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THEMED ARTICLE y Parkinson’s Disease

Review

New targets for deep brain stimulation treatment of Parkinson’s disease Expert Rev. Neurother. 13(12), 1319–1328 (2013)

Anna Castrioto1,2 and Elena Moro*1 1 Movement Disorders Centre, Department of Psychiatry and Neurology, CHU de Grenoble – CS10217, 38043 Grenoble Cedex 09, France 2 Clinica Neurologica, Universita` di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy *Author for correspondence: Tel.: +33 047 676 9452 Fax: +33 047 676 5631 [email protected] [email protected]

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) has been shown to be an effective treatment for patients with Parkinson’s disease. Strong clinical evidence supports the improvement of motor and non-motor complications and quality of life, with some data suggesting that GPi DBS might be less effective than STN DBS. However, neither STN nor GPi stimulation provides a satisfactory control of non-dopaminergic symptoms, such as gait and balance impairment and cognitive decline, which are frequent and disabling symptoms in advanced Parkinson’s disease patients. Therefore, several efforts have been made to discover alternative and new targets to overcome these current DBS limitations. Among these new targets, the stimulation of the pedunculopontine nucleus has initially appeared encouraging. However, findings from different double-blind trials have mitigated the enthusiasm. A multi-target strategy aimed at improving symptoms with different pathogenetic mechanisms might be a promising approach in the next years. KEYWORDS: basal ganglia • centromedian-parafascicular complex • closed-loop stimulation • deep brain stimulation • mesencephalic locomotor region • Parkinson’s disease • pedunculopontine nucleus • substantia nigra • zona incerta

The treatment of Parkinson’s disease (PD) has been revolutionized by the introduction of deep brain stimulation (DBS) surgery, a procedure which allows delivering continuous current to brain targets. The first systematic application of DBS in PD dates back to 1987, when Benabid et al. targeted the thalamic ventral intermediate nucleus (Vim) for the treatment of tremor [1]. Since then, DBS has become an established treatment in PD and other movement disorders, and other brain structures, besides Vim, have been studied, that is, the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi). It became evident that the stimulation of Vim allowed only the control of tremor, whereas subthalamic and pallidal stimulation also improved rigidity and bradykinesia. STN DBS has been shown to be superior to the best medical treatment in the control of motor fluctuations and dyskinesia, and in the improvement of quality of life [2,3]. Its effects have been shown to persist over many years [4]. Hence, the STN has become the most widely used DBS target. Although STN stimulation represents a breakthrough in the treatment of PD, it does www.expert-reviews.com

10.1586/14737175.2013.859987

not satisfactorily improve the symptoms that do not respond to dopaminergic treatment, such as axial signs (postural instability, freezing of gait, posture abnormalities, dysarthria) and cognitive decline. These symptoms are the main source of disability for patients with advanced PD, the main burden for their caregivers and the main challenge to deal with for physicians. The pathogenesis of these symptoms appears to be complex and linked to the involvement of non-dopaminergic structures. Therefore, DBS of different new brain targets is under investigation. In this review, we will focus on new experimental brain targets for PD, and specifically the pedunculopontine nucleus (PPN), the caudal zona incerta (cZi), the thalamic centromedian-parafascicular (CMPf)complex, the substantia nigra pars reticulate (SNr), and we will also discuss different therapeutic strategies, such as multi-target stimulation. The pedunculopontine nucleus

The PPN is part of the so-called mesencephalic locomotor region, a functional area of

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Table 1. Studies on pedunculopontine nucleus stimulation†. Study (year)

Patients (n)

Target

Study design

Outcome

Ref.

Stefani et al. (2007)

6

Bil PPN + STN

2–6 months assessment

Improvement of UPDRS scores

[23]

Moro et al. (2010)

6

Unil PPN

Double-blind assessment ON vs OFF stimulation at 3 & 12 months

No improvement in UPDRS III; Improvement in falls (UPDRS II)

[25]

Ferraye et al. (2010)

6 PD with STN stim

Bil PPN + STN

1 year; double-blind crossover at 4–6 months

Improvement of FoG & falls related to FoG at 1 year; no improvement in the double-blind assessment

[24]

Thevathasan et al. (2011)

5 PD

Bil PPN

2-year gait and falls questionnaire

Improvement at 2 years; no significant improvement in UPDRS scores for gait and postural stability

