Spinal cord stimulation restores locomotion in animal models of Parkinson's disease

Abstract

Dopamine replacement therapy is useful for treating motor symptoms in the early phase of Parkinson's disease, but it is less effective in the long term. Electrical deep-brain stimulation is a valuable complement to pharmacological treatment but involves a highly invasive surgical procedure. We found that epidural electrical stimulation of the dorsal columns in the spinal cord restores locomotion in both acute pharmacologically induced dopamine-depleted mice and in chronic 6-hydroxydopamine-lesioned rats. The functional recovery was paralleled by a disruption of aberrant low-frequency synchronous corticostriatal oscillations, leading to the emergence of neuronal activity patterns that resemble the state normally preceding spontaneous initiation of locomotion. We propose that dorsal column stimulation might become an efficient and less invasive alternative for treatment of Parkinson's disease in the future.

Figures

Figure 1. Acute inhibition of dopamine synthesis produces a Parkinsonian state

(A) Examples of LFP spectrograms and firing rate plots recorded in MI during two 5-minute periods before and after dopamine depletion. Top row: locomotion during recording periods, second row: LFP power, third row: LFP power standardized to the non-depleted 5-minute period, fourth row: close-up of low-frequency range shown in third row. Note the increased power in low frequencies in the depleted state (black arrows) and the relative normalization of spectral power upon locomotion (red arrow). Bottom row: average firing per second for 6 MI units. (B) Set-up for electrical stimulation of dorsal columns: The stimulation electrode (red) is implanted above the spinal cord and connection wires are passed subcutaneously to a connector attached to the skull. Two stimulus-isolator units provide biphasic constant-current pulses at desired frequency and intensity. (C) Schematic dorsal (left) and sagittal view (right) of the implanted electrode. r: rostral; c: caudal.

Figure 2. DCS restores locomotion and desynchronizes corticostriatal activity

(A) Relative change in amount of locomotion in depleted and non-depleted mice (DCS frequencies specified on x-axis, n.V: trigeminal nerve stimulation; mean and SD shown, means for all conditions before and after depletion are significantly different, α = 0.005). (B) DCS preferentially increases the fraction of faster movement components in dopamine depleted animals but not in controls. (C) Average spectrograms of striatal LFPs and firing rates recorded around 300 Hz stimulation events (yellow bar), top row: LFP power (n = 21 events; black trace denotes spectral index, see main text) second row: LFP power standardized to first 240 s. Row 4 and 5, respectively: firing rate for 98 striatal and 96 cortical units (standardized to firing rates during first 240 s and ordered by responsiveness after DCS (19), n = 36 events). Neurons exhibiting significant changes during the 30s-period following stimulation (black line) are indicated with red and blue rectangles (excitatory and inhibitory responses). Middle row: Average locomotion (n = 36 events).

Figure 3. Activity patterns during spontaneous locomotion

(A) Average spectrogram of striatal LFP aligned to the onset of spontaneous locomotion in control (n = 115 events) and dopamine-depleted condition (n = 51 events). The gradual shift from lower to higher frequencies indicated by the average spectral index (black trace) starts before locomotion onset (dashed white line). (B) Standardization of spectrogram relative to directly preceding non-locomotion periods (collected between 20 to 10 s prior to locomotion onset from 112 stationary 10 s periods). (C) Firing rate (binned at 0.5 s) of striatal and MI units around the onset of spontaneous locomotion. Significant changes in firing rate (as compared to stationary period) are indicated with magenta (excitatory) and blue (inhibitory response) crosses. (D) Average locomotion during recorded events.

Figure 4. DCS restores locomotion in severely dopamine-depleted mice and in chronically lesioned rats

(A) The cumulative amount of locomotion scored in animals receiving DCS in combination with successive L-DOPA injections (black) was significantly higher at all time points than what was observed for the group only receiving L-DOPA (gray). (B) DCS (yellow shaded area) induced a prominent increase in locomotion in 6-OHDA lesioned rats (shaded area around trace is SEM) compared to preceding non-DCS sessions. In the sham group, in contrast, DCS caused a moderate response comparable to non-DCS sessions (mean ± SEM, n = 64 stimulation and 64 control sessions for both sham treated and lesioned rats). (C) DCS specifically increases locomotion in 6-OHDA lesioned rats (mean and SEM shown; all means are significantly different to the others, p < 0.001, Kruskal-Wallis and Dunn’s multiple comparison test; flashes indicate DCS sessions). (D) A preferential relative increase of faster movement components locomotion was found in the 6-OHDA lesioned group reflecting alleviation of bradykinetic symptoms. Ratios of the sum of recorded locomotion episodes in three speed intervals [DCS/non-DCS sessions] are shown.