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• Single stimuli applied to the pedunculopontine tegmental nucleus (PPTg) modulate the blink reflex (BR) in Parkinson's disease. • The action of the PPTg on the BR differs from the action exerted by other basal ganglia nuclei. • The PPTg has a critical role in the pathway mediating the prepulse inhibition of the BR. To investigate the effects on the blink reflex (BR) of single stimuli applied to the pedunculopontine tegmental nucleus (PPTg). The BR was evoked by stimulating the supraorbital nerve (SON) in fifteen patients suffering from idiopathic Parkinson's disease (PD) who had electrodes monolaterally or bilaterally implanted in the PPTg for deep brain stimulation (DBS). Single stimuli were delivered to the PPTg through externalized electrode connection wires 3–4 days following PPTg implantation. PPTg stimuli increased the latency and reduced duration, amplitude and area of the R2 component of the BR in comparison to the response recorded in the absence of PPTg stimulation. These effects were independent of the side of SON stimulation and were stable for interstimulus interval (ISI) between PPTg prepulse and SON stimulus from 0 to 110 ms. The PPTg-induced prepulse inhibition of the BR was bilaterally present in the brainstem. The R1 component was unaffected. The prepulse inhibition of the R2 component may be modulated by the PPTg. These findings suggest that abnormalities of BR occurring in PD may be ascribed to a reduction of basal ganglia-mediated inhibition of brainstem excitability. [ABSTRACT FROM AUTHOR]

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region. [ABSTRACT FROM AUTHOR]

Abstract: The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson''s disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7–11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7–11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes. [Copyright &y& Elsevier]

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92–3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs. [ABSTRACT FROM AUTHOR]

The pattern of neuronal discharge within the basal ganglia is disturbed in Parkinson''s disease (PD). In particular, there is a tendency for neuronal elements to synchronise at around 20 Hz in the absence of dopaminergic treatment, whereas this activity can be replaced by spontaneous synchronisation at much higher frequencies (>70 Hz) following dopaminergic treatment [J. Neurosci. 21 (2001) 1033; Brain 126 (2003) 2153]. In two PD patients (3 sides), we show that stimulating the subthalamic area at around 20 Hz exacerbates synchronisation at similar frequencies in the globus pallidus interna, the major output structure of the human basal ganglia. In contrast, stimulating the subthalamic area at >70 Hz suppresses pallidal activity at about 20 Hz. Clinically, stimulation of the subthalamic area at similar high frequencies reverses parkinsonism and forms the basis of therapeutic deep brain stimulation in PD. The results point to a possible common mechanism by which both dopaminergic treatment associated synchronisation of subthalamic activity at very high frequency and synchronisation imposed by therapeutic stimulation of the subthalamic area inhibit an abnormal and potentially deleterious synchronisation of basal ganglia output at around 20 Hz. If this activity is unchecked by synchronisation at higher frequency, then pathological 20-Hz oscillations may cascade through the basal ganglia, increasing at subsequent levels of processing. [Copyright &y& Elsevier]

The recent introduction of frameless devices has enabled stereotactic neurosurgery to reach a level of accuracy that is comparable to traditional frame-based methodologies. Among frameless devices, the Nexframe appears to be very useful in implanting electrodes into the subthalamic nucleus or other structures for deep brain stimulation in Parkinson’s disease. However, frameless devices, including the Nexframe, limit the possibility of intraoperative visual control of the placement of electrodes in the brain. Utilizing intraoperative O-arm Computed tomography (CT) scan or high-field Magnetic Resonance Imaging (MRI) could overcome this limitation, but their high cost restricts their use. Thus, in this paper we propose an innovation in Nexframe surgical planning that allows the intraoperative use of a C-arm X-ray apparatus to establish: (1) the progression of the electrode guide tube and the electrode in the brain; (2) the accuracy of the electrode trajectory; and (3) the correct attainment of the target. The proposed frameless technique using the Nexframe has been developed and successfully applied in our practice. It was shown to be helpful in overcoming the major issues that are usually encountered when electrodes are placed in the brain with frameless neurosurgery and reduced the risk of having to re-operate on patients to reposition the electrodes. [ABSTRACT FROM AUTHOR]