[26]

Khan et al. (2011)

7 PD

Bil PPN + cZi

Preop and 1-year postop off-on meds, off-on stim assessment

Improvement of motor and axial signs off meds with PPN, cZi both on; improvement of axial scores on meds with combined cZi-PPN stim

[27]

† Only studies with preoperative and postoperative assessments and with postoperative changes compared with before surgery were included. cZi: Caudal zona incerta; FoG: Freezing of gait; PD: Parkinson’s disease; PPN: Pedunculopontine nucleus; STN: Subthalamic nucleus; UPDRS: Unified Parkinson’s Disease Rating Scale.

the mesencephalon with a crucial role in locomotion [5]. Electrical stimulation of this area can induce controlled locomotion on a treadmill in decerebrated animals [6–9]. The PPN receives inputs from the cortex, the limbic system, the basal ganglia, the spinal cord and the brainstem, especially the ascending activating reticular system. Its efferents include an ascending system toward the thalamus and the basal ganglia (mainly the STN and the SN), and a descending system toward the cerebellum and the spinal cord [5]. The PPN is bounded laterally by the medial lemniscus, and medially by the superior cerebellar peduncle and its decussation. Rostrally, its anterior part reaches the SN and its posterior part the retrorubral field. Caudally, it contacts the pontine reticular formation ventrally, and dorsally the cuneiform and subcuneiform nuclei. The most caudal pole of the PPN is adjacent to the locus coeruleus [5]. The PPN consists of two parts: the pars dissipata, located at the rostrocaudal axis and composed by different neuron subtypes (cholinergic, glutamatergic and other types), and the pars compacta (PPNc), located dorsolaterally with a higher population of cholinergic neurons [10]. Experimental studies suggest that both GABA and acetlcholine reduce cholinergic PPN activity and locomotion, whereas glutamate increases cholinergic activity and locomotion [5]. In primate studies, unilateral radiofrequency lesions of the PPN induced transient akinesia, whether bilateral lesions caused sustained akinesia [11]. Excitotoxic unilateral lesions of the PPN with kainic acid produced contralateral hemiparkinsonism with a flexed posture [12]. A recent study has showed that in non-parkinsonian monkeys cholinergic lesions within the PPN induced posture and gait disorders which were not improved by apomorphine [13]. In humans, a key role of the PPN in gait and posture has been suggested 1320

by the occurrence of the inability to stand and walk after a hemorrhage into the tegmentum of the posterior midbrain [14]. In healthy humans, an increased activation of mesencephalic locomotor region, more particularly of the PPN, has been shown in a recent fMRI study during fast imagined gait compared with normal imagined gait [13]. PD patients with freezing of gait presented with an increased activation of the mesencephalic locomotor region compared with PD patients without freezing [15]. Neuropathological studies in PD patients have showed a degeneration of nearly 50% of the PPNc cholinergic neurons [16–18]. Moreover, a more pronounced cholinergic loss within the PPN has been found in PD patients with postural instability compared with those without postural instability [13]. In non-human primate studies, application of the GABA inhibitor bicuculline or low-frequency stimulation (10–30 Hz) of the PPN increased motor activity, whereas high frequency stimulation achieved opposite results (decreased motor activity) [19,20]. In 2005, two independent groups firstly reported promising results of bilateral PPN stimulation in PD patients [21,22]. Following these reports, other studies investigated the effects of PPN DBS in PD (TABLE 1), with mixed results [23–29]. Moro et al. studied the effects of unilateral PPN stimulation in six PD patients. At 3 and 12 months of follow-up, the double-blind assessments did not show any significant improvement in the motor scores [25]. Nevertheless, there was a significant reduction in falls 1 year after surgery [25]. In another study, the effects of bilateral PPN stimulation was investigated in six PD patients with severe freezing and previous bilateral STN DBS surgery. There was an improvement of freezing in the off-medication state at 1 year after surgery, but no improvement in the double-blind assessments [24]. Interestingly, Expert Rev. Neurother. 13(12), (2013)

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Table 2. Studies on posterior subthalamic area/caudal zona incerta. Study (year)

Follow-up (months)

Study

PD patients (n)

Target

Tremor

Rigidity

Bradykinesia

Ref.

