23659458; 24390223).

## **Author details**

after the 1-year stimulation, the parameters seemed to stabilize. By contrast, Kumar et al. [90] reported that it was necessary to increase the current intensity over time to control tremor. This increase in amplitude is undesirable, as it often causes paresthesia and cerebellar adverse effects [83, 91]. During the follow-up, some tolerance (necessity to gradually increase the voltage to control tremor) and a rebound effect (tremor much worse than before when the stimulator is switched off) can develop [86, 89]. This affects an action tremor more frequently. Switching off the stimulator at night can sometimes limit the tolerance effect. Recurrence of

The stimulation-induced side effects of Vim DBS are reversible, and usually mild and accept‐ able. Incidences of stimulation-related complications reported at long-term (greater than 5 years) follow-up include paresthesia (4–38%), dysarthria (3–36%), dystonia/hypertonia (3– 16%), gait disturbance (11–16%), balance disturbance (5%), and cognitive dysfunction (2%). Among these adverse effects, non-adjustable and long-lasting complications include dysarth‐ ria (10–27%), paresthesia (16%), gait disturbance (7%), dystonia (5%), upper limb ataxia (3– 4%), and disequilibrium (3–4%) [88, 100, 101]. Pahwa et al. [101] described occurrences of persistent complications, including dysarthria, disequilibrium, and gait disturbance, after

The incidence of infection appears to be 0–11% during the early follow-up periods and 0– 8% throughout the postoperative course [87, 88, 100]. Hardware failures are occasionally found in the stimulator (0–3%), the DBS lead (0–8%), or the cable (0–3%); skin erosion (0– 4%) and hematoma requiring evacuation of the stimulator (0–3%) have also been reported

Vim DBS is an appropriate first-line treatment for medically intractable tremor in patients with PD. Although its therapeutic effects on ADL outcome decreases gradually after the surgery, long-term tremor suppression remains stable. We suggest that Vim DBS is useful for patients with tremor-dominant PD, who manifest slow progression of disease and a good response of

This work was supported in part by the Grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant-in-aid for Scientific Research, 23500428; 21390269;

tremor is seen in ~5% of patients several weeks or years after surgery [83, 92].

bilateral stimulation, even when the stimulus parameters were optimized.

non-tremor PD symptoms to dopaminergic therapy.

**4.5. Adverse events**

200 A Synopsis of Parkinson's Disease

[87, 88, 100].

**5. Conclusions**

**Acknowledgements**

23659458; 24390223).

Naoki Tani1 , Ryoma Morigaki2 , Ryuji Kaji3 and Satoshi Goto2

\*Address all correspondence to: sgoto@clin.med.tokushima-u.ac.jp

1 Department of Neurosurgery, Otemae Hospital, Osaka, Japan

2 Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Bioscien‐ ces, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan

3 Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan

## **References**


[9] Sakai, ST.; Inase, M. & Tanji, J. (1996). Comparison of cerebellothalamic and pallido‐ thalamic projections in the monkey (Macaca fuscata): a double anterograde labeling study. J Comp Neurol. 368 (2): 215-228.

[22] Selikhova, M.; Williams, DR.; Kempster, PA.; Holton, JL.; Revesz, T. & Lees, AJ. (2009). A clinico-pathological study of subtypes in Parkinson's disease. Brain. 132 (Pt

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

203

[23] Kaufman, MJ. & Madras, BK. (1991). Severe depletion of cocaine recognition sites as‐ sociated with the dopamine transporter in Parkinson's-diseased striatum. Synapse. 9

[24] Niznik, HB.; Fogel, EF.; Fassos, FF. & Seeman, P. (1991). The dopamine transporter is absent in parkinsonian putamen and reduced in the caudate nucleus. J Neurochem.

