New Targets for Deep Brain Stimulation Treatment of PD / "DBS-2" - (2013)













New Targets for Deep Brain Stimulation Treatment of Parkinson's Disease

Anna Castrioto; Elena Moro


Expert Rev Neurother. 2013;13(12):1319-1328



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 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 (CM-Pf)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 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 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, 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 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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