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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]

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]

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 µs, 100–1000 µA). 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. [ABSTRACT FROM AUTHOR]

Synchronization of neuronal activity evident in the local field potential (LFP) recorded in the subthalamic region of patients with Parkinson's disease occurs at low frequencies (< 30 Hz) and, in some patients following treatment with levodopa, at high frequencies between 65 and 85 Hz. Here we investigate the functional relationship between these different activities by determining whether spontaneous fluctuations in their strength are correlated across time. To this end, we analysed recordings of LFPs from macroelectrodes inserted in the subthalamic area of 16 patients with Parkinson's disease, after treatment with anti-parkinsonian medication. Time-evolving autospectra of LFPs with significant 65–85 Hz peaks (from 21 sides) were computed and correlations between frequency components determined over time. LFP activity in the 5–32 Hz band was significantly negatively correlated with that in the 65–85 Hz band in data averaged across all 21 sides, as well as in 15 (71%) of the individual records. Negative correlations were relatively selective for interactions between these frequency bands and occurred over time epochs of as little as 40 s. They occurred about 50 min after levodopa and were recorded concurrently with contralateral levodopa-induced dyskinesias in all but four cases. Positive correlations were not seen between activities in the 5–32 Hz and 65–85 Hz bands. The spontaneous negative correlations suggest a reciprocal relationship between population synchrony in the high- and low-frequency ranges, and raise the possibility that spontaneous fluctuations in the balance between these activities may contribute to levodopa-induced dyskinesias. [ABSTRACT FROM AUTHOR]