Advertisement

Motor and Non-motor Effects of PPN-DBS in PD Patients: Insights from Intra-operative Electrophysiology

  • Alessandro Stefani
  • Salvatore Galati
  • Mariangela Pierantozzi
  • Antonella Peppe
  • Livia Brusa
  • Vincenzo Moschella
  • Francesco Marzetti
  • Paolo Stanzione
Conference paper
Part of the Advances in Behavioral Biology book series (ABBI, volume 58)

Abstract

Three decades of basic research have focused on the multiple functions sub-served by the pedunculopontine nucleus (PPN) in mammals. Yet, far from understood is the impact that lesioning PPN or modulating PPN-fugal pathways have on motor, limbic and/or associative domains. Recently, we have pioneered the low-frequency deep brain stimulation (DBS) of pontine tegmental areas in severely parkinsonian patients, aiming at providing new insights in the knowledge of this puzzling region. Here we show that, under PPN-DBS, significant amelioration of axial and hypokinetic signs occurs (although to a lesser extent than following STN-DBS in the same patients), together with a normalization of the spinal H reflex. Furthermore, PPN-DBS improves REM sleep behaviour disorder and attentive and cognitive executive performances.

As a first step to understand the limited motor response to PPN-DBS, systematic intra-operative recordings in STN were performed during PPN-DBS at 25 Hz. Almost each STN cell showed significant and long-lasting changes of the mean firing frequency during PPN stimulation. However, PPN-ON caused two conflicting effects: a dramatic decrease of the ongoing firing in bursting STN neurons and a large excitatory effect in irregular and tonic neurons. If dampening of STN bursting units seems to be in accord with the PPN therapeutic role, the simultaneous excitatory influence in non-bursting cells might counteract the efficacy on motor signs.

As a further step to understand the mechanisms underlying non-motor benefits, FDG-PET imaging was routinely performed in different conditions (PPN-OFF, PPN-ON). These investigations might clarify whether PPN-ON influences the subcortico-cortical pathways responsible for learning processes and goal-directed behaviours. Preliminary data confirm the possibility that PPN-DBS affects multiple ascending pathways involving intralaminar thalamic nuclei and the ventral tegmental area.

These findings confirm a complex interplay between PPN, basal ganglia and cortical regions. However, the size of the inserted electrode, extension of the electrical field and inter-individual anatomical differences of the surgical targeting do not allow us to draw any definite conclusions.

Keywords

Firing Rate Deep Brain Stimulation Epworth Sleepiness Scale Pittsburgh Sleep Quality Index Trail Make Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Introduction

The human pedunculopontine nucleus (PPN) is located in the ponto-mesencephalic region delimited in its lateral boundaries by the lemniscus medialis and in its medial margins by the superior cerebellar peduncle (Olszewski and Baxter 1982; Muthusamy et al. 2007). In rats, PPN extends from the posterior pole of the substantia nigra (SN) back to the lateral tip of the superior cerebellar peduncle (Jackson and Crossman 1983; Garcia-Rill 1991). Histochemical evidence suggests that PPN has two main sub-regions: the pars compacta (PPNc) and the pars dissipata (PPNd) (Mesulam et al. 1989). These compartments are characterized by the predominance of different cell populations (Takakusaki et al. 1996; Bevan and Bolam 1995), the most clearly identifiable being the acetylcholine (ACh) neurons in the Ch5 area (Mesulam et al. 1989). Ch5 neurons send, among others, sensory information to the thalamus and the SN, pars compacta (SNc). On the other hand, the non-cholinergic compartment (characterized by the presence of GABAergic and, mostly, glutamatergic neurons) receives corticostriatal inputs and projects to structures involved in motor control, such as the internal pallidum (GPi), the SN pars reticulata (SNr) and the subthalamic nucleus (STN) as part of the corticostriatal loop system (Calzavara et al. 2007).

Experimental data in animals showed a clear role of PPN in shaping motor performance (Garcia-Rill et al. 1987; Kelland and Asdourian 1989; Takakusaki et al. 2003). Interestingly, a moderate degree of PPN neuronal degeneration occurs in human extrapyramidal disorders such as idiopathic Parkinson’s disease (PD) (Zweig et al. 1989; Pahapill and Lozano 2000). However, PPN is by no means simply identified as a locomotor structure, and a wide body of evidence shows that it is critically involved in the analysis of reinforcement, learning and attention (Florio et al. 1999; Winn 2005). In addition, diffuse ascending cholinergic projections from the brainstem affect rapid-eye-movement sleep (Rye 1997). Further, experimental evidence suggests that the PPN is also involved in anti-nociception and startle reactions (Reese et al. 1995).