[25] Seibyl, JP.; Marek, K.; Sheff, K.; Zoghbi, S.; Baldwin, RM.; Charney, DS., van Dyck, CH. & Innis, RB. (1998). Iodine-123-beta-CIT and iodine-123-FPCIT SPECT measure‐ ment of dopamine transporters in healthy subjects and Parkinson's patients. J Nucl

[26] Helmich, RC.; Janssen, MJ.; Oyen, WJ.; Bloem, BR. & Toni, I. (2011). Pallidal dysfunc‐ tion drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 69 (2):

[27] Rossi C, Frosini D, Volterrani D, De Feo P, Unti E, Nicoletti V, et al. Differences in nigro-striatal impairment in clinical variants of early Parkinson's disease: evidence from a FP-CIT SPECT study. European journal of neurology : the official journal of

[28] Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, Kirsch, CM. & Dillmann, U. (2007). Striatal FP-CIT uptake differs in the subtypes of early Parkin‐

[29] Magistretti, PJ.; Pellerin, L.; Rothman, DL. & Shulman, RG. (1999). Energy on de‐

[30] Mure, H.; Hirano, S.; Tang, CC.; Isaias, IU.; Antonini, A.; Ma, Y.; Dhawan, V. & Eidel‐ berg, D. (2011). Parkinson's disease tremor-related metabolic network: characteriza‐

[31] Parker, F.; Tzourio, N.; Blond, S.; Petit, H. & Mazoyer, B. (1992). Evidence for a com‐ mon network of brain structures involved in parkinsonian tremor and voluntary re‐

[32] Boecker, H.; Wills, AJ.; Ceballos-Baumann, A.; Samuel, M.; Thomas, DG.; Marsden, CD. & Brooks, DJ. (1997). Stereotactic thalamotomy in tremor-dominant Parkinson's

[33] Wielepp, JP.; Burgunder, JM.; Pohle, T.; Ritter, EP.; Kinser, JA. & Krauss, JK. (2001). Deactivation of thalamocortical activity is responsible for suppression of parkinsoni‐ an tremor by thalamic stimulation: a 99mTc-ECD SPECT study. Clin Neurol Neuro‐

disease: an H2(15)O PET motor activation study. Ann Neurol. 41 (1): 108-111.

tion, progression, and treatment effects. Neuroimage. 54 (2): 1244-1253.

the European Federation of Neurological Societies. 2010; 17(4): 626-30.

son's disease. J Neural Transm. 114 (3): 331-335.

petitive movement. Brain Res. 584 (1-2): 11-17.

mand. Science. 283 (5401): 496-497.

surg. 103 (4): 228-231.

11): 2947-2957.

56 (1): 192-198.

Med. 39 (9): 1500-1508.

(1): 43-49.

269-281.


[22] Selikhova, M.; Williams, DR.; Kempster, PA.; Holton, JL.; Revesz, T. & Lees, AJ. (2009). A clinico-pathological study of subtypes in Parkinson's disease. Brain. 132 (Pt 11): 2947-2957.

[9] Sakai, ST.; Inase, M. & Tanji, J. (1996). Comparison of cerebellothalamic and pallido‐ thalamic projections in the monkey (Macaca fuscata): a double anterograde labeling

[10] Gallay, MN.; Jeanmonod, D.; Liu, J. & Morel, A. (2008). Human pallidothalamic and cerebellothalamic tracts: anatomical basis for functional stereotactic neurosurgery.

[11] Strick, PL. (1976). Activity of ventrolateral thalamic neurons during arm movement.

[12] Asanuma, C.; Thach, WR.; & Jones, EG. (1983). Anatomical evidence for segregated focal groupings of efferent cells and their terminal ramifications in the cerebellothala‐

[13] Vitek, JL.; Ashe, J.; DeLong, MR. & Alexander, GE. (1994). Physiologic properties and somatotopic organization of the primate motor thalamus. J Neurophysiol. 71 (4):

[14] Vitek, JL.; Ashe, J,; DeLong, MR. & Kaneoke, Y. (1996). Microstimulation of primate motor thalamus: somatotopic organization and differential distribution of evoked

[15] Rispal-Padel, L.; Harnois, C. & Troiani, D. (1987). Converging cerebellofugal inputs to the thalamus. I. Mapping of monosynaptic field potentials in the ventrolateral nu‐

[16] Rispal-Padel, L.; Troiani, D. & Harnois, C. (1987). Converging cerebellofugal inputs to the thalamus. II. Analysis and topography of thalamic EPSPs induced by conver‐ gent monosynaptic interpositus and dentate inputs. Exp Brain Res. 68 (1): 59-72. [17] Craig, AD. (2008). Retrograde analyses of spinothalamic projections in the macaque monkey: input to the ventral lateral nucleus. J Comp Neurol. 508 (2): 315-328.

