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Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PPN neurons following STN-HFS was a 5-20 s excitation, which was present in 76.6% of responsive neurons in comparison to 15.4% and 9.1% of neurons responsive in intact and in 6-hydroxydopamine-lesioned rats, respectively. Neurons responsive to STN-HFS in the three experimental groups showed either a sharp positively skewed distribution of interspike intervals or multisecond oscillations in autocorrelograms. The results support that STN-HFS modulates the PPN through a balance of excitatory and inhibitory influences, which may be independent from the dopaminergic nigral neurons. In the absence of inhibitory EP fibres, the direct excitatory influence exerted by the STN on the PPN appears to predominate.

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.

Object: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets., Methods: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects., Conclusions: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.

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]

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]