In PD as well as in PD disease models (6-OHDA and MPTP), a classical scientific cornerstone consists of attributing a key pathogenetic role to overactive GPi and SNr inhibitory output to the thalamic relay nuclei in producing hypokinesia. Similar observations may apply to GPi and SNr projections towards the PPN: a hypoactive (and apoptotic) PPN is unable to send its physiological excitatory output to the SNc, contributing to basal ganglia dysbalance (Breit et al. 2001). This hypothesis was tested in MPTP-lesioned non-human primates, where low-frequency stimulation of PPN area was effective in alleviating akinesia (Nandi et al. 2002). Likewise, we have recently demonstrated that the PPN may indeed be targeted with reliable safety in humans as well, and that PPN activation is well associated with STN (Mazzone et al. 2005; Stefani et al. 2007). However, PPN is not established yet as an alternative clinical target to STN or GPi, since the impact of PPN stimulation alone on global motor scores remains modest and shows a small decline of efficacy upon chronic stimulation (Stefani et al. 2007).

The present chapter describes the most clear-cut motor and non-motor effects that low-frequency (25 Hz) PPN stimulation promotes in PD patients.

2 Methods

The six PD patients selected for simultaneous bilateral implantation of STN and PPN met the UK PDS Brain Bank diagnostic criteria for idiopathic PD. They all presented severe axial signs (scarcely responsive to dopaminergic agents), although a disabling freezing was present in only three. Written, informed consent was obtained from the patients, and the Local Ethics Committee approved the protocols.

2.1 Neurosurgery

The surgical procedure is described elsewhere (Stefani et al. 1997; Peppe et al. 2004; Mazzone et al. 2005). Briefly, the electrodes (Medtronic 3389) were implanted in PPN and STN in each hemisphere through a double-arch system (Peppe et al. 2004). Target coordinates and trajectories were determined as follows: for STN – the midpoint of the anterior commissure–posterior commissure (AC–PC) line, 11–12 mm lateral to the midline of the third ventricle, 4 mm below AC–PC (the angle in the sagittal plane was 80°–85° and was 75°–80° in the coronal plane to obtain an extra-ventricular and extra-capsular trajectory), and for PPN, a simple indication of a fixed angle range in the sagittal plane sounds improper, given the high inter-individual variability. The key landmark to minimize surgical risks is the floor of the fourth ventricle (parallel to the brainstem axis). Therefore, in each patient, the trajectory was performed parallel to the floor of the fourth ventricle. However, for better coordinates and the clear description of PPN (and its caudal representation, the nucleus of the tegmenti pedunculopontine, PPTg), consider Fig. 1 and Mazzone et al. 2008.
Fig. 1

Three-dimensional reconstruction of the PPN, pars disseminata (blue) and pars compacta (yellow) with representation of the lead trajectory (dark red). Note the lamina quadrigemina (white) and the third ventricle (light brown). Background: axial slide of angio-CT scan with overlying 2D slides from Schaltenbrand–Wahren brain atlas (Tc 0, Tc −3)

2.2 Patient Evaluation

The careful clinical evaluation of this new combination of targets required a complex series of observations for each patient [see Fig. 3 in Stefani et al. (2007)]. Briefly, comparative evaluations allowed us to establish as optimal the following standard stimulus parameters: for PPN (bipolar contacts 0–1/4–5) = 60-μs pulse width, 25 Hz, 1.5–2 V; for STN (monopolar contact 1 or 2 and 5 or 6) = 90-μs pulse width, 185 Hz, 1.5–2.4 V. OFF-therapy evaluations were performed after an overnight therapy suspension (CAPIT protocol; Langston et al. 1992) and started between 2 and 3 months post-surgery. The specific stimulation condition (STN or PPN or both) was randomly activated and kept blinded to the single neurologist in charge of the clinical evaluations. DBS (PPN or STN or combined activation) was maintained for about 24 h in order to avoid additive or artefactual response.
Fig. 3

Simplified scheme of PPN-fugal projections as supported by clinical findings

Each clinical evaluation included the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS-III). To evaluate gait and posture, we focused on the relevant UPDRS-III items (items 27–30) plus, more recently, a three-dimensional approach using an optoelectronic system (SMART system, BTS Padova, Italy) to measure the three coordinates of retro-reflective markers. Six video cameras were placed along an 8-m walkway; the working volume (2 × 3 × 6 m3) is calibrated by sweeping it with the three-marker wand provided, that is, by successively moving the wand up and down several times parallel to each axis. After three-dimensional (3D) calibration, the spatial accuracy of the system is less than 0.5 mm. For correct positioning of markers a common ‘Davis’ protocol was used. Twenty-three spherical markers (10 mm diameter) were attached to the subject’s body with double-sided tape, according to the marker configuration of the Davis model, except for the calves; thigh markers were attached approximately 7–10 cm away from the skin on iron sticks.

