Skip to main content
NCBI home page
Journal of Neurophysiology logoLink to Journal of Neurophysiology
. 2015 Feb 11;113(9):3038–3046. doi: 10.1152/jn.01072.2014

Effects of subthalamic deep brain stimulation on blink abnormalities of 6-OHDA lesioned rats

Jaime Kaminer 1, Pratibha Thakur 2, Craig Evinger 3,4,✉
PMCID: PMC4455559  PMID: 25673748

Abstract

Parkinson's disease (PD) patients and the 6-hydroxydopamine (6-OHDA) lesioned rat model share blink abnormalities. In view of the evolutionarily conserved organization of blinking, characterization of blink reflex circuits in rodents may elucidate the neural mechanisms of PD reflex abnormalities. We examine the extent of this shared pattern of blink abnormalities by measuring blink reflex excitability, blink reflex plasticity, and spontaneous blinking in 6-OHDA lesioned rats. We also investigate whether 130-Hz subthalamic nucleus deep brain stimulation (STN DBS) affects blink abnormalities, as it does in PD patients. Like PD patients, 6-OHDA-lesioned rats exhibit reflex blink hyperexcitability, impaired blink plasticity, and a reduced spontaneous blink rate. At 130 Hz, but not 16 Hz, STN DBS eliminates reflex blink hyperexcitability and restores both short- and long-term blink plasticity. Replicating its lack of effect in PD patients, 130-Hz STN DBS does not reinstate a normal temporal pattern or rate to spontaneous blinking in 6-OHDA lesioned rats. These data show that the 6-OHDA lesioned rat is an ideal model system for investigating the neural bases of reflex abnormalities in PD and highlight the complexity of PD's effects on motor control, by showing that dopamine depletion does not affect all blink systems via the same neural mechanisms.

Keywords: blink reflex, Parkinson's disease, basal ganglia, spontaneous blinking

parkinson's disease (PD) patients display obvious voluntary motor deficits, but disruptions of voluntary movement in rodent models of PD are not as apparent as those of PD patients (Bove et al. 2005; Cenci et al. 2002). Nevertheless, the blink and stretch reflex abnormalities of PD patients (Agostino et al. 1987; Berardelli et al. 2001; Cody et al. 1986; Duysens et al. 2010; Kimura 1973; Rothwell et al. 1983; Sunohara et al. 1985; Tatton and Lee 1975) and rodent models of PD (Basso et al. 1993; Wolfarth et al. 1996) are nearly identical. For example, both PD patients and the 6-hydroxydopamine (6-OHDA) rat model of PD exhibit strong reflex blink hyperexcitability. These data suggest that blink abnormalities of the rat 6-OHDA lesion model of PD are ideal for testing treatment options and identifying the neural circuits and modifications that create PD reflex movement abnormalities.

High-frequency subthalamic nucleus deep brain stimulation (STN DBS) is an accepted treatment for advanced PD (Benabid et al. 2009; Bronstein et al. 2011) and restores some aspects of blinking in PD patients (Bologna et al. 2012). One effect of 130-Hz STN DBS is disruption of the basal ganglia's characteristic hypersynchronized beta band activity seen in both PD patients (Dorval et al. 2010; Ray et al. 2008; Wingeier et al. 2006) and in the 6-OHDA rat model of PD (Lehmkuhle et al. 2009; Li et al. 2007; McConnell et al. 2012). The therapeutic effectiveness of high-frequency STN DBS may be a result of reducing this 10- to 30-Hz beta-oscillation. Consistent with this interpretation, beta frequency STN DBS of normal rats causes the same reflex blink abnormalities as occur in PD patients (Kaminer et al. 2014). If 130-Hz STN DBS reduces beta band oscillations in 6-OHDA lesioned rats, then we predict that this frequency will eliminate blink abnormalities in 6-OHDA lesioned rats, whereas STN DBS in the beta frequency range will not improve blinking.