Velasco et al. (2001)

12

Preoperative vs postoperative

10

Raprl

#

#

No change

[49]

Kitagawa et al. (2005)

24

On vs off stimulation off-meds

8

Zi/Raprl

# (78%)

# (92.7%)

# (65.7%)

[50]

Plaha et al. (2006)

6

On vs off stimulation off-meds

27

cZi

# (93%)

# (76%)

# (65%)

[48]

20

Dorsomedial to STN

# (86%)

# (52%)

# (56%)

17

STN

# (61%)

# (50%)

# (59%)

Carrillo-Ruiz et al. (2008)

12

Postoperative vs preoperative

5

Raprl

# (90%)

# (94%)

# (75%)

[51]

Blomstedt et al. (2012)

18

On vs off stimulation off-meds

14 (13 unilateral, 1 bilateral)

cZi

# (82.2%)

# (34.3%)

# (26.7%)

[52]

cZi: Caudal zona incerta; PD: Parkinson’s disease; Raprl: Prelemniscal radiation.

patients with electrodes located more posteriorly presented with the best improvement, suggesting also a possible involvement of the cuneiform and sub-cuneiform nuclei [24]. Thevathasan et al. reported an improvement of gait and falls with bilateral PPN stimulation 2 years after surgery [26]. In a double-blind study assessing seven PD patients with bilateral PPN stimulation using gait analysis during unilateral, bilateral and OFF-stimulation, bilateral PPN stimulation was able to better improve objective freezing of gait, but not deficits in step length [30]. These findings [30], as well as those of another study comparing bilateral and unilateral PPN with and without cZi stimulation [28], suggest that bilateral PPN stimulation might be more effective than unilateral stimulation. However, another study performing gait analysis in five PD patients with bilateral STN and PPN stimulation during different conditions of stimulation and medication, found no additional effects of stimulation in the on-medication condition, and an improvement of some kinematic variables only when both targets were stimulated in the off-medication condition, suggesting a synergistic effects of STN and PPN DBS [31]. PPN stimulation might influence the quality of sleep by increasing the REM sleep, as documented with polysomnography studies [32]. Interestingly, it has been reported that PPN stimulation could increase alertness at low frequency [23,33], whereas it induced non-rapid eye movement sleep at higher frequency [33]. As such, the increase of alertness might somehow contribute also to the improvement of freezing and falling observed with PPN DBS. However, in a study investigating the reaction time in PD patients with PPN stimulation there was more an improvement of speed of the reaction time rather than of accuracy, suggesting that the improvement in gait and falling could be independent from attention [34]. Low-frequency stimulation (below 70 Hz) appears to be more effective than high-frequency stimulation, although different ranges of www.expert-reviews.com

frequencies have been used in the different studies [35]. The increase of stimulation parameters can be limited by the occurrence of contralateral paresthesia (linked to the current diffusion to the medial lemniscus), oscillopsia (likely due to the current diffusion to fibers from the uncinate fasciculus of the cerebellum and the superior cerebellar peduncle) [36], and myoclonus (probably due to the stimulation to the thalamic projections) [24,37]. It has also been reported a progressive loss of benefit [23] and the development of tolerance to PPN stimulation, requiring an overnight arrest of the stimulation [24]. In conclusion, the clinical results of PPN stimulation in PD are still inconsistent. Several reasons might explain these discrepancies. One of the main drawbacks is due to the difficulty in targeting the PPN (lack of clear neurophysiological activity and acute clinical benefit during surgery), often resulting in targeting and stimulating different brain regions. Indeed, the electrode location varies substantially among the studies [10,24,25,38–42]. To this regard, since the PPN nucleus is a heterogeneous nucleus, with boundaries not well defined, novel alternative MRI-based targeting has been proposed as more accurate than traditional atlas targeting [43]. Moreover, it is not clear whether the best site of stimulation is within the PPN or the adjacent areas (i.e., the subcuneiform nucleus). Additionally, studies on PPN stimulation have enrolled a limited number of patients and have used different inclusion criteria. Other issues in interpreting the results are represented by the use of bilateral [23,24,26] versus unilateral stimulation [25], as well as of isolated PPN stimulation [26] versus combined PPN and STN [23,24] or STN area stimulation [27–29]. The stimulation of one target indeed might influence the activity of the other [35]. As such, data on PPN stimulation need to be confirmed by larger and better focused studies.