Cognitive evaluations were performed by a neuropsychologist [blind to the DBS condition (PPN-ON/STN-OFF vs. PPN-OFF/STN-OFF)] in the morning, after overnight drug therapy suspension (CAPIT). Re-tests were performed by using parallel test forms to avoid learning-related phenomena. The order of presentation of the parallel forms was appropriately counterbalanced. Cognitive functions were assessed by using the following tests: the California Verbal Learning test and Digit Span test for memory, the Trail Making test (TMT) for attention and executive functions, FAS for verbal fluency, the object naming test for naming and the classical Rey figure for visuo-spatial ability.

In four out of six double-implanted PD patients (mean age 62.8 ± 2.2; disease duration 11.8 ± 3.5 years) sleep was extensively studied. Three sleep scales were administered: Parkinson’s Disease Sleep Scale (PDSS), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). All patients underwent the following modalities: STN-ON + PPN-ON, STN-ON + PPN-OFF, STN-ON + PPN-cyclic (nighttime-ON). Each condition was maintained for 2 weeks, and patients compiled PDSS, ESS and PSQI at the end of each step. Stimulation parameters remained constant as well as l-DOPA dosage.

Polysomnography (PSG) recordings were carried out in a single case (not included in the group of six patients described earlier) using a dynamic 32-channel system polygraph with standard montage before surgery (Romigi et al. 2006). Post-surgery, to minimize DBS-induced artefacts during PSG, STN-DBS was delivered bipolar without a significant worsening in comparison to monopolar stimulation, and the following montage was utilized: F3-C4, F4-C3 and O1-O2, according to the Iranzo protocol (Iranzo et al. 2002). PSG sessions consisted of two consecutive 24-h PSGs carried out using the first night as an adaptation night in each condition (de novo, pre-surgery, STN-ON, PPN-ON). The scorers were blind to the order of the post-surgery recordings (excerpts in Table 2).
Table 2

Polysomnographic parameters under STN-DBS vs. PPN-DBS

Sleep parameters

DBS-OFF

STN-ONa

PPN-ONa

 

Sleep efficiency (%)

74.5

88.9

90

 

Stage 1 (%)

26

15.9

13.4

 

Stage 2 (%)

38

57

50.9

 

Slow wave stages (%)

6.8

8.9

11.2

 

REM%

4

5.3

12.9

 

Awakenings (n)

53

19

17

 

REM (n)

2

3

4

 

STN-DBS parameters = 2.8 V, 185 Hz, 90 μs, bipolar STIM (contact 2+, 1−); PPN-DBS parameters: 2 V, 25 Hz, 60 μs, bipolar STIM (contact 1+, 0−)

a Data represent mean of two nights (the second one of each PSG protocol)

2.3 Peri-operative Recordings

This chapter deals mainly with STN extracellular activity recorded in PD patients (three of those undergoing stereotactic surgery), in particular before and during PPN-DBS (right after PPN implantation). Extracellular units were amplified (ISO-DAM8; World Precision Instruments, Hertfordshire, UK), sampled (50 KHz) on-line with our artefact suppression method (Galati et al. 2006), stored into a computer connected to a CED 1401 interface and analyzed off-line using the Spike 2 Analysis Program (Cambridge Electronic Design, Cambridge, UK). PPN-DBS, through a Medtronic external device Model 3625, consisted of 60-µs width and 2–3-V pulses, delivered bipolar (contacts 0–1) at 10–25 Hz. STN spike features are described in detail elsewhere (Galati et al. 2008).

In 48 STN neurons, the spiking activity was evaluated 3–10 min before, during (10 min) and after PPN-DBS (3–10 min, Fig. 2). Differences in the spontaneous discharge pattern of STN neurons were determined by comparing the inter-spike interval histograms (ISIH). ISIH analysis was performed using a 1-ms bin width, mean interval, coefficients of variation (CV = standard deviation of the mean interval/mean interval) and asymmetry index (mode/mean interval). To investigate whether there was any clustering of spikes in spontaneous discharge, auto-correlograms (AutoCrls) were constructed for each unit before and during PPN-DBS; exemplary post-stimulus histograms were examined during either 10 or 25-Hz PPN stimulation [for details and statistical analysis, see Galati et al. (2008)].
Fig. 2

On the left, electrophysiological identification characterization of three main modality patterns of STN unit firing discharges: bursty, irregular and regular. On the right, examples of rate meter recordings showing the clear-cut effects promoted by the condition PPN-ON. Twenty-five hertz PPN-DBS decreased the STN firing activity when in bursty units (upper line), whilst increasing firing rate in regular and irregular neurons units (Galati et al. 2008)