PD also disrupts reflex plasticity (Battaglia et al. 2006; Chong et al. 2000; Horak et al. 1992; MacAskill et al. 2002; White et al. 1983). The trigeminal blink reflex provides a model for this type of plasticity. Depending upon its timing relative to reflex blink occurrence, high-frequency stimulation of the supraorbital branch of the trigeminal nerve can increase or decrease the amplitude of subsequent reflex blinks for a period of at least 1 h (Mao and Evinger 2001; Ryan et al. 2014). Both PD in humans and 6-OHDA lesions in rats impair this form of trigeminal blink reflex plasticity (Battaglia et al. 2006; Kaminer et al. 2014). We predict that 130-Hz STN DBS will restore normal reflex blink plasticity in 6-OHDA lesioned rats. The abnormal basal ganglia activity of PD could impair reflex plasticity by preventing expression of the plasticity, blocking induction of the plasticity, or a combination of the two processes. We propose to investigate the mechanism involved by presenting 130-Hz STN DBS only during the induction of blink reflex plasticity.

In addition to its effects on trigeminal reflex blinks, PD reduces the rate of spontaneous blinking (Bologna et al. 2012; Karson et al. 1982; Korosec et al. 2006). Consistent with the loss of dopaminergic neurons with PD, dopamine receptor blockade in normal primates and rodents reduces the spontaneous blink rate (Kaminer et al. 2011; Lawrence and Redmond 1991; Taylor et al. 1999) and disrupts the temporal organization of spontaneous blinking (Kaminer et al. 2011). It is unknown whether 6-OHDA lesion rats exhibit a similar reduction in spontaneous blink rate and disruption of the temporal organization of blinking. We measure spontaneous blinking in 6-OHDA lesioned rats and test whether 130-Hz STN DBS restores normal spontaneous blinking.

MATERIALS AND METHODS

Experiments were performed on 13 male Sprague-Dawley rats (350–550 g) maintained on a reversed 12:12-h light/dark cycle and fed ad libitum. All experiments received approval by the Stony Brook University Institutional Animal Care and Use Committee and complied with all Federal, State, and University regulations and guidelines regarding the use of animals in research.

Surgery.

Under general anesthesia (ketamine, 90 mg/kg, and xylazine, 10 mg/kg), rats received a pair of unilateral 6-OHDA injections of 7.5 and 6 μg into the right substantia nigra pars compacta and medial forebrain bundle (Basso et al. 1993). They were then implanted unilaterally with laboratory-designed stimulating electrodes in the STN. The stimulation electrodes were 4 twisted stainless steel Teflon-coated wires (0.003-in. diameter bare, 0.0055-in. coated; A-M Systems, Everett, WA). Electrodes were implanted stereotaxically into the right STN (AP: −3.8 mm, ML: 2.5 mm) (Paxinos and Watson 1998). Final electrode position was determined by recording through one of the DBS leads to find an increase in neural activity as the electrode moved through the zona incerta into the STN. After STN implantation, rats were prepared for chronic recording of the left orbicularis oculi EMG (OOemg) and stimulation of the left supraorbital (SO) branch of the trigeminal nerve (Basso et al. 1993; Dauvergne and Evinger 2007; Evinger et al. 1993). Wires were led subcutaneously to a connector embedded in a dental acrylic platform on the skull. The platform was attached to the skull by four stainless-steel screws. A silver wire connected to one of the stainless-steel screws served as the ground. Rats received analgesic (ketorolac, 7 mg/kg) for at least 24 h after the surgery. Rats were alert and eating within 24 h of the surgery. The experiments began 10 days after surgery. After completion of experiments, rats were anesthetized with ketamine, 90 mg/kg, and xylazine, 10 mg/kg, and perfused intracardially with 6% dextran in 0.1 M phosphate buffer followed by 4% paraformaldehyde in 0.1 M phosphate buffer. The brains were cryoprotected and sectioned at 40 μm, and every other section was stained with cresyl violet to identify DBS electrode location or immunohistochemically for tyrosine hydroxylase to assess lesion magnitude (Basso et al. 1993). Tyrosine hydroxylase staining revealed full unilateral lesions of the substantia nigra pars compacta in all thirteen 6-OHDA injected rats. All but one rat had correct STN electrode placement. This rat's data were not included in the results.

Procedures.