[18] Stochl, J.; Boomsma, A.; Ruzicka, E.; Brozova, H. & Blahus, P. (2008). On the structure of motor symptoms of Parkinson's disease. Mov Disord. 23 (9): 1307-1312.

[19] Rajput, AH.; Voll, A.; Rajput, ML.; Robinson, CA. & Rajput, A. (2009). Course in Par‐ kinson disease subtypes: A 39-year clinicopathologic study. Neurology. 73 (3):

[20] Paulus, W. & Jellinger, K. (1991). The neuropathologic basis of different clinical sub‐ groups of Parkinson's disease. J Neuropathol Exp Neurol. 50 (6): 743-755.

[21] Hirsch, EC.; Mouatt, A.; Faucheux, B.; Bonnet, AM.; Javoy-Agid, F.; Graybiel, AM. & Agid, Y. (1992). Dopamine, tremor, and Parkinson's disease. Lancet. 340 (8811):

motor responses among subnuclei. J Neurophysiol. 75(6): 2486-95.

study. J Comp Neurol. 368 (2): 215-228.

Brain Struct Funct. 212 (6): 443-463.

1498-1513.

202 A Synopsis of Parkinson's Disease

206-212.

125-126.

Journal of neurophysiology. 39 (5): 1032-1044.

mic pathway of the monkey. Brain Res. 286 (3): 267-297.

cleus of the thalamus. Exp Brain Res. 68 (1): 47-58.


[34] Rezai, AR.; Lozano, AM.; Crawley, AP.; Joy, ML.; Davis, KD.; Kwan, CL.; Dostrov‐ sky, JO.; Tasker, RR. & Mikulis, DJ. (1999). Thalamic stimulation and functional mag‐ netic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. J Neurosurg. 90 (3): 583-590.

[46] Lamarre, Y. & Joffroy, A. Experimental tremor in monkey: activity of thalamic and precentral cortical neurons in the absence of peripheral feedback. In: Poirier LJ, Sourkes TI, Bedard P, editors. Adcances in Neurology. New York: Raven Press; 1979.

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

205

[47] Ohye, C.; Bouchard, R.; Larochelle, L.; Bedard, P.; Boucher, R.; Raphy, B. & Poirier, LJ. (1970). Effect of dorsal rhizotomy on postural tremor in the monkey. Exp Brain

[48] Lee, RG. & Stein, RB. (1981). Resetting of tremor by mechanical perturbations: a com‐ parison of essential tremor and parkinsonian tremor. Ann Neurol. 10 (6): 523-531. [49] Kobayashi, K.; Katayama, Y.; Kasai, M.; Oshima, H.; Fukaya, C. & Yamamoto, T. (2003). Localization of thalamic cells with tremor-frequency activity in Parkinson's

[50] Brodkey, JA.; Tasker, RR.; Hamani, C.; McAndrews, MP.; Dostrovsky, JO. & Lozano, AM. (2004). Tremor cells in the human thalamus: differences among neurological dis‐

[51] Hirai, T.; Shibazaki, T.; Nakajima, H.; Imai, S. & Ohye, C. (1979). Minimal effective lesion in the stereotactic treatment of tremor. Appl Neurophysiol. 42 (5): 307-308. [52] Nagaseki, Y.; Shibazaki, T.; Hirai, T.; Kawashima, Y.; Hirato, M.; Wada, H.; Wada, H.; Miyazaki, M. & Ohye, C. (1986). Long-term follow-up results of selective VIM-

[53] Katayama, Y.; Kano, T.; Kobayashi, K.; Oshima, H.; Fukaya, C. & Yamamoto, T. (2005). Difference in surgical strategies between thalamotomy and thalamic deep brain stimulation for tremor control. Journal of neurology. 252 (Suppl 4): IV17-IV22.