Despite consensus on some neurophysiological hallmarks of the Parkinsonian state (such as beta) band increase) a single mechanism is unlikely to explain the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Most experimental evidence to date correlates with an extreme degree of nigral neurodegeneration and not with different stages of PD progression. It seems inappropriate to combine substantially different patients – newly diagnosed, early fluctuators or advanced dyskinetic individuals – within the same group. An efficacious STN‐DBS imposes a new activity pattern within brain circuits, favouring alpha‐ and gamma‐like neuronal discharge, and restores the thalamo‐cortical transmission pathway through axonal activation. In addition, stimulation via the dorsal contacts of the macro‐electrode may affect cortical activation antidromically. However, basal ganglia (BG) modulation remains cardinal for 'OFF'‐'ON' transition (as revealed by cGMP increase occurring during STN‐DBS in the substantia nigra pars reticulata and internal globus pallidus). New research promises to clarify to what extent STN‐DBS restores striato‐centric bidirectional plasticity, and whether non‐neuronal cellular actions (microglia, neurovascular) play a part. Future studies will assess whether extremely anticipated DBS or lesioning in selected patients are capable of providing neuroprotection to the synuclein‐mediated alterations of synaptic efficiency. This review addresses these open issues through the specific mechanisms prevailing in a given disease stage. In patients undergoing early protocol, alteration in endogenous transmitters and recovery of plasticity are concurrent players. In advanced stages, re‐modulation of endogenous band frequencies, disruption of pathological pattern and/or antidromic cortical activation are, likely, the prominent modes. This manuscript proposes a new perspective in interpreting the efficacy of STN‐DBS in PD patients. The main concept is that the burden of neurodegeneration and PD stage represent the major factors. Whereas rescuing neuroplasticity plus rebalancing of endogenous band frequencies are early players, instead, in advanced PD stages, antidromic impact on cortex and circuitry disruption exert major roles. The understanding of the specific mechanisms prevalent in any given subject is crucial for on‐going trials, either experimenting adaptive DBS or targeting young patients. [ABSTRACT FROM AUTHOR]

Despite consensus on some neurophysiological hallmarks of the Parkinsonian state (such as beta) band increase) a single mechanism is unlikely to explain the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Most experimental evidence to date correlates with an extreme degree of nigral neurodegeneration and not with different stages of PD progression. It seems inappropriate to combine substantially different patients – newly diagnosed, early fluctuators or advanced dyskinetic individuals – within the same group. An efficacious STN‐DBS imposes a new activity pattern within brain circuits, favouring alpha‐ and gamma‐like neuronal discharge, and restores the thalamo‐cortical transmission pathway through axonal activation. In addition, stimulation via the dorsal contacts of the macro‐electrode may affect cortical activation antidromically. However, basal ganglia (BG) modulation remains cardinal for 'OFF'‐'ON' transition (as revealed by cGMP increase occurring during STN‐DBS in the substantia nigra pars reticulata and internal globus pallidus). New research promises to clarify to what extent STN‐DBS restores striato‐centric bidirectional plasticity, and whether non‐neuronal cellular actions (microglia, neurovascular) play a part. Future studies will assess whether extremely anticipated DBS or lesioning in selected patients are capable of providing neuroprotection to the synuclein‐mediated alterations of synaptic efficiency. This review addresses these open issues through the specific mechanisms prevailing in a given disease stage. In patients undergoing early protocol, alteration in endogenous transmitters and recovery of plasticity are concurrent players. In advanced stages, re‐modulation of endogenous band frequencies, disruption of pathological pattern and/or antidromic cortical activation are, likely, the prominent modes. This manuscript proposes a new perspective in interpreting the efficacy of STN‐DBS in PD patients. The main concept is that the burden of neurodegeneration and PD stage represent the major factors. Whereas rescuing neuroplasticity plus rebalancing of endogenous band frequencies are early players, instead, in advanced PD stages, antidromic impact on cortex and circuitry disruption exert major roles. The understanding of the specific mechanisms prevalent in any given subject is crucial for on‐going trials, either experimenting adaptive DBS or targeting young patients. [ABSTRACT FROM AUTHOR]

Objectives To investigate the effect of pure passive movement on both cortical and subcortical somatosensory evoked potentials (SEPs). Methods Median nerve SEPs were recorded in 8 patients suffering from Parkinson’s disease (PD) and two patients with essential tremor. PD patients underwent electrode implantation in the subthalamic (STN) nucleus (3 patients) and pedunculopontine (PPTg) nucleus (5 patients), while 2 patients with essential tremor were implanted in the ventral intermediate nucleus (VIM) of the thalamus. In anesthetized patients, SEPs were recorded at rest and during a passive movement of the thumb of the stimulated wrist from the intracranial electrode contacts and from the scalp. Also the high-frequency oscillations (HFOs) were analyzed. Results Amplitudes of both deep and scalp components were decreased during passive movement, but the reduction was higher at cortical than subcortical level. Also the HFOs were reduced by movement. Conclusion The different amount of the movement-related decrease suggests that the cortical SEP gating is not only the result of a subcortical somatosensory volley attenuation, but a further mechanism acting at cortical level should be considered. Significance Our results are important for understanding the physiological mechanism of the sensory–motor interaction during passive movement. [ABSTRACT FROM AUTHOR]