3 Results

3.1 Acute and Long-Lasting Motor Effect

The main aim of PPN implantation was to provide specific benefits on gait (mostly in patients whose freezing was scarcely responsive to the best drug combinations). So far, the results in this small cohort lead to doubtful conclusions, since the responses obtained are highly variable. On the one hand, all patients reported a significant amelioration of gait sub-items when PPN and STN were switched ON together (Stefani et al. 2007), whilst the impact of PPN stimulation alone was slight to modest in four and rather impressive only in the other three patients. When gait analysis was performed with a three-dimensional blinded approach, we could confirm the effect of PPN and STN in recovering the kinetic and kinematic alterations observed in PD patients during OFF-therapy-OFF-DBS, expressed as percentage differences with healthy subjects (Peppe et al., unpublished observations). This reduction was particularly important when both stimuli were simultaneously switched ON, as an additional action of PPN on STN activity, which is even more pronounced when PPN is added to STN and l-DOPA therapy.

Table 1 summarizes gait subscores, comparing ‘acute’ (1 week) and chronic (12 months) motor effects induced by PPN-ON and STN-ON (185 Hz). Noticeably, these ‘declining’ gait responses occurred despite the homogeneous (6 out of 6!) PPN-mediated change of Hoffman reflex threshold [up to normalization, see Pierantozzi et al. (2008)] and a great improvement of their quality of life (Stefani et al. 2007).
Table 1

Early and long-lasting effects of PPN-DBS (25 Hz) and PPN plus STN-DBS (185 Hz) on gait sub-items (summation of items 27–30 from UPDRS-III)

Patient

OFF

PPN-DBS (1 week)

PPN-DBS (12 months)

STN and PPN-DBS (1 week)

STN and PPN-DBS (12 months)

 

1

12

6

9

5

8

 

2

13

5

8

4

6

 

3

10

3

6

2

6

 

4

13

5

9

4

9

 

5

13

5

8

6

8

 

6

10

5

6

4

5

 

Mean

11.8

4.8

7.7

4.2

7

 

SD

1.4

0.9

1.3

1.3

1.5

 

A prolonged efficacy (>40%) was observed only in patients 2, 3 and 6

3.2 Cognitive Effects

PPN-ON significantly improved cognitive functions in the following domains: verbal long-term memory assessed with California Verbal Learning test and delayed recall and executive functions as revealed by TMT and FAS (data not shown). A clear sensation of ‘well-being’ was also reported by all patients as PPN stimulation was turned on. These preliminary observations are being correlated with changes of cerebral metabolic activity, as studied and quantified by FDG-PET (Brusa et al., 2008).

3.3 Effects on Sleep

In the PPN-cyclic condition, the group of four PD patients reported a clear improvement of nocturnal motor restlessness (PDSS item 4: PPN-cyclic 7.5 ± 3.3, PPN-ON 5.3 ± 2, PPN-OFF 5.5 ± 3; PDSS item 5: PPN-cyclic 9 ± 1, PPN-ON 5 ± 3, PPN-OFF 6.9 ± 4), psychosis (PDSS items 6: PPN-cyclic 8.3 ± 3, PPN-ON 7.3 ± 1.8, PPN-OFF 7.7 ± 1.8; PDSS item 7: PPN-cyclic 10, PPN-ON 8 ± 1.4, PPN-OFF 8.4 ± 1.7) and daytime sleepiness (PDSS item 15: PPN-cyclic 8 ± 3, PPN-ON 5.9 ± 1, PPN-OFF 6.3 ± 2.2) (data not shown). ESS scores equally indicated reduced daytime sleepiness in PPN-cyclic (PPN-cyclic 4 ± 2.8, PPN-ON 5.5 ± 2.9, PPN-OFF 8.9 ± 2.8).

In another recently implanted PD patient (UM, 49 years), we had the opportunity to monitor PSG alterations before and after surgery and determined whether the effects of low-frequency PPN-DBS differed from those detected under 185-Hz STN-DBS (Table 2). PSG parameters, in the pre-surgery phase, revealed a clear sleep disruption (number awakenings, increased stage 1 sleep, loss of REM sleep, Table 2). After surgery, PPN-ON (25 Hz) and STN-DBS, to a lesser extent, promoted a better stability and continuity of nocturnal sleep, expressed by the increase from 74 to 90% of sleep efficiency, a mild reduction of stage 1, a 30% increase of stage 2 and a 70% decrease of awakenings (Romigi et al. 2008). Appealingly, under PPN-DBS these changes were associated with a relevant increase in REM sleep (up to 13%) (Table 2). By contrast, STN-DBS (185 Hz), albeit providing a better control of nocturnal akinesia, failed to affect the occurrence and duration of REM epochs.