In all experiments, the SO stimulus current was twice the threshold (T) current at which a 100-μs stimulus reliably elicited the R1 component of the reflex blink. The threshold current was determined at the beginning of each day for each rat. Threshold varied little across days (Ryan et al. 2014). We attempted to maximize the effect of STN DBS on blinking without causing any abnormal motor behavior. We found that biphasic 100-μA, 100-μS STN DBS delivered at either 130 Hz or 16 Hz did not cause any irregular motor behaviors or STN tissue damage and that 130-Hz STN DBS modified blinking.

Blink reflex excitability.

We evaluated the effects of a beta frequency, 16-Hz, and 130-Hz STN DBS on trigeminal blink excitability using the paired stimulus paradigm. Rats underwent three blocks of twenty trials comprised of pairs of 2T SO with a 100-ms interstimulus interval. Trials occurred pseudorandomly with a 20 ± 5 s intertrial interval. During each block, the rat received 16- or 130-Hz STN DBS or No DBS. They experienced all three conditions each day. STN DBS began 5 min before a block and terminated immediately after completing the block of 20 trials. There were 5 min between blocks. Because our previous study (Basso et al. 1993) demonstrated that the side contralateral to the 6-OHDA lesion exhibited the largest changes in blink excitability, we only examined OOemg activity contralateral to the 6-OHDA lesion and the STN stimulating electrode.

Blink reflex plasticity.

To investigate the effects of 130- or 16-Hz STN DBS on blink reflex plasticity, we utilized a protocol previously designed to depress blink reflex gain (Mao and Evinger 2001), adapted for use in rodents (Ryan et al. 2014). A 2T SO high-frequency stimulus (HFS, 400 Hz) was delivered before the R2 component of the SO-evoked blink reflex (HFS-B). Each day's data collection consisted of five blocks: 1) pre-HFS-B (Fig. 1, Pre); 2) HFS-B treatment (Fig. 1, HFS-B); 3) immediately post-HFS-B (Fig. 1, T0); 4) 30 min post-HFS-B (Fig. 1, T30); and 5) 60 min post-HFS-B (Fig. 1, T60). HFS-B trials induced blink plasticity, and the three post-HFS-B blocks revealed expression of the plasticity relative to the blinks before HFS-B treatment. Pre- and post-HFS blocks were the same for all experiments. In these blocks, rats received 20 trials of a pair of 2T SO stimuli separated by 100 ms with an intertrial interval of 20 ± 5 s. Each HFS treatment trial consisted of a single SO stimulus at 2T to evoke a reflex blink followed by five, 400-Hz 2T SO stimuli delivered before the onset of the R2 component of the OOemg activity. The sixty HFS trials also occurred with a 20 ± 5 s intertrial interval. During the plasticity paradigm, rats received either No STN DBS, 16-Hz, or 130-Hz STN DBS in a counterbalanced design. Rats were in the same DBS stimulus condition for at least 10 days of experiments before switching to a different DBS condition. In these experiments, STN DBS began before testing blink threshold and continued throughout the entire day's experiment. Three rats also underwent a protocol in which 130-Hz STN DBS was only turned on 5 min prior to HFS-B treatment and turned off immediately after HFS-B treatment concluded (130-D). Post-HFS data collection began 5 min after 130-Hz STN DBS was turned off in this paradigm.

Fig. 1.

Fig. 1.

Open in a new tab

Diagram of the blink reflex plasticity paradigms. Triangles show a twice-threshold 100-μs supraorbital nerve stimulus. In the primary paradigm, deep brain stimulation (DBS) of the subthalamic nucleus (STN) began 5 min before data collection and continued throughout the experiment. In the 130-D paradigm, 130-Hz subthalamic nucleus DBS only occurred while the rat received HFS-B.

Spontaneous blinking.

We monitored spontaneous blinking in three rats with and without 130-Hz STN DBS. Using a counterbalanced design, we collected 35 min of spontaneous blinking for both conditions each day. This duration of data collection was critical because our previous study demonstrated that short periods of data collection overestimated the blink rate (Kaminer et al. 2011). The first 5 min of data were not analyzed to allow the rats to habituate to the experimental setup. In addition to using the OOemg to monitor spontaneous blinks, we also recorded lid movements with an infrared detector (Weiss and Disterhoft 2008).

