Reply to: Deep brain stimulation in Parkinson's disease can mimic the 300 Hz subthalamic rhythm Subthalamic high-frequency stimulation drives subthalamic oscillatory activity at stimulation frequency while firing rate is reduced
1 Laboratoire de Neurophysiologie, Université Victor Ségalen Bordeaux, France 2 Department of Neurology, CHU Pellegrin Bordeaux, France 3 Neurophysique et Physiologie du Système Moteur, Université Paris V Paris, France
Correspondence to: Dr Wassilios Meissner, CNRS UMR 5543, Université Victor Ségalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France E-mail: wassilios.meissner{at}umr5543.u-bordeaux2.fr
We have read with interest the letter by Foffani and Priori that will be published online alongside the same issue of Brain. Foffani and Priori hypothesize that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) might induce oscillatory activity around 250 Hz in the basal ganglia network. To verify this assumption, we performed a new analysis of our entire data set, where we tried to be as close as possible to the analysis described in our recent publication (for details, see Meissner et al., 2005
). Accordingly, single-cell oscillations and synchronized oscillatory activity between pairs of neurons were assessed by calculating auto-correlograms (AC) and cross-correlograms (CC), respectively (1000 ms offset with a bin width of 1 ms instead of 5 ms to enable the analysis of frequencies up to 350 Hz). For each AC and CC the power spectrum was calculated between 3 and 350 Hz and the oscillatory activity was assessed for three distinct frequency bands: 3–30 Hz as in our recent publication, 31–200 Hz and 201–350 Hz. A peak in the power spectrum was considered to be significant if it was higher than the mean power of the entire spectrum [(3–350 Hz) + 5 SD] and if it had an oscillatory index >10%. The standard deviation was individually calculated for each frequency band using the two other frequency bands (i.e. for the 3–30 Hz band, the standard deviation was calculated in the 31–350 Hz range). Differences of AC and CC between the experimental states were assessed by using z-tests.
Total single oscillatory activity was 95.1% in the normal state and 92.9% in the parkinsonian state (Fig. 1A, z = 0.1, P > 0.5) and was mainly related to oscillatory activity in the 3–30 Hz frequency band (3–30 Hz: 90.2% versus 83.7%, z = 0.7, P > 0.05; 31–200 Hz: 4.9% versus 5.1%, z = –0.4, P > 0.5; 201–350 Hz: 2.4% versus 4.1%, z = –0.01, P > 0.5). The strong oscillatory activity in the normal state and the absence of a significant increase in the parkinsonian state are explained by the observation that the power spectrum in the 31–200 Hz and 201–350 Hz bands were generally flat, but contributed to the calculation of the mean and standard deviation for the 3–30 Hz band, rendering the analysis very sensitive for that frequency band.
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Total synchronized oscillatory activity between pairs of neurons was 40.4% in the normal and 50.0% in the parkinsonian state (Fig. 1B, z = 1.1, P > 0.05). MPTP treatment significantly increased synchronized oscillatory activity in the 3–30 Hz frequency band (8.8% versus 23.3%, z = 2.2, P < 0.05), while no significant differences were observed for both higher frequency bands (31–200 Hz: 7.0% versus 8.7%, z = 0.1, P > 0.5; 201–350 Hz: 24.6% versus 18.0%, z = 0.9, P > 0.05).
STN–HFS in the parkinsonian state induced strong oscillatory activity in the 31–200 Hz band at the stimulation frequency of 130 Hz (Fig. 1C and D, single neuron: 93.0%; pairs of neurons: 100.0%), while STN–HFS decreased the firing rate of subthalamic neurons to 48.9% of baseline values (Meissner et al., 2005). Only 7.3% of single neurons showed significant oscillatory activity in the 3–30 Hz band and 2.3% in the 201–350 Hz band. When comparing these values with the MPTP-treated state, differences were significant for the 3–30 Hz and the 31–200 Hz band (3–30 Hz: z = 8.4, P < 0.001; 31–200 Hz: z = 10.1, P < 0.001; 201–350 Hz: z = 0.04, P > 0.5). Synchronized oscillatory activity during STN–HFS was exclusively present in the 31–200 Hz frequency band. Differences between MPTP and MPTP + HFS states were significant for all frequency bands (3–30 Hz: z = 3.4, P < 0.001; 31–200 Hz: z = 11.7, P < 0.001; 201–350 Hz: z = 2.9, P < 0.5).
As shown in our previous paper, the recovery of the mean firing probability of STN neurons between two electrical stimuli is represented by a sigmoid function: f(t) = F0/(1 + exp (–k (t – t0))), where F0 is the baseline firing rate, t the time in seconds, k = 4.5 ± 0.6 ms–1 and t0 = 4.4 ± 0.2 ms (Fig. 2A). To strengthen our in vivo data using a theoretical approach, two neurons were generated by an inhomogeneous Poisson process, with a firing probability following the sigmoid function along time (Fig. 2B). Consequently, AC, CC and their power spectra were calculated. As shown in Fig. 2C, oscillatory activity at the stimulation frequency is present at the single-cell level and between both generated neurons.