[54] Hariz, MI. & Hirabayashi, H. (1997). Is there a relationship between size and site of the stereotactic lesion and symptomatic results of pallidotomy and thalamotomy?

[55] Atkinson, JD.; Collins, DL.; Bertrand, G.; Peters, TM.; Pike, GB. & Sadikot, AF. (2002). Optimal location of thalamotomy lesions for tremor associated with Parkinson dis‐ ease: a probabilistic analysis based on postoperative magnetic resonance imaging

[56] Schnitzler, A. & Gross, J. (2005). Normal and pathological oscillatory communication

[57] Hutchison, WD.; Dostrovsky, JO.; Walters, JR.; Courtemanche, R.; Boraud, T.; Gold‐ berg, J. & Brown, P. (2004). Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings. J Neurosci. 24 (42):

disease and essential tremor. Acta Neurochir. 87 (Suppl): 137-139.

p. 109-122.

Res. 10 (2): 140-150.

orders. J Neurosurg. 101 (1): 43-47.

thalamotomy. J Neurosurg. 65 (3): 296-302.

Stereotact Funct Neurosurg. 69 (1-4 Pt 2): 28-45.

in the brain. Nat Rev Neurosci. 6 (4): 285-296.

9240-9243.

and an integrated digital atlas. J Neurosurg. 96 (5): 854-866.


[46] Lamarre, Y. & Joffroy, A. Experimental tremor in monkey: activity of thalamic and precentral cortical neurons in the absence of peripheral feedback. In: Poirier LJ, Sourkes TI, Bedard P, editors. Adcances in Neurology. New York: Raven Press; 1979. p. 109-122.

[34] Rezai, AR.; Lozano, AM.; Crawley, AP.; Joy, ML.; Davis, KD.; Kwan, CL.; Dostrov‐ sky, JO.; Tasker, RR. & Mikulis, DJ. (1999). Thalamic stimulation and functional mag‐ netic resonance imaging: localization of cortical and subcortical activation with

[35] Perlmutter, JS.; Mink, JW.; Bastian, AJ.; Zackowski, K.; Hershey, T.; Miyawaki, E.; Koller, W. & Videen, TO. (2002). Blood flow responses to deep brain stimulation of

[36] Haslinger, B.; Boecker, H.; Buchel, C.; Vesper, J.; Tronnier, VM.; Pfister, R.; Alesch, F.; Moringlane, JR.; Krauss, JK.; Conrad, B.; Schwaiger, M. & Ceballos-Baumann, AO. (2003). Differential modulation of subcortical target and cortex during deep brain

[37] Fukuda M, Barnes A, Simon ES, Holmes A, Dhawan V, Giladi N, Fodstad H, Ma Y, Eidelberg D. (2004). Thalamic stimulation for parkinsonian tremor: correlation be‐ tween regional cerebral blood flow and physiological tremor characteristics. Neuro‐

[38] Perlmutter, JS. & Mink, JW. (2006). Deep brain stimulation. Ann Rev Neurosci. 29:

[39] Ohye, C. & Narabayashi, H. (1979). Physiological study of presumed ventralis inter‐

[40] Ohye, C.; Shibazaki, T.; Hirai, T.; Wada, H.; Hirato, M. & Kawashima, Y. (1989). Fur‐ ther physiological observations on the ventralis intermedius neurons in the human

[41] Kiss, ZH.; Davis, KD.; Tasker, RR.; Lozano, AM.; Hu, B. & Dostrovsky, JO. (2003). Kinaesthetic neurons in thalamus of humans with and without tremor. Exp Brain

[42] Lenz, FA.; Kwan, HC.; Dostrovsky, JO.; Tasker, RR.; Murphy, JT. & Lenz, YE. (1990). Single unit analysis of the human ventral thalamic nuclear group. Activity correlated

[43] Lenz, FA.; Kwan, HC.; Martin, RL.; Tasker, RR.; Dostrovsky, JO. & Lenz, YE. (1994). Single unit analysis of the human ventral thalamic nuclear group. Tremor-related ac‐