3.4 Effects of PPN-DBS on STN Neurons

On the basis of the firing pattern analysis, STN single units (n = 48) were divided into the following subgroups: (1) Burst-like firing activity (45%, characterized by the appearance of burst-like clustering of action potentials separated by periods of absence of discharge or by low-frequency activity, Fig. 2), (2) irregular firing activity (30%, characterized by a flat, i.e., random, distribution of the ISIs, which sometimes showed mild positive skewing and an auto-correlogram with less than two peaks, Fig. 2) and (3) regular/tonic firing activity (25%, displaying a symmetric peak in the ISIH and an auto-correlogram with at least three identifiable peaks, Fig. 2).

Out of the neurons displaying a clustered, train-like discharge activity, 20 cells (90%) showed a statistically significant decrease in firing rate during PPN-DBS (Fig. 2). This response had a mean latency of 35.73 ± 15.02 s (under steady state 2 V STIM) and a mean magnitude of 62% ± 17. No variation in waveform or firing pattern was observed during PPN-DBS (not shown). The firing rate partially returned to pre-stimulus level after 3-min OFF-STIM. Post-stimulus histogram (PSTH) and raster plots did not reveal any short-term inhibition around each PPN stimulus (data not shown).

In contrast, the activity of all but one (13/14) of the irregularly discharging units exhibited a statistical significant increase in spike frequency from 21% (±8.2) to 34% (±14) with a latency of 10 ± 7.26 s (Fig. 2). No changes in morphology of waveforms, ISIHs and auto-correlograms were evident during PPN-DBS. The firing rate did not recover fully to pre-stimulus levels after the end of PPN-DBS. PSTH and raster plots did not show any increase of firing probability within 40 ms before or after each PPN stimulus (data not shown).

Similarly, 25-Hz PPN-DBS caused a statistically significant increase in the mean firing rate of most tonic regular units (10/12, 83.33%). This response had a mean latency of 25.3 ± 7.8 s and a mean magnitude of 20% (±14%). The waveform, ISIHs and auto-correlograms did not change during PPN-DBS. However, no long-term slow oscillations were observed during PPN-DBS (Fig. 2).

In each unit ‘subtype’ we also tested ten PPN-STIM (n = 2 for any given patterning) and never detected significant changes of firing rate and PSTH (data not shown).

4 Discussion

The data so far collected indicate that PPN-DBS has a profound impact on different motor and non-motor functions. On the one hand, it was shown that PPN-ON may ameliorate hypokinetic signs (about 30%), but the results were modest when compared with STN-mediated benefits (Stefani et al. 2007). In addition, the improvement in gait control was fluctuating and not fully convincing. Actually, four out of the six original patients took advantage of a cyclic PPN activation (overnight) together with a continuous STN stimulation. On the other hand, we found significant changes in sleep macrostructure as well as an interesting beneficial impact on some, mainly executive, cognitive functions.

4.1 Motor Effects

As far as the slightly disappointing clinical motor effects are concerned, the peri-operative recordings may offer some clues. First, the ability of PPN 25-Hz stimulation to affect the on-going firing rate in almost all STN neurons is an unequivocal proof of the strong interplay between the two stations. Whether PPN-STN connections are direct or indirect through multi-synaptic mechanisms (i.e., through GPi) cannot be fully resolved by electrophysiology performed on humans in the surgery room. However, the evidence of a PPN-mediated change of firing frequency in 90% of recorded STN neurons without altering PSTH or shifting the firing pattern would seem to indicate a PPN-driven direct mechanism that simultaneously affects different STN neurons. Alternatively, the described changes of STN firing discharge may require complex alterations, involving other basal ganglia stations such as GPi or ‘extra-basal ganglia’ areas such as the intralaminar thalamus.

The second relevant finding is the lack of PSTH changes in STN cells during 25 and 10-Hz PPN stimulation; thus, it is plausible that firing rate changes are not related to changes in fast excitatory neurotransmission (at least in our experimental conditions of stimulus intensity) but, rather, to neuromodulatory transmitter(s) not strictly responsible for fast transmission. The cholinergic nature of the PPN-STN pathway has been supported by morphological studies (Lavoie and Parent 1994), also suggesting the possibility of co-expression of ACh and glutamate. Indeed, a direct axo-dendritic synapse, as occurs between PPN terminals and dendrites of STN neurons, might modulate the on-going excitability by releasing ACh without any short latency effect at this stimulation intensity. The direct excitation described on this pathway could be also ascribed to the release of glutamate but the latter usually requires different stimulus intensities.

Third, the delivery of PPN-ON at 25 Hz excited irregular and tonic cells and inhibited neurons dominated by train-like pattern. An increased burstiness is acknowledged as a disease hallmark correlated with PD pathophysiology (Bergman et al. 1994); the PPN-mediated reduction of firing discharge in bursty cells is in line with this theory. Hence, the dramatic inhibition of STN bursts may underlie, at least in part, the efficacy of PPN-DBS. On the other hand, the simultaneous presence of a strong PPN-mediated excitation on about 50% STN neurons may counterbalance the beneficial decline in burstiness.