Data collection and analysis.

All data were collected as rats moved freely in their home cage in a darkened room during their subjective night. OOemg signals were amplified, filtered at 0.3–5 kHz, collected at 4 kHz per channel, and stored for later offline analysis on laboratory-developed software (Dauvergne and Evinger 2007). Blink amplitude was determined by integrating the rectified OOemg activity of each blink component.

As with clinical analysis of trigeminal blink reflex excitability in PD patients (Agostino et al. 1987), we quantified trigeminal reflex blink excitability by dividing blink amplitude evoked by the second SO (test response) by the amplitude of the blink elicited by the first SO (condition response). We calculated R1 and R2 blink component excitability separately.

In humans, HFS-B treatment depressed the R2 component of subsequent blinks (Mao and Evinger 2001). We, however, investigated the effects of HFS-B on the R1 component of the blink reflex, as it is the largest component of the blink reflex in nonprimate mammals and exhibits the same changes as R2 in the HFS-B paradigm (Ryan et al. 2014). We normalized all within-day blink amplitudes by dividing each OOemg amplitude by the median pre-HFS OOemg amplitude. As there was no difference between post-HFS blocks (Ryan et al. 2014), post-HFS blink amplitude was averaged over all three posttreatment blocks. The normalized mean pre-HFS blink amplitude was subtracted from the normalized mean postblink amplitude. As the blink-evoking stimulus remained constant throughout the day (Ryan et al. 2014), this short-term change in blink amplitude following HFS-B was a gain change.

We calculated two measures of long-term modifications induced by HFS-B treatment. For each day of treatment, we determined the mean amplitude of 2T SO evoked blinks pre-HFS relative to the median pre-HFS amplitude on the first day of HFS-B treatment. If HFS-B treatment produced a long-term reduction in the ability of trigeminal circuits to drive blinks, then pre-HFS blink amplitude should decrease across days of HFS treatment. Second, to determine if repeated HFS-B treatment became more effective at reducing within-day blink gain with repetition, we plotted the gain change each day as a function of the number of days of treatment. If the treatment became more effective at modifying trigeminal reflex blink gain across repeated treatments, then the gain changes should be larger in later days of treatment than in the early days of HFS-B.

We employed a variety of mathematical measures to identify and characterize temporal patterns of spontaneous blinking (Kaminer et al. 2011) in addition to the typical measures of blink rate and interblink interval (IBI). For the temporal analysis, we treated each spontaneous blink as a point process, a unitary event that occurred at the start of a spontaneous blink. To identify temporal organization in the pattern of spontaneous blinking, we divided the period of data collection into 1-s bins and determined the blink rate (blinks/min) for each bin spanning the analysis period to create a blink frequency histogram. Using MATLAB scripts, we calculated the autocorrelation of the frequency histogram to identify cyclical patterns of spontaneous blinking. A fast Fourier transform (FFT) was then performed on the autocorrelation to quantify the dominant frequency of cyclical components of the spontaneous blink pattern.

We used the Fano factor, normalized variance, to characterize the periodicity of the spontaneous blink pattern further. The Fano factor was calculated using counting intervals that increased in 1-s increments. For example, the analysis period was divided into 1-s bins and the number of blinks occurring in each bin determined. The Fano factor for this counting interval was the variance divided by the mean number of blinks averaged over all bins for this counting interval. This calculation was repeated for each counting interval, e.g., 2 s, 3 s, 4 s. We plotted the Fano factor as a function of the counting intervals on a log-log plot (see Fig. 5). If the occurrence of spontaneous blinks followed a Poisson distribution, then the Fano factor would be 1 at all counting intervals. If occurrence of spontaneous blinks was not independent, however, the Fano factor increases with the counting interval (Eden and Kramer 2010).

Fig. 5.

Fig. 5.