[44] Lenz, FA.; Tasker, RR.; Kwan, HC.; Schnider, S.; Kwong, R.; Murayama, Y.; Dostrov‐ sky, JO. & Murphy, JT. (1988). Single unit analysis of the human ventral thalamic nu‐ clear group: correlation of thalamic "tremor cells" with the 3-6 Hz component of

[45] Ohye, C.; Saito, U.; Fukamachi, A. & Narabayashi, H. (1974). An analysis of the spon‐ taneous rhythmic and non-rhythmic burst discharges in the human thalamus. J Neu‐

tivity in functionally identified cells. Brain. 117 ( Pt 3): 531-543.

medius neurons in the human thalamus. J Neurosurg. 50 (3): 290-297.

implanted electrodes. J Neurosurg. 90 (3): 583-590.

thalamus. Neurology. 58 (9): 1388-1394.

stimulation. Neuroimage. 18 (2): 517-524.

thalamus. J Neurophysiol. 61 (3): 488-500.

with movement. Brain. 113 ( Pt 6): 1795-1821.

parkinsonian tremor. J Neurosci. 8 (3): 754-764.

image. 21 (2): 608-615.

Res. 150 (1): 85-94.

rol Sci. 22 (2): 245-259.

229-257.

204 A Synopsis of Parkinson's Disease


[58] Timmermann, L.; Gross, J.; Dirks, M.; Volkmann, J.; Freund, HJ. & Schnitzler, A. (2003). The cerebral oscillatory network of parkinsonian resting tremor. Brain. 126 (Pt 1): 199-212.

[70] Bronte-Stewart, H.; Barberini, C.; Koop, MM.; Hill, BC.; Henderson, JM. & Wingeier, B. (2009). The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation. Exp Neurol. 215 (1): 20-28.

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

207

[71] Ray, NJ.; Jenkinson, N.; Wang, S.; Holland, P.; Brittain, JS.; Joint, C.; Stein, JF. & Aziz, T. (2008). Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dop‐

[72] Kühn, AA.; Kupsch, A.; Schneider, GH. & Brown, P. (2006). Reduction in subthala‐ mic 8-35 Hz oscillatory activity correlates with clinical improvement in Parkinson's

[73] Brown, P.; Oliviero, A.; Mazzone, P.; Insola, A.: Tonali, P. & Di Lazzaro, V. (2001). Dopamine dependency of oscillations between subthalamic nucleus and pallidum in

[74] Fogelson, N.; Kuhn, AA.; Silberstein, P.; Limousin, PD.; Hariz, M.; Trottenberg, T.; Kupsch, A. & Brown, P. (2005). Frequency dependent effects of subthalamic nucleus

[75] Chen, CC.; Litvak, V.; Gilbertson, T.; Kuhn, A.; Lu, CS.; Lee, ST.; Tsai, CH.; Tisch, S.; Limousin, P.; Hariz, M. & Brown, P. (2007). Excessive synchronization of basal gan‐ glia neurons at 20 Hz slows movement in Parkinson's disease. Exp Neurol. 205 (1):

[76] Eusebio, A.; Chen, CC.; Lu, CS.; Lee, ST.; Tsai, CH.; Limousin, P.; Hariz, M. & Brown, P. (2008). Effects of low-frequency stimulation of the subthalamic nucleus on move‐

[77] Reck, C.; Florin, E.; Wojtecki, L.; Krause, H.; Groiss, S.; Voges, J.; Maarouf, M.; Sturm, V.; Schnitzler, A. & Timmermann, L. (2009). Characterisation of tremor-associated lo‐ cal field potentials in the subthalamic nucleus in Parkinson's disease. Eur J Neurosci.