4.2 Non-motor Effects

Regardless of the questionable impact on the motor parkinsonian signs, PPN-DBS demonstrated a striking influence on nocturnal sleep structure and cognitive performance.

In several previous manuscripts, no beneficial increase in REM phase was detected under STN-DBS, even in the presence of longer periods of uninterrupted sleep and reduction of sleep fragmentation. STN-mediated benefits were attributed to a better nocturnal mobility. By contrast, our data revealed a selective recovery of REM sleep induced by low-frequency PPN-DBS.

The most parsimonious explanation of PPN-mediated effects on sleep structure is that low-frequency PPN-DBS modifies the functional activity of its subpopulation of cholinergic neurons, activating muscarinic receptors and rebalancing REM-sleep physiology through the projection to the thalamus (Rye 1997). However, the electrode catheter size and the spread of the electrical field, compared with the limited extension of brainstem structures, do not exclude the possible involvement of the locus coeruleus (whilst the lack of PPN-DBS-mediated effects on the slow wave phase seems to point out a critical role of serotonin). In any case, our result is the first in vivo non-lesional confirmation of the ancient theory by Moruzzi’s group on ‘midpoint’ brain stem structure involvement in sleep (Batini et al. 1958).

In addition, the improvement of executive functions, just following PPN-ON, together with subjective ‘good feelings’ highlights interesting other possibilities. First, PPN sends an abundant contingent of fibres towards the intra-laminar thalamic nuclei, whose involvement in limbic/motor interfaced circuitries is well documented. Second, the reported beneficial effect we observed by means of neuropsychological evaluations could be referred to the spread of the electrical effect to nearby nuclei and in particular to the locus coeruleus, known to be involved in arousal and attention due to its diffuse noradrenergic projections directed to the cortex. Third, as emphasized by the group of Winn (Anderson et al. 2006), this nucleus could modulate projections to the prefrontal cortex, ventral striatum and accumbens through its ascending output directed toward dopaminergic neurons of the ventral tegmental area and SNc, to the intralaminar nuclei of thalamus and to STN and GP. This interpretation takes for granted several assumptions, such as the presumption that we are modulating only or mainly the PPN itself. This, of course, is not the case, because the active part of the catheter (>7 mm) overcomes the rostrocaudal extension of PPN (about 4 mm in humans). A well-designed long-lasting study on effects influenced by each electrical contact (in monopolar modality) could provide more specific results or interpretations. That said, further understanding of the PPN fine functional anatomy could be achieved with single unit or intracellular recordings from PPN sub-portions in mammalian disease models (Florio et al. 2007).

5 Conclusions

5.1 Is PPN-DBS (at 10–25 Hz in Our Protocol) Re-activating Impaired Pathways?

The evidence by which PPN-DBS helps to restore a more physiological sleep structure and to improve attentive and executive functions suggests (albeit heuristically) that the stimulation, instead of simply abolishing a gross over-excitability, imposes new activity patterns in otherwise impaired/silent fibre pathways. Our findings highlight once more that DBS should not be considered as a simple ‘resetting’ or jamming device (Stefani et al. 2005). Moreover, the present findings suggest that PPN should not be viewed as a mere station for processing descending output to the spinal cord (Pierantozzi et al. 2008). Instead, it appears to exert also a strong influence onto ascending pathways, as hypothesized by Mena-Segovia et al. (2004), who assume the PPN and the BG structures to be a functional integrated system. Furthermore, the ongoing imaging studies (which seem to correlate cognitive benefits with increased metabolic activity in prefrontal areas as well as ventral striatum) strongly support Winn’s views, indicating PPN as an active player in ‘limbic-reward’ circuitries (Winn 2005) (Fig. 3).

5.2 Is PPN-DBS Mostly Affecting Non-motor and Not Strictly Dopamine-Centred Functions?

Strong evidence supports the critical involvement of non-motor non-dopaminergic brain-stem areas in the natural history of extra-pyramidal disorders (Braak et al. 2003). Our studies demonstrate that PPN-DBS promotes a general improvement of sleep efficiency and cognitive performance, hard to attribute to a mere change of endogenous dopamine release and availability. For example, REM sleep alterations are probably related to degenerative processes of non-dopaminergic circuitries and indeed largely unaffected by dopamine-centred therapy or standard stereotactic neurosurgery. Hopefully, new research lines in rodents (i.e., unequivocal identification of PPN neuronal subtypes and their complex relationship with surrounding structures) will elucidate these aspects.