Open in a new tab

Spontaneous blink data from 6-OHDA lesioned rats with 130-Hz STN DBS (130 Hz) and without DBS (No DBS) and from Control rats. A: mean blink rate over a 30-min period for Control rats and 6-OHDA rats with and without 130 Hz DBS. B: mean slope of the counting interval-Fano factor relationship for normal data (black bars) and shuffled data (open bars) for Control rats, and 6-OHDA lesioned rats with and without 130-Hz DBS. C: log Fano factor as a function of the log counting interval (black line) and five shuffles of the interblink interval (gray lines) for a Control rat. D: Log Fano factor as a function of the log counting interval (black line) and five shuffles of the interblink interval (gray lines) for a 6-OHDA lesioned rat without DBS. E: an autocorrelation of blink occurrence using 10-s bins for normal (black line) and shuffled (gray line) data for a Control rat. F: an autocorrelation of blink occurrence using 10-s bins for normal (black line) and shuffled (gray line) data for a 6-OHDA lesioned rat without DBS. G: mean peak power of the fast Fourier transform of the autocorrelation of blink occurrence for normal data (black bar) and shuffled data (open bar) for Control and 6-OHDA lesioned rats with and without 130-Hz DBS. H: mean dominant frequency of the fast Fourier transform of the autocorrelation of blink occurrence for normal data (black bar) and shuffled data (open bar) for Control and 6-OHDA lesioned rats with and without 130-Hz DBS. Control data are from Kaminer et al. (2011). Error bars are SE.

To test whether the temporal organization of spontaneous blinks was critical in these measurements, we randomly shuffled the IBI order and recalculated the autocorrelation, FFT, and Fano factor for these randomized blink sequences. Shuffling did not change the mean blink rate or IBI distribution. For comparison with the 6-OHDA rat data in Fig. 5, we utilized data from normal rats collected in a previous study (Kaminer et al. 2011).

Statistical tests of significance (P < 0.05) were performed with SPSS software (SPSS, Chicago, IL) using an ANOVA with post hoc Tukey tests, paired or independent t-tests. Data were presented as means ± SE. Regressions were performed using linear, power, logarithmic, and exponential curves. The function generating the highest correlation was employed to describe the data.

RESULTS

Blink reflex excitability.

Parkinsonian patients and the rat 6-OHDA lesion model of PD exhibit hyperexcitability of the R2, but not the R1, component of the trigeminal reflex blink circuit (Fig. 2A, top traces) (Agostino et al. 1987; Basso et al. 1993). The 130-Hz STN DBS significantly reduced R2 excitability by 50 ± 10% relative to the No DBS condition (t6 = 5.19, P < 0.01; Fig. 2, A and B) but did not alter R1 excitability significantly (t6 = −0.61, P > 0.05; Fig. 2, A, middle traces, and B). In contrast, 16-Hz STN DBS did not significantly alter either R1 (t5 = −0.52, P > 0.05; Fig. 2, A and B) or R2 (t5 = −0.17, P > 0.05; Fig. 2, A, bottom traces, and B) excitability. In reducing blink excitability, 130-Hz STN DBS could increase condition blink amplitude or decrease test blink amplitude. As with PD patients receiving 130-Hz STN DBS (Bologna et al. 2012), DBS did not affect condition R2 amplitude in 6-OHDA lesioned rats (Fig. 2A, Condition, compare middle and top traces) (t7 = 0.16, P > 0.05). Instead, 130-Hz STN DBS reduced R2 excitability by decreasing test blink R2 amplitude (Fig. 2A, Test, compare middle and top traces) (t7 = 1.87, P = 0.052).

Fig. 2.

Fig. 2.

Open in a new tab

Effects of DBS of the subthalamic nucleus at different frequencies on trigeminal reflex blink excitability. A: from the same 6-OHDA lesioned rat, individual records of condition and test blinks evoked by supraorbital nerve stimulation (▲) without DBS and while receiving 130- and 16-Hz DBS. B: excitability of trigeminal reflex blinks (test/condition) for the R1 and R2 components relative to the No DBS condition with 130- or 16-Hz DBS averaged across all rats and days. Error bars are SE.

Blink reflex plasticity.