[78] Reck, C.; Himmel, M.; Florin, E.; Maarouf, M.; Sturm, V.; Wojtecki, L.; Schnitzler, A.; Fink, GR. & Timmermann, L. (2010). Coherence analysis of local field potentials in the subthalamic nucleus: differences in parkinsonian rest and postural tremor. Eur J

[79] Gildenberg, PL. History of Movement Disorder Surgery. In: Lozano A, editor. Move‐

[80] Kelly PJ. Stereotactic thalamotomies. In: Koller W, Pulson G, editors. Therapy of Par‐

[81] Guridi, J. & Lozano, AM. (1997). A brief history of pallidotomy. Neurosurgery. 41(5):

ment Disorder Surgery Prog Neurol Surg. Basel: Karger; 2000. p. 1-20.

kinson's Disease. 2nd ed. New York: Mecel Dekker; 1995. p. 331-351.

amine and deep brain stimulation. Exp Neurol. 213 (1): 108-113.

stimulation in Parkinson's disease. Neurosci Lett. 382 (1-2): 5-9.

ment in Parkinson's disease. Exp Neurol. 209 (1): 125-130.

disease. Eur J Neurosci. 23 (7): 1956-1960.

214-221.

29 (3): 599-612.

1169-80.

Neurosci. 32 (7): 1202-1214.

Parkinson's disease. J Neurosci. 21 (3): 1033-1038.


[70] Bronte-Stewart, H.; Barberini, C.; Koop, MM.; Hill, BC.; Henderson, JM. & Wingeier, B. (2009). The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation. Exp Neurol. 215 (1): 20-28.

[58] Timmermann, L.; Gross, J.; Dirks, M.; Volkmann, J.; Freund, HJ. & Schnitzler, A. (2003). The cerebral oscillatory network of parkinsonian resting tremor. Brain. 126 (Pt

[59] Raz, A.; Vaadia, E. & Bergman, H. (2000). Firing patterns and correlations of sponta‐ neous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phe‐ nyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism. J Neurosci. 20 (22):

[60] Lemstra, AW.; Verhagen-Metman, L.; Lee, JI.; Dougherty, PM. & Lenz, FA. (1999). Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the in‐ ternal segment of the globus pallidus in patients with Parkinson's disease. Neurosci

[61] Hurtado, JM.; Rubchinsky, LL.; Sigvardt, KA.; Wheelock, VL. & Pappas, CT. (2005). Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson's

[62] Salenius, S.; Avikainen, S.; Kaakkola, S.; Hari, R. & Brown, P. (2002). Defective corti‐ cal drive to muscle in Parkinson's disease and its improvement with levodopa. Brain.

[63] Pollok, B.; Makhloufi, H.; Butz, M.; Gross, J.; Timmermann, L.; Wojtecki, L. & Schnit‐ zler, A. (2009). Levodopa affects functional brain networks in Parkinsonian resting

[64] Logothetis, NK. & Wandell, BA. (2004). Interpreting the BOLD signal. Annu Rev

[65] Wu, T.; Chan, P. & Hallett, M. (2010). Effective connectivity of neural networks in au‐ tomatic movements in Parkinson's disease. Neuroimage. 49 (3): 2581-2587.

[66] Brown, P. (2003). Oscillatory nature of human basal ganglia activity: relationship to

[67] Klostermann, F.; Nikulin, VV.; Kuhn, AA.; Marzinzik, F.; Wahl, M.; Pogosyan, A.; Kupsch, A.; Schneider, GH.; Brown, P. & Curio, G. (2007). Task-related differential dynamics of EEG alpha- and beta-band synchronization in cortico-basal motor struc‐

[68] Paradiso, G.; Cunic, D.; Saint-Cyr, JA.; Hoque, T.; Lozano, AM.; Lang, AE. & Chen, R. (2004). Involvement of human thalamus in the preparation of self-paced movement.

[69] Kühn, AA.; Williams, D.; Kupsch, A.; Limousin, P.; Hariz, M.; Schneider, GH.; Yar‐ row, K. & Brown, P. (2004). Event-related beta desynchronization in human subthala‐

mic nucleus correlates with motor performance. Brain. 127 (Pt 4): 735-746.

the pathophysiology of Parkinson's disease. Mov Disord. 18 (4): 357-363.

1): 199-212.

206 A Synopsis of Parkinson's Disease

8559-8571.

Lett. 267 (2): 1291-32.

125 (Pt 3): 491-500.

Physiol. 66: 735-769.

disease. J Neurophysiol. 93 (3): 1569-1584.

tremor. Mov Disord. 24 (1): 91-98.

tures. Eur J Neurosci. 25 (5): 1604-1615.