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The posterior subthalamic area/cZi

Recently, the posterior subthalamic area (PSA) has been suggested as an alternative DBS target for PD (TABLE 2). This is not a new target, because lesions had extensively been done in this area for the control of tremor [44–46]. The PSA is located below the ventral thalamus, lateral to the red nucleus and posteromedial to the STN [46]. It includes the zona incerta (ZI) and the prelemniscal radiation. The ZI is a small cellular nucleus that covers the STN, lying between the fields of Forel. The pallidothalamic tract is composed by the ansa lenticularis and the fasciculus lenticularis (or Forel field H2), both taking origin from the GPi [47]. The two fibers tracts merge into the fasciculus thalamicus (or Forel field H1) before entering the thalamus. The pallidothalamic fibers surround dorsally and medially the STN, separating it from the ZI rostromedially and from the prelemniscal radiation and the red nucleus more medially [48]. The cerebellothalamic tract connects the deep cerebellar nuclei with the thalamus passing through the superior cerebellar pedunculus and its decussation, and to the red nucleus anteriorly [47]. Several surgical centers have investigated the effects of PSA stimulation, with different groups using a different nomenclature. Plaha et al. refer to this area using the term cZi to distinguish between a caudal and a more rostral part [48]. Stimulation of this area seems to provide an optimal control of tremor, rigidity and to some extent of bradykinesia as well (TABLE 2) [49–52], possibly even better than STN stimulation [48]. Nevertheless, these findings should be taking cautiously since the experience with cZi DBS is little (the number of patients included is small and no randomized studies are available). Moreover, potential chronic side effects might prevent from taking advantage of the actual improvement. Speech worsening in patients with STN stimulation can be related to electrodes located more medially [53], probably due to the current spread to the cerebellothalamic tract. Moreover, diffusion of current to the pallidothalamic fibers, located medially to the STN, could block the effects of levodopa (reducing dyskinesia, but worsening bradykinesia and freezing) [54–57]. Thus, stimulation of this area can be complicated on one hand by the occurrence of dysarthria and postural instability, linked to the diffusion of current to the cerebellothalamic tract [58], and to the other hand by blocking levodopa effects. A few studies have investigated the effect on speech of the cZi stimulation compared with STN stimulation [59–61]. A recent study has shown that whereas stimulation within the STN increased voice intensity, stimulation within the cZi worsened it [59]. Karlsson et al. found a more detrimental effect on articulation of speech by cZi compared with STN stimulation [61]. The centromedian-parafascicular complex

The CM-Pf complex is part of the caudal intralaminar nuclei of the thalamus and has a critical role on arousal, sensory awareness, pain control, behavior and cognition [62]. The CM nucleus is associated with the sensorimotor striatum, whereas the Pf nucleus with the limbic and associative striatum [62]. 1322

The CM-Pf complex has important reciprocal connections with the basal ganglia and undergoes partial neurodegeneration in PD [63]. In the hemi-parkinsonian rat, high-frequency stimulation of the CM-Pf complex had an anti-akinetic effect in the off-levodopa condition, whereas it had an anti-dyskinetic effect in the on-levodopa condition [63]. Some clinical data in humans have also pointed out its possible role in dyskinesias [64–66]. Indeed, the stimulation of this region for pain control showed by serendipity to also improve involuntary movements [66]. In some PD patients with thalamic stimulation, an improvement of tremor and dyskinesias was observed [67]. Postoperative MRIs showed that the control of both tremor and dyskinesia was associated with a more posterior and deeper position of the electrodes, corresponding to the CM-Pf complex [68]. More recently, a multi-target strategy with double STN or GPi and CM-Pf stimulation has been experimented in few PD patients [69,70]. CM-Pf stimulation could improve tremor and dyskinesias, although slightly less than GPi. Moreover, CM-Pf stimulation might slightly reduce bradykinesia and rigidity, but less than STN or GPi stimulation [70]. Further studies are necessary to support these preliminary observations. Combined targets

