High-frequency stimulation of the subthalamic nucleus restores neural and behavioral functions during reaction time task in a rat model of Parkinson's disease

Abstract

Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson's disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico-basal ganglia regions of partially bilateral DA- lesioned rats. We recorded neural activity with a multiple-channel single-unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6-OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6-OHDA lesioned rats, and restored operational behavior-related neural responses in cortico-basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion-induced impairment of RT performance is associated with changes in neural activity in the cortico-basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long-lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating cortico-basal ganglia circuits.

Fig. 1

The cumulative distribution of RT in 10 rats before and after successful DA depletion. Correct and late responses are summed up together in the distribution. Grey and dark lines indicate the result during the pre-lesion (naïve) and post-lesion (PD) sessions, respectively. Marked right-shift of the cumulative frequency distribution curve can be seen after DA depletion.

Fig. 2

Examples of typical neural responses to different behavioral events. Raster and peri-event histograms during RT tasks are displayed for each neuron. Panels A–D and E representatively illustrate neural response (excitatory and inhibitory) to following events: cuelight, nosepoke, lever press, tone, and lever release, respectively. Panel F shows two typical neurons with biphasic responses (excitatory/inhibitory or inhibitory/excitatory).

Fig. 3

A summary of neural responses from different brain regions before and after successful DA-lesion. The percent of responsive neurons in MI, SNr and STN brain regions during nosepoke (top), lever press (middle) and lever release (bottom) behavior were shown in the figure. Blank and grey bars indicate data from rats under intact (naive) and lesioned (PD) conditions. Dopamine lesion significantly reduced neuronal responses on nosepoke in all three brain areas, on lever-press in two out of three areas, while no changes were found in any brain area for the lever-release. *, **, and ***: Chi-square test, P < 0.05, P < 0.01, and P < 0.001, respectively.

Fig. 4

An example of the beneficial effect of DBS on RT performance. A: Cumulative RT performance was shown in frequency curves plotted over time. Dopamine lesion alone induced a marked elevation of late responses. B: Changes of RT performance with DBS (stimulation on) and without DBS (stimulation off). Correct responses notably increased following STN DBS, an effect which continued even after DBS ceased. The plots in (C) and (D) illustrate the percentage of correct, early, and late performance in the same rat as in (A) and (B), respectively. E: Mean and standard error of RTs in the same session before, during and after DBS. Mean RT was significantly decreased during and after DBS. *, **: P < 0.05, P < 0.01; respectively, ANOVA followed by Duncan’s post-hoc test.

Fig. 5

Types and examples of neural responses to DBS. A: Colorcoded image plot of neuronal firing patterns (z-scores over the baseline) revealed by cluster analysis. Warm colors (red to yellow) represent elevated firing rates, as indicated by z-scores bigger than 2. Conversely, cold colors (blue to cyan) represent lowered firing rates. Each horizontal line represents the one neuron. C1 through C4 represent four categories of neural firing patterns with distinct features. B: Rearrangement of clusters into each brain areas. Firing patterns were sorted by recording region (MI, STN and SNr). Most cluster 1 neurons were found in STN. C: Representative examples from each cluster. This time histogram plot revealed that cluster 1 neurons showed sharp and strong response to DBS, especially at the first several minutes; cluster 2 neurons showed mild response that lasts through the DBS period; cluster 3 neurons gradually increase their firing rates after DBS; cluster 4 neurons showed either inhibitory or no response at all to DBS. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 6

Neural responses and task-dependent modulation with DBS. A: Examples of peri-event rasters and histograms for a neuron recorded in the STN, before, during, and after stimulation. There is no meaningful modulation of neural activity with lever press in the pre- and during-stimulation periods. However, a consistent response to lever press was observed following STN HFS. Note that the baseline firing rate (before lever press) is increased during and post-stimulation. B: Neural responses related to nosepoke, lever press and lever release behavior in the MI, SNr and STN before (blank bars) and after DBS (grey bars). A global increase of neuronal responses were observed after DBS. *, **: Chi-square test, P < 0.05 and P < 0.01, respectively.