Brain. 127 (Pt 12): 2717-2731.


[82] Hassler, R.; Riechert, T.; Mundinger, F.; Umbach, W. & Ganglberger, JA. (1960). Phys‐ iological observations in stereotaxic operations in extrapyramidal motor disturban‐ ces. Brain. 83: 337-350.

[93] Wu, YR.; Levy, R.; Ashby, P.; Tasker, RR. & Dostrovsky, JO. (2001). Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Mov Disord. 16 (2):

Current Use of Thalamic Vim Stimulation in Treating Parkinson's Disease

http://dx.doi.org/10.5772/57105

209

[94] Montgomery, EBJr. & Baker, KB. (2000). Mechanisms of deep brain stimulation and future technical developments. Neurol Res. ogical research. 22 (3): 259-266.

[95] Vitek, JL. (2002). Mechanisms of deep brain stimulation: excitation or inhibition. Mov

[96] Anderson, TR.; Hu, B.; Iremonger, K. & Kiss, ZH. (2006). Selective attenuation of af‐ ferent synaptic transmission as a mechanism of thalamic deep brain stimulation-in‐

[97] Anderson, T.; Hu, B.; Pittman, Q. & Kiss, ZH. (2004). Mechanisms of deep brain stim‐ ulation: an intracellular study in rat thalamus. J Physiol. 559 (Pt 1): 301-313.

[98] Bekar, L.; Libionka, W.; Tian, GF.; Xu, Q.; Torres, A.; Wang, X.; Lovatt, D.; Williams, E.; Takano, T.; Schnermann, J.; Bakos, R. & Nedergaard, M. (2008). Adenosine is cru‐ cial for deep brain stimulation-mediated attenuation of tremor. Nat Med. 14 (1):

[99] Tawfik, VL.; Chang, SY.; Hitti, FL.; Roberts, DW.; Leiter, JC.; Jovanovic, S. & Lee, KH. (2010). Deep brain stimulation results in local glutamate and adenosine release: in‐

[100] Rehncrona, S.; Johnels, B.; Widner, H.; Tornqvist, AL.; Hariz, M. & Sydow, O. (2003). Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind as‐

[101] Pahwa, R.; Lyons, KE.; Wilkinson, SB.; Simpson, RKJr.; Ondo, WG.; Tarsy, D.; Norre‐ gaard, T.; Hubble, JP.; Smith, DA.; Hauser, RA. & Jankovic J. (2006). Long-term eval‐ uation of deep brain stimulation of the thalamus. J Neurosurg. 104 (4): 506-512.

vestigation into the role of astrocytes. Neurosurgery. 67 (2): 367-375.

208-216.

75-80.

Disord. 17 (Suppl 3): S69-S72.

duced tremor arrest. J Neurosci. 26 (3): 841-850.

sessments. Mov Disord. 18 (2): 163-170.


[93] Wu, YR.; Levy, R.; Ashby, P.; Tasker, RR. & Dostrovsky, JO. (2001). Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Mov Disord. 16 (2): 208-216.

[82] Hassler, R.; Riechert, T.; Mundinger, F.; Umbach, W. & Ganglberger, JA. (1960). Phys‐ iological observations in stereotaxic operations in extrapyramidal motor disturban‐

[83] Benabid, AL.; Pollak, P.; Gao, D.; Hoffmann, D.; Limousin, P.; Gay, E.; Payen, I. & Be‐ nazzouz, A. (1996). Chronic electrical stimulation of the ventralis intermedius nu‐ cleus of the thalamus as a treatment of movement disorders. J Neurosurg. 84 (2):

[84] Benabid, AL.; Pollak, P.; Gervason, C.; Hoffmann, D.; Gao, DM.; Hommel, M.; Perret, JE. & de Rougemont, J. (1991). Long-term suppression of tremor by chronic stimula‐

[85] Pollak, P.; Benabid, AL.; Limousin, P. & Benazzouz, A. (1997). Chronic intracerebral

[86] Koller, W.; Pahwa, R.; Busenbark, K.; Hubble, J.; Wilkinson, S.; Lang, A.; Tuite, P.; Sime, E.; Lozano, A.; Hauser, R.; Malapira, T.; Smith, D.; Tarsy, D.; Miyawaki, E.; Norregaard, T.; Kormos, T. & Olanow, CW. (1997). High-frequency unilateral thala‐ mic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol.