References

  1. Anderson HL, Latimer MP and Winn P (2006) Intravenous self-administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus. Eur J Neurosci 23: 2169–2175.CrossRefGoogle Scholar
  2. Batini C, Moruzzi G, Palestini M, Rossi GF and Zancheti A (1958) Presistent patterns of wakefulness in the pretrigeminal midpontine preparation. Science 128: 30–32.CrossRefPubMedGoogle Scholar
  3. Bergman H, Wichmann T, Karmon B and DeLong MR (1994) The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 72: 507–520.PubMedGoogle Scholar
  4. Bevan MD and Bolam JP (1995) Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat. J Neurosci 15: 7105–7120.PubMedGoogle Scholar
  5. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN and Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197–211.CrossRefPubMedGoogle Scholar
  6. Breit S, Bouali-Benazzouz R, Benabid AL and Benazzouz A (2001) Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat. Eur J Neurosci 14: 1833–1842.CrossRefPubMedGoogle Scholar
  7. Brusa L, Morchella V, Stanzione P, Ceravolo R, Pierantozzi M, Galati S, Stefani A (2008) PPN-DBS improves cognitive performance in Parkinsonian patients. Eur J Neurol (submitted for publication).Google Scholar
  8. Calzavara R, Mailly P and Haber SN (2007) Relationship between the corticostriatal terminals from areas 9 and 46, and those from area 8A, dorsal and rostral premotor cortex and area 24c: an anatomical substrate for cognition to action. Eur J Neurosci 26: 2005–2024.CrossRefPubMedGoogle Scholar
  9. Florio T, Capozzo A, Puglielli E, Pupillo R, Pizzuti G and Scarnati E (1999) The function of the pedunculopontine nucleus in the preparation and execution of an externally-cued bar pressing task in the rat. Behav Brain Res 104: 95–104.CrossRefPubMedGoogle Scholar
  10. Florio T, Scarnati E, Confalone G, Minchella D, Galati S, Stanzione P, Stefani A and Mazzone P (2007) High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat. Eur J Neurosci 25: 1174–1186.CrossRefPubMedGoogle Scholar
  11. Galati S, Mazzone P, Fedele E, Pisani A, Peppe A, Pierantozzi M, Brusa L, Tropepi D, Moschella V, Raiteri M, Stanzione P, Bernardi G and Stefani A (2006) Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson’s disease. Eur J Neurosci 23: 2923–2928.CrossRefPubMedGoogle Scholar
  12. Galati S, Scarnati E, Mazzone P, Stanzione P and Stefani A (2008) PPN-DBS promotes excitation and inhibition in human PD STN. Neuroreport 19: 661–666.CrossRefPubMedGoogle Scholar
  13. Garcia-Rill E (1991) The pedunculopontine nucleus. Prog Neurobiol 36: 363–389.CrossRefPubMedGoogle Scholar
  14. Garcia-Rill E, Houser CR, Skinner RD, Smith W and Woodward DJ (1987) Locomotion-inducing sites in the vicinity of the pedunculopontine nucleus. Brain Res Bull 18: 731–738.CrossRefPubMedGoogle Scholar
  15. Iranzo A, Vallderiola F, Santamaria J, Tolosa E and Rumià J (2002) Sleep symptoms and polysomnographic architecture in advanced Parkinson’s disease after chronic bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatr 72: 661–664.CrossRefPubMedGoogle Scholar
  16. Jackson A and Crossman AR (1983) Nucleus tegmenti pedunculopontinus: efferent connections with special reference to the basal ganglia, studied in the rat by anterograde and retrograde transport of horseradish peroxidase. Neuroscience 10: 725–765.CrossRefPubMedGoogle Scholar
  17. Kelland MD and Asdourian D (1989) Pedunculopontine tegmental nucleus-induced inhibition of muscle activity in the rat. Behav Brain Res 34: 213–234.CrossRefGoogle Scholar
  18. Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T and Watts R (1992) Mov Disord 7: 2–13.CrossRefPubMedGoogle Scholar
  19. Lavoie B and Parent A (1994) Pedunculopontine nucleus in the squirrel monkey: distribution of cholinergic and monoaminergic neurons in the mesopontine tegmentum with evidence for the presence of glutamate in cholinergic neurons. J Comp Neurol 344: 190–209.CrossRefPubMedGoogle Scholar
  20. Mazzone P, Lozano A, Stanzione P, Galati S, Peppe A, Scarnati E and Stefani A (2005) Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson’s disease. Neuroreport 16: 1879–1883.CrossRefGoogle Scholar
  21. Mazzone P, Sposato S, Insola A, Di Lazzaro V and Scarnati E (2008). Stereotactic surgery of nucleus tegmenti pedunculopontini. Br J Neurosurg 22: S33–S40. Google Scholar