Objective To investigate the generators of the somatosensory evoked potential (SEP) components recorded from the Pedunculopontine Tegmental nucleus (PPTg). Methods Twenty-two patients, suffering from Parkinson’s disease (PD), underwent electrode implantation in the PPTg area for deep brain stimulation (DBS). SEPs were recorded from the DBS electrode contacts to median nerve stimulation. Results SEPs recorded from the PPTg electrode contacts could be classified in 3 types, according to their waveforms. (1) The biphasic potential showed a positive peak (P16) whose latency (16.05 ± 0.61 ms) shifted of 0.18 ± 0.07 ms from the lower to the upper contact of the electrode. (2) The triphasic potential showed an initial positive peak (P15) whose latency (15.4 ± 0.2 ms) did not change across the DBS electrode contacts. (3) In the last SEP configuration (mixed biphasic and triphasic waveform), the positive peak was bifid including both the P15 and P16 potentials. Conclusion While the P16 potential is probably generated by the somatosensory volley travelling along the medial lemniscus, the P15 response represents a far-field potential probably generated at the cuneate nucleus level. Significance Our results show the physiological meaning of the somatosensory responses recorded from the PPTg nucleus area. [ABSTRACT FROM AUTHOR]

The pedunculopontine tegmental nucleus (PPTg) relays basal ganglia signals to the thalamus, lower brainstem and spinal cord. Using the 6-hydroxydopamine (6-OHDA) rat model of parkinsonism, we investigated whether deep brain stimulation (DBS) of the PPTg (40Hz, 60μs, 200-400μA) may influence the preparative and executive phases in a conditioned behavioural task, and the motor asymmetries induced by apomorphine. In the conditioned task, rats had to press two levers according to a fixed delay paradigm. The 6-OHDA lesion was placed in the right medial forebrain bundle, i.e. contralaterally to the preferred forepaw used by rats to press levers in the adopted task. The stimulating electrode was implanted in the right PPTg, i.e. contralateral to left side, which was expected to be most affected. The lesion significantly reduced correct responses from 63.4% to 16.6%. PPTg-DBS effects were episodic; however, when rats successfully performed in the task (18.9%), reaction time (468.8±36.5ms) was significantly increased (589.9±45.9ms), but not improved by PPTg-DBS (646.7±33.8ms). Movement time was significantly increased following the lesion (649.2±42.6ms vs. 810.9±53.0ms), but significantly reduced by PPTg-DBS (820.4±39.4ms) compared to sham PPTg-DBS (979.8±47.6ms). In a second group of lesioned rats, rotations induced by apomorphine were significantly reduced by PPTg-DBS compared to sham PPTg-DBS (12.2±0.6 vs. 9.5±0.4 mean turns/min). Thus, it appears that specific aspects of motor deficits in 6-OHDA-lesioned rats may be modulated by PPTg-DBS. [ABSTRACT FROM AUTHOR]

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson's disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered. [ABSTRACT FROM AUTHOR]

Abstract: The present paper was aimed at investigating the effect of low-frequency electrical stimulation (25 Hz) of the peduncolopontine (PPN) area on working memory (WM) functioning in patients with Parkinson''s disease (PD). Five PD patients who underwent simultaneous PPN area- and subthalamic nucleus-deep brain stimulation (DBS) implantation participated in the study. PD patients were evaluated in the morning at least 12 h after antiparkinsonian therapy withdrawal in two conditions: i) after continuous PPN area stimulation (Off Therapy/On PPN: “On” condition); ii) at least 120 min after PPN area had been switched “Off” (Off Ther/Off PPN: “Off” condition). The experimental WM task consisted of an n-back paradigm with verbal and visual-object stimuli. PD patients showed a consistent response time decrease on both the verbal and the visual-object tasks passing from the “Off” to the “On” condition (p < 0.05). However, the accuracy score did not significantly differ between the two experimental conditions. The present findings, although preliminary, suggest that PPN area stimulation facilitates the speed processing of information in the content of WM, possibly through the modulation of the attentional resources. [Copyright &y& Elsevier]