STN stimulation alone greatly improves cardinal PD signs and motor and non-motor fluctuations [2–4,71], but it is not able to manage levodopa unresponsive symptoms, such as axial signs and cognitive impairment. On the other hand, the stimulation of the other ‘alternative targets’ has showed to be neither equal nor superior to the STN in improving levodopa responsive signs. For instance, PPN stimulation can improve, although not consistently, axial signs but not the other PD cardinal signs [24,25]. Hence, stimulation of combined targets has been postulated in order to better address different PD symptoms. The stimulation of combined targets might allow a modulation of the basal ganglia loop due to the reciprocal strong interconnection among these structures, as the case for PPN and STN. So far, different target combinations have been tried. Studies investigating combined bilateral PPN and STN stimulation have showed no antagonism, but rather an additive effect [23,35]. Other studies have focused on the combination of bilateral PPN and cZi stimulation [27–29]. In a PET study, combined low-frequency PPN/cZi stimulation induced additive brain activation changes [29]. In a group of seven PD patients, PPN or cZi stimulation alone and combined stimulation significantly improved motor axial scores in the off-medication condition [27]. However, combined stimulation did not provide any significant further improvement compared with cZi stimulation alone [27]. Conversely, in the on-medication condition only combined cZi and PPN stimulation achieved a significant improvement of axial signs [27]. Interestingly, the authors found different effects at different stimulation frequencies [27,29]. When stimulating PPN alone, 10–20 Hz allowed the greatest postural instability improvement, but worsened gait. Stimulation with frequencies above 60 Hz improved gait, but worsened Expert Rev. Neurother. 13(12), (2013)

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New targets for deep brain stimulation treatment of Parkinson’s disease

postural instability. The best compromise was achieved with 60 Hz stimulation. Stimulation of cZi alone achieved the best results at frequencies around 130 Hz. However, when combined stimulation of PPN and cZi was performed, stimulation of cZi at 130 Hz was associated with postural instability impairment. The best compromise was stimulation of both targets with frequencies around 60 Hz. These different frequency effects of combined stimulation have not been for STN and PPN stimulation [24]. In this study, the assessment in the off-STN stimulation condition was not performed because not tolerated by the patients (marked worsening of parkinsonian symptoms following the arrest of STN stimulation – unpublished data). These different results might depend on the different target choices in these two studies [24,27]. It has been described that stimulation of pallidothalamic fibers might block the effects of levodopa, and thus induce a worsening of axial signs. Since pallidothalamic fibers pass through the Zi and medially to the STN before reaching the thalamus, it cannot be excluded that stimulation of the cZi at high frequency might diffuse to the pallidofugal fibers. The SNr is the main output nucleus of the basal ganglia along with the GPi. Combined STN-SNr stimulation has also been proposed in order to better manage axial signs. The effects of bilateral SNr DBS on different parameters of gait have been investigated in seven PD patients with bilateral STN stimulation [72]. In this study, patients were assessed with stimulation either of the contacts within the SNr or within the STN (all contacts were in the same lead). SNr DBS allowed only control of axial signs, whereas STN stimulation allowed also control of distal parkinsonian signs. Lately, a case report of combined bilateral stimulation of both STN and SNr has been published [73]. Interestingly, in this report the authors used interleaving stimulation, a new approach allowing delivering the current simultaneously on two different contacts on the same lead in alternating order. There was a slight improvement of gait with STN stimulation alone, and a sustained improvement with combined STN and SNr stimulation. Following this observation, a double-blind crossover trial comparing STN stimulation and interleaving stimulation of STN and SNr is underway and the results are awaited [74]. Alternative targets for non-motor symptoms in PD

The bulk of the studies on DBS in PD has focused on motor symptoms. However, PD is not a mere motor disorder. Several non-motor symptoms develop at different stages of disease, and among them cognitive impairment is certainly one of the most disabling for patients and caregivers. Dementia affects almost 30% of PD patients and mild cognitive impairment around 15–20% of patients at early stages of disease [75]. In a longitudinal study at 20 years from the disease onset, around 80% of patients had developed dementia [76]. Management of cognitive impairment at present is based on pharmacological and physical treatment and it is still unsatisfactory. Recently, in a patient undergoing hypothalamic www.expert-reviews.com