  22. Mena-Segovia J, Bolam JP and Magill PJ (2004) Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family? Trends Neurosci 27: 585–588.CrossRefPubMedGoogle Scholar
  23. Mesulam MM, Geula C, Bothwell MA and Hersh LB (1989) Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons. J Comp Neurol 283: 611–633.CrossRefPubMedGoogle Scholar
  24. Muthusamy KA, Aravamuthan BR, Kringelbach ML, Jenkinson N, Voets NL, Johansen-Berg H, Stein JF and Aziz TZ (2007) Connectivity of the human pedunculopontine nucleus region and diffusion tensor imaging in surgical targeting. J Neurosurg 107: 814–820.CrossRefPubMedGoogle Scholar
  25. Nandi N, Aziz TZ, Giladi N, Winter J and Stein JF (2002) Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus. Brain 125: 2418–2430.CrossRefPubMedGoogle Scholar
  26. Olszewski JD and Baxter DW (1982) Cytoarchitecture of the Human Brain Stem. Karger, Basel.Google Scholar
  27. Pahapill PA and Lozano AM (2000) The pedunculopontine nucleus and Parkinson’s disease. Brain 123: 1767–1783.CrossRefPubMedGoogle Scholar
  28. Peppe A, Pierantozzi M, Bassi A, Altibrandi MG, Brusa L, Stefani A, Stanzione P and Mazzone P (2004) Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease. J Neurosurg 101: 195–200.CrossRefPubMedGoogle Scholar
  29. Pierantozzi M, Calmieri MG, Galati S, Stanzione P, Peppe A, Troppi D, Brusa L, Pisani A, Moschella V, Marciani MG, Mazzone P and Stefani A (2008) Pedunculopontine nucleus deep brain stimulation changes spinal cord excitability in Parkinson’s disease patients. J Neural Transm 115: 731–735.CrossRefPubMedGoogle Scholar
  30. Reese NB, Garcia-Rill E and Skinner RD (1995) The pedunculopontine nucleus – auditory input, arousal and pathophysiology. Prog Neurobiol 47: 105–133.CrossRefPubMedGoogle Scholar
  31. Romigi A, Stanzione P, Marciani MG, Izzi F, Placidi F, Cervellino A, Giacomini P, Brusa L, Grossi K and Pierantozzi M (2006) Effect of cabergoline added to levodopa treatment on sleep–wake cycle in idiopathic Parkinson’s disease: an open label 24-hour polysomnographic study. J Neural Transm 113: 1909–1913.CrossRefPubMedGoogle Scholar
  32. Romigi A, Placidi F, Peppe A, Pierantozzi M, Izzi F, Brusa L, Galati S, Moschella V, Marciani MG, Mazzone P, Stanzione P and Stefani A (2008) Pedunculopontine nucleus stimulation influences REM sleep in Parkinson’s disease. Eur J Neurol 15: e64–e65.CrossRefPubMedGoogle Scholar
  33. Rye DB (1997) Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 20: 757–788.PubMedGoogle Scholar
  34. Stefani A, Stanzione P, Bassi A, Mazzone P, Vangelista T and Bernardi G (1997) Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson’s disease: clinical score and internal globus pallidus activity. J Neural Transm 104: 895–904.CrossRefPubMedGoogle Scholar
  35. Stefani A, Fedele E, Galati S, Pepicelli O, Frasca S, Pierantozzi M, Peppe A, Brusa L, Orlacchio A, Hainsworth AH, Gattoni G, Stanzione P, Bernardi G, Raiteri M and Mazzone P (2005) Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients. Ann Neurol 57: 448–452.CrossRefPubMedGoogle Scholar
  36. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E and Mazzone P (2007) Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 130: 1596–1607.CrossRefPubMedGoogle Scholar
  37. Takakusaki T, Shiroyama T, Yamamoto T and Kitai ST (1996) Cholinergic and noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labelling. J Comp Neurol 371: 345–361.CrossRefPubMedGoogle Scholar
  38. Takakusaki K, Habaguchi T, Ohtinata-Sugimoto J, Saitoh K and Sakamoto T (2003) Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction. Neuroscience 119: 293–308.CrossRefPubMedGoogle Scholar
  39. Winn P (2005) How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J Neurol Sci 248: 234–250.CrossRefGoogle Scholar
  40. Zweig RM, Jankel WR, Hedreen JC, Mayeux R and Price DL (1989) The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26: 41–46.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Alessandro Stefani
    • 1
  • Salvatore Galati
    • 1
  • Mariangela Pierantozzi
    • 1
  • Antonella Peppe
    • 1
  • Livia Brusa
    • 1
  • Vincenzo Moschella
    • 1
  • Francesco Marzetti
    • 1
  • Paolo Stanzione
    • 1
  1. 1.Clinica Neurologica, Department of NeuroscienceUniversity Tor VergataRomeItaly

Personalised recommendations