[87] Schuurman, PR.; Bosch, DA.; Merkus, MP. & Speelman, JD. (2008). Long-term fol‐ low-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov

[88] Hariz, MI.; Krack, P.; Alesch, F.; Augustinsson, LE.; Bosch, A.; Ekberg, L.; Johansson, F.; Johnels, B.; Meyerson, BA.; N'Guyen, JP.; Pinter, M.; Pollak, P.; von Raison, F.; Re‐ hncrona, S.; Speelman, JD.; Sydow, O. & Benabid, AL. (2008). Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up. J Neurol

[89] Hariz, MI.; Shamsgovara, P.; Johansson, F.; Hariz, G. & Fodstad, H. (1999). Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinso‐

[90] Kumar, K.; Kelly, M. & Toth, C. (1999). Deep brain stimulation of the ventral inter‐ mediate nucleus of the thalamus for control of tremors in Parkinson's disease and es‐

[91] Yamamoto, T.; Katayama, Y.; Kano, T.; Kobayashi, K.; Oshima, H. & Fukaya, C. (2004). Deep brain stimulation for the treatment of parkinsonian, essential, and post‐ stroke tremor: a suitable stimulation method and changes in effective stimulation in‐

[92] Tasker, RR. (1998). Deep brain stimulation is preferable to thalamotomy for tremor

nian and essential tremor. Stereotact Funct Neurosurg. 72 (2-4): 208-218.

sential tremor. Stereotact Funct Neurosurg. 72 (1): 47-61.

tion of the ventral intermediate thalamic nucleus. Lancet. 337 (8738): 403-406.

stimulation in Parkinson's disease. Adv Neurol. 74: 213-20.

ces. Brain. 83: 337-350.

203-214.

208 A Synopsis of Parkinson's Disease

42 (3): 292-299.

Disord. 23 (8): 1146-1153.

Neurosurg Psychiatry. 79 (6): 694-699.

tensity. J Neurosurg. 101 (2): 201-209.

suppression. Surg Neurol. 49 (2): 145-153.


**Chapter 9**

**Deep Brain Stimulation for**

**Camptocormia Associated**

Naoki Tani, Ryuji Kaji and Satoshi Goto

Additional information is available at the end of the chapter

of medically refractory camptocormia in patients with PD.

Camptocormia, which is also known as bent spine syndrome, is characterized by abnormal posture of the trunk with marked forward flexion of the thoracolumbar spine, which increases during standing and walking and abates in the recumbent position (Azher & Jankovic, 2005). Camptocormia is a disabling symptom that occurs during the course of Parkinson's disease (PD), but the optimized medical and surgical therapy for PD-associated camptocormia remains to be established (Finsterer & Strobl, 2010; Doherty et al., 2011). PD-associated camptocormia is generally thought to be unresponsive to levodopa (Azher & Jankovic, 2005). In most patients with PD, the extreme anterior bending is not or poorly improved, or even worsened, in response to levodopa administration, and the severity of the bent spine is often unchanged during the medication-on and -off phases (Melamed & Djaldetti, 2006), although an excep‐ tional case has been reported (Ho et al., 2007). Although some reports have shown that deep brain stimulation (DBS) in the subthalamic nucleus (STN) (Hellmann et al., 2006; Yamada et al., 2006; Sako et al., 2009; Umemura et al., 2010; Capelle et al., 2011; Asahi et al., 2011) and globus pallidus internus (GPi) (Micheli et al., 2005; Capelle et al., 2011; Thani et al., 2011) is effective in treating camptocormia, the overall efficacy of DBS in relieving PD-associated camptocormia has not been determined. This review introduces the use of DBS in the treatment

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**with Parkinson's Disease**

http://dx.doi.org/10.5772/57103

**1. Introduction**

**Chapter 9**