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stimulation for the treatment of morbid obesity it was serendipitously discovered that the stimulation of the fornix/ hypothalamus could evoke detailed autobiographic memory events in a reproducible and consistent manner [77]. Following this unexpected observation, a Phase I trial of fornix/ hypothalamic stimulation has been carried out in six patients with mild-moderate Alzheimer’s disease. Preliminary results showed a reversal of the impaired glucose hypometabolism in the temporal and parietal cortex at PET scans and a slower than expected decline of the Mini-Mental State Examination score [78]. Larger randomized studies are needed to confirm this preliminary data. Nevertheless, taking also into consideration that the pattern of cognitive impairment in PD is quite different, the rationale of fornix stimulation in PD patients remains to be demonstrated. Concerning sleep, a positive effect on sleep and daytime sleepiness has been reported with PPN stimulation (see above) [23,32,33,79]. Controversy on classical targets for DBS GPi versus STN

There is still some debate on whether the STN or the GPi should be the preferred target in PD patients. In the 1990s, the initial clinical data mainly favored STN stimulation because of a greater reduction of dopaminergic medication and more stable results over time [80,81]. Recently, the US Veteran Affairs study, a large randomized double-blind trial with a follow-up up to 36 months, has shown that the two targets were equally effective, and with less cognitive side effects in the GPi group [82,83]. However, the global motor improvement achieved with stimulation in this study was less consistent and remarkable than expected [84]. Some concerns have been raised about possible detrimental cognitive and behavioral effects induced directly by STN stimulation [85], thus suggesting the GPi as a preferable target in the presence of preoperative neuropsychiatric symptoms. Behavioral issues are frequent non-motor symptoms in PD. They can be devised in hypodopaminergic symptoms, when deriving from a deficit of dopamine state (such as depression, apathy and anxiety), and hyperdopaminergic symptoms, when caused by an overdose of dopaminergic medication (including dopamine dysregulation syndrome, impulsive behaviors and punding) [71,86]. The effect of STN DBS on hyperdopaminergic syndromes has been controversial [87,88]. While in the acute postoperative phase, STN DBS might induce hypomania or frank mania, in the long-term the chronic and marked reduction of dopaminergic medication allows the control of the hyperdopaminergic syndrome. Indeed, a recent prospective study has showed that hyperdopaminergic syndrome completely disappears after STN surgery with a chronic drastic dopaminergic medication reduction [71]. More recently, a larger randomized trial comparing STN and GPi stimulation specifically designed to investigate the superiority of GPi on mood, cognition and behavior, has failed in finding any differences in cognitive and behavioral 1323

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outcomes, while showing a superiority of motor effects with STN stimulation [89]. However, the choice of the target remains a complex issue, involving also the specific surgical center experience with the two targets The GPi indeed is a larger nucleus, ideally easier to target and not requiring a substantial modification of medical treatment and a meticulous programming of stimulation parameters.

motor cortex, but with inconclusive results [95–103]. Moreover, in all this case studies, the evaluations were conducted in an open-label fashion. A recent study reported no improvement at the 3-months double-blind and 1-year open assessments [104]. Another study reported some improvement in axial signs [105]. Overall to date, there is not enough evidence to recommend extradural motor cortex in PD.

Bilateral versus unilateral STN DBS

Expert commentary

Since PD becomes always a bilateral disease within its course, bilateral STN DBS has preferentially been performed. However, some studies have highlighted that unilateral STN DBS can be an effective alternative therapeutic approach, being associated not only with contralateral but also ipsilateral improvement, although to a less extent (see [90] for a review). Moreover, the concept of a dominant STN has been recently suggested, coming from the observation that in some patient the stimulation of one STN can be as effective as the stimulation of both STN together [91]. To date, it seems reasonable to propose unilateral STN DBS to patients with a very asymmetrical disease [92].

DBS surgery has changed the therapeutic approach to PD, allowing the management of motor fluctuations and dyskinesia. This benefit has been proven to be sustained over many years [4]. Recent evidence supports the use of STN DBS even earlier within the course of the disease [3]. Unfortunately, DBS is not a neuroprotective therapy for PD and does not prevent the disease to progress. In addition, STN stimulation is not effective on postural instability, gait impairment and cognitive decline, which represent a main burden for patient and caregivers. Many efforts have been directed in order to discover other alternative targets, but so far none of these seems to be consistently effective on axial signs. Unfortunately to date, most of these new alternative targets remain experimental. The available data are too scarce to allow defining guidelines for the clinicians. Results from studies assessing the stimulation of the PPN region, although promising, are still controversial. Methodological issues, mainly concerning targeting, patient selection, electrode position as well as stimulation parameters, can account for these discrepancies and should be solved by larger and better designed trials in the near future. Other possible interesting approaches to address both dopaminergic and non-dopaminergic symptoms might be represented by a multi-target strategy or ‘intelligent’ stimulation devices.