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Although the detection thresholds were slightly different than in our first analysis, the present results confirm our previous findings that STN–HFS reduces abnormal oscillatory activity in the 3–30 Hz band. However, STN–HFS also induced a strong oscillatory activity at the stimulation frequency, suggesting that STN–HFS creates a new oscillatory state and is not simply inhibiting abnormal oscillations. Our results confirm further the existence of oscillatory activity at higher frequencies. Interestingly, such activity is almost exclusively seen at the population level and, in the normal state, is higher than those in the 3–30 Hz band (8.8% versus 24.6%, Fig. 1A and B). However, no significant differences were found between the normal and the parkinsonian states for either the 31–200 Hz band or the 201–350 Hz band. STN–HFS almost completely abolished oscillatory activity in the 201–350 Hz band in contrast to the expectation of Foffani et al. (2006)
. Only one single neuron showed significant oscillatory activity at 260 Hz, while significant oscillations were absent in that frequency band at the population level during stimulation.
In a recent contribution, Hashimoto et al. (2003) showed two excitatory responses in the globus pallidus internus (GPi) during STN–HFS around 2.5–4.5 and 5.5–7.0 ms after the onset of the electrical pulse (Hashimoto et al., 2003). Referring to these results, Foffani and Priori hypothesize that STN–HFS might induce synchronized oscillatory activity in the GPi in a frequency around 250 Hz. The results of several studies suggest that STN–HFS might have distinct effects on STN neurons with inhibition of the soma (cell body) and activation of axons (Windels et al., 2000; Maurice et al., 2003; Tai et al., 2003; Filali et al., 2004; McIntyre et al., 2004; Welter et al., 2004; Meissner et al., 2005; Stefani et al., 2005). Thus, the first excitatory response of GPi neurons during STN–HFS might be due to direct activation of STN axons, while the second response might be related to the activity of the soma. This hypothesis would not contradict the observation that we did not find oscillatory activity in the STN at 250 Hz during stimulation. However, it is difficult to believe that the recovery of STN firing activity, reaching baseline values 
7 ms after each electrical stimulus, could elicit such a strong excitatory response of GPi neurons, largely exceeding baseline firing rate of GPi neurons (Hashimoto et al., 2003). Beyond this point, we should remain cautious when interpreting the data of Hashimoto et al. (2003) since (i) their study did not intend to directly assess the impact of STN–HFS on oscillatory activity of GPi neurons and (ii) it is impossible to predict the activity at the population level as evidenced by cross-correlation of two simultaneously recorded neurons or local field potentials (LFP) when performing single-unit recordings.
In a previous publication, Foffani et al. (2003) reported dopamine-dependent oscillatory activity around 300 Hz in the STN of parkinsonian patients that increases with levodopa administration and movement. On the basis of this observation, they have hypothesized that STN–HFS could act through a re-establishment of an oscillatory activity around 250–350 Hz in the basal ganglia circuitry. As mentioned above, our results do not allow us to infer the activity of GPi neurons during STN stimulation. However, as shown above, we did not find significant oscillatory activity in the 201–350 Hz frequency band in the STN during stimulation. In contrast, STN–HFS significantly decreased synchronized oscillations in the 201–350 Hz band between pairs of STN neurons. Moreover, oscillatory activity in the 201–350 Hz band was not significantly different between the normal and the parkinsonian states challenging the pathophysiological role of oscillations >200 Hz. But are basal ganglia single-cell and LFP recordings really measuring the same thing? The results of several studies in rodents, non-human primates and PD patients have suggested that LFP recordings correlate with spiking activity within the STN or other basal ganglia nuclei (Levy et al., 2002; Goldberg et al., 2004; Magill et al., 2004; Trottenberg et al., 2006). However, the strength of this correlation in the basal ganglia is weak since the ‘spike-LFP correlation measure’ in the GPi is small in the normal and parkinsonian states in non-human primates, while a significant increase occurs in the striatum in the parkinsonian state (Goldberg et al., 2004). Furthermore, the shape of the cross-correlogram between two simultaneously recorded neurons cannot be predicted from the LFP in the GPi, while synchronized oscillatory activity in the striatum can be predicted from the LFP in the parkinsonian state (Goldberg et al., 2004). Taken together, LFP recordings within the basal ganglia might not necessarily reflect single-unit activity. Since modifications in LFP recordings precede the time of spike emission by tens of milliseconds, they might represent neuronal input, a summation of excitatory postsynaptic potential (EPSP) and inhibitory postsynaptic potential (IPSP) or fluctuations of the membrane potential that could have impact on the firing probability depending on other factors such as the level of dopamine depletion.
To summarize, STN–HFS induces strong oscillatory activity in the STN at the stimulation frequency, while oscillations in the 3–30 Hz and 201–350 Hz frequency band are suppressed. The results of an increasing number of experimental studies have shown that oscillatory activity co-varies with different experimental states (normal, MPTP, HFS), indicating a modification of the dynamic properties of the basal ganglia network that might underlie the onset, worsening or reduction of symptoms in PD and other movement disorders. However, a solid causal link between oscillatory activity in any frequency band and clinical symptoms is still lacking, making future studies indispensable.
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