Abstract: Combined deep brain stimulation of the subthalamic (STN) and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced Parkinson''s disease. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. We studied five advanced Parkinson''s disease patients who underwent combined deep brain stimulation (STN + PPN). Overall cognitive profile did not change. On the contrary, an interesting trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) was found when stimulating the STN, and also the PPN, when the STN was switched off. These findings replicate previous observations on the STN, and provide the rationale for further investigation of the role of the PPN in processing linguistic grammar. [Copyright &y& Elsevier]

Abstract: Objective: To investigate whether recording from deep intracerebral (IC) electrodes can disclose laser evoked potential (LEP) components generated under the cerebral cortex. Methods: LEPs were recorded to hand and/or perioral region stimulation from 7 patients suffering from Parkinson’s disease, who underwent implant of IC electrodes in the globus pallidum pars interna (GPi), in the subthalamic nucleus (STN) and in the pedunculopontine nucleus (PPN). LEPs were obtained from the IC electrode contacts and from the Cz vertex, referred to the nose. Results: The scalp traces showed a triphasic response (P1-N2-P2). The IC electrodes recorded two main components (ICP2 and ICN2), showing the same latencies as the scalp N2 and P2 potentials, respectively. The ICP2-ICN2 complex was sometimes preceded by a ICP1 wave at the same latency of the scalp P1 response. Conclusions: The LEP components recorded from the IC electrodes mirrored the ones picked up from the Cz lead, thus suggesting that they are probably generated by the opposite pole of the same cortical sources producing the scalp responses. Significance: In the IC traces, there was no evidence of earlier potentials possibly generated within the thalamus or of subcortical far-field responses. This means that the nociceptive signal amplification occurring within the cerebral cortex is necessary to produce identifiable LEP components. [Copyright &y& Elsevier]

Abstract: The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus—STN or the internal pallidus—GPi) plus an innovative one (CM/Pf) in well-identified Parkinson’s disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation—DBS – in STN – , n =2) and disabling involuntary movements, partially responsive to GPi–DBS (n =6). When considering global UPDRS scores, CM/Pf–DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions. [Copyright &y& Elsevier]

Bilateral peduncolopontine nucleus (PPN) and subthalamic nucleus (STN) deep brain stimulation (DBS) was performed in six-advanced Parkinson’s disease (PD) patients. We report the effect of both PPN-DBS (25 Hz) and STN-DBS (185 Hz) on patient spinal reflex excitability by utilizing the soleus-Hoffman reflex (HR) threshold. Compared to controls ( n = 9), patients showed an increase of HR-threshold, which was scarcely affected by levodopa, but significantly reduced by DBS. In particular, we found that PPN-DBS alone, or plus STN-DBS induced a complete recovery of HR-threshold up to control values. The HR-threshold changes, although do not allow to investigate the contribution of specific intraspinal pathways, suggest that PPN may play a key-role in modulating spinal excitability in PD possibly by improving the basal ganglia-brainstem descending system activity. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the reduction of amplitude of the scalp somatosensory evoked potentials (SEPs) during movement (gating) is due to an attenuation of the afferent volley at subcortical level.Methods: Median nerve SEPs were recorded from 9 patients suffering from Parkinson''s disease, who underwent implant of intracerebral (IC) electrodes in the subthalamic nucleus or in the globus pallidum. SEPs were recorded from Erb''s point ipsilateral to stimulation, from the scalp surface and from the IC leads, at rest and during a voluntary flexo-extension movement of the stimulated wrist. The recorded IC traces were submitted to an off-line filtering by a 300–1500 bandpass to obtain the high-frequency SEP bursts.Results: IC leads recorded a triphasic component (P1–N1–P2) from 14 to 22 ms of latency. The amplitudes of the scalp N20, P20 and N30 potentials and of the IC triphasic component were significantly decreased during movement, while the peripheral N9 amplitude remained unchanged. Also the IC bursts, whose frequency was around 1000 Hz, were reduced in amplitude by the voluntary movement.Conclusions: Since the IC triphasic component is probably generated by neurons of the thalamic ventro-postero-lateral nucleus, which receive the somatosensory afferent volley, the P1–N1 amplitude reduction during movement suggests that the gating phenomenon involves also the subcortical structures. [Copyright &y& Elsevier]