Novel alternative stimulation of old traditional target: closed-loop stimulation

In the ‘standard’ DBS technique, a stimulus is delivered to a brain target at predefined electrical parameters, independently by ongoing neural activity. This can be a very important limit of DBS, for example, by depleting current when not needed. Recently, an alternative adaptive paradigm of stimulation has been proposed, the so-called closed-loop stimulation [93]. According to this novel adaptive paradigm, stimulation is real-time adjusted to the ongoing neural activity, such as oscillatory activity. Lately, the effects of ‘closed-loop’ GPi stimulation have been investigated in two MPTP parkinsonian monkeys. A closed-loop system allows automatically changing the output based on the difference between the feedback signals to the input signals. Closed-loop stimulation determined a dramatic decrease of discharge rate, virtually abolishing the oscillatory activity, and allowing a greater improvement of akinesia compared with the standard GPi ‘open-loop’ paradigm of stimulation [93]. A wireless instantaneous neurochemical concentration sensor (WINCS), a device allowing near-real time detection of neurochemical changes, has been recently developed. In a near future, the WINCS could integrate a closed-loop DBS system as electrochemical feedback, which would allow a better adaptation of stimulation parameters [94]. These preliminary results seem promising and encourage new investigations to determine the safety, feasibility and efficacy of this closed-loop paradigm in humans. Extradural motor cortex stimulation

Chronic extradural motor cortex stimulation has been proposed as an alternative surgical procedure in PD patients with contraindication to DBS. Several small case series reported some improvement of PD cardinal signs following chronic extradural 1324

Five-year view

The management of axial symptoms and cognitive decline represents the main challenge in the treatment of advanced PD. In the next years, attention will be focused on the attempt to clarify controversies concerning potential promising targets, as well as the best site to stimulate within the PPN area. Another breakthrough might be represented by innovation in delivering stimulation, such as adaptive paradigms of stimulation, in which neural activity might be used as a real-time feedback to adapt stimulation. In animal models, this paradigm of stimulation has been shown to be more advantageous than traditional non-adaptive stimulation [93]. Financial & competing interests disclosure

E Moro has received honoraria from Medtronic for consulting service and lecturing as well as research grant support from the Canadian Institutes of Health Research, CurePSP and St. Jude Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Expert Rev. Neurother. 13(12), (2013)

New targets for deep brain stimulation treatment of Parkinson’s disease

Review

Key issues • Management of axial signs (postural instability, freezing) and cognitive decline in Parkinson’s disease is unsatisfactory with the current medical treatment. • Subthalamic nucleus stimulation is an effective treatment for motor complications and dyskinesia in Parkinson’s disease, but is less effective on axial signs. • Alternative treatments for axial signs and cognitive decline are urgently needed. • Experimental and clinical findings suggest that the pedunculopontine nucleus (PPN) is implicated in gait. As such, stimulation of the PPN Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by National University of Singapore on 05/24/14 For personal use only.

has been proposed to manage postural instability and gait impairment. • Results of PPN stimulation for gait and postural instability are still controversial. • Caudal zona incerta stimulation has been suggested to be the preferred target in Parkinson’s disease, particularly in the tremordominant type. Potential disabling side effects, that is, dysarthria, balance issues, worsening of levodopa response, with electrodes implanted in the caudal zona incerta might overweight its beneficial effects. • A multi-target approach has been considered to improve dopaminergic and non-dopaminergic symptoms. • Alternative paradigm of stimulation of traditional targets, as closed-loop stimulation, might increase benefit of stimulation.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1

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Schuepbach WM, Rau J, Knudsen K et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368(7), 610–622 (2013).

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Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch. Neurol. 68(12), 1550–1556 (2011).

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Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease. Brain 123 (Pt 9), 1767–1783 (2000).

•

A review on anatomical and functional connections of the pedunculopontine nucleus (PPN).

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