Like the impaired blink reflex plasticity with PD (Battaglia et al. 2006), the 6-OHDA rat model of PD exhibited the same disruption of plasticity (t8 = 2.08, P > 0.05; Fig. 3, No DBS) (Kaminer et al. 2014). For 10 consecutive days, we tested the effects of 16-Hz STN DBS and 130-Hz STN DBS delivered throughout the blink plasticity paradigm in 6-OHDA lesioned rats. During 16-Hz STN DBS, HFS-B treatment showed insignificant reductions in blink amplitude (13.7 ± 6.3%, t5 = 2.26, P > 0.05, Fig. 3, 16 Hz). Thus the responses of rats not receiving DBS at the 3 time points (Fig. 3A, No DBS, T0, T30, and T60) were nearly identical to those of rats receiving 16-Hz stimulation (Fig. 3A, 16 Hz, T0, T30, T60). Furthermore, no plasticity was evident as the responses at these SO stimulation times did not differ from those seen before stimulation (Fig. 3A, Pre for No DBS and 16 Hz). When rats received 130-Hz STN DBS, however, HFS-B treatment significantly decreased blink amplitude over all time points (28.4 ± 6.4%, t8 = 4.73, P < 0.001, Fig. 3, 130 Hz) similar to the degree of depression observed in normal rats (Ryan et al. 2014). A repeated-measures ANOVA performed on five rats that received all three DBS conditions (No DBS, 130 Hz, and 16 Hz) revealed a significant main effect of treatment condition (F2,8 = 10.60, P < 0.01; Fig. 3B). Post hoc analyses demonstrated that the 130-Hz STN DBS condition differed significantly from the No DBS condition (P < 0.05) and the 16-Hz STN DBS condition (P < 0.05), but there were no significant differences between the No DBS and the 16-Hz STN DBS conditions (P > 0.05). Therefore, 130-Hz STN DBS restored blink reflex plasticity in this rat model of PD.

Fig. 3.

Fig. 3.

Open in a new tab

A: individual records from one 6-OHDA lesioned rat in the plasticity paradigm designed to decrease blink amplitude. Records are taken before (Pre), immediately after (T0), 30 min after (T30), and 60 min (T60) after HFS-B treatment while the rat received either no deep brain stimulation of the subthalamic nucleus (No DBS), 130-Hz DBS, or 16-Hz DBS throughout the experimental paradigm. ▲, 100-μs stimulation of the supraorbital nerve. B: average gain change with HFS-B treatment across days and rats with HFS-B treatment for 6-OHDA rats receiving No DBS, 16-Hz, or 130-Hz STN DBS throughout the entire experiment or 130-Hz STN DBS only during the HFS-B treatment (130-D). Error bars are SE.

The 130 Hz STN DBS may enable induction of the HFS-induced gain change, permit expression of the gain change, or affect both aspects of this blink plasticity. We investigate this issue by presenting 130-Hz STN DBS only during the HFS-B treatment (130-D). If 130-D restores normal plasticity, then abnormal basal ganglia activity with PD primarily impairs the induction of blink plasticity and does not significantly affect expression of the plasticity.

Presentation of 130-Hz STN DBS during only the HFS-B allowed HFS-B treatment to reduce blink amplitude significantly (29.6 ± 8.0%; t2 = 4.52, P < 0.05, Fig. 3, 130-D). A repeated-measures ANOVA performed on three rats that received both 130-Hz conditions (130 and 130-D) and the No DBS condition revealed a significant main effect of treatment condition (F2,4 = 14.68, P < 0.01; Fig. 3). Post hoc analyses demonstrated a significant difference between the 130-D and No DBS conditions (P < 0.01). As there were no significant differences between 130 and 130-D on gain change (P > 0.05), we collapsed the groups for subsequent analyses of long-term modifications.

In normal rats, averaging gain changes across days obscured the long-term enhanced effectiveness of HFS-B treatment in depressing reflex blink gain and the progressive weakening of the trigeminal system's drive on reflex blinks (Ryan et al. 2014). Given that 6-OHDA lesioned rats without 130-Hz STN DBS did not show short-term gain changes (Fig. 3, No DBS), we predicted that rats in this condition would not exhibit any long-term modifications. When rats did not undergo STN DBS, there was no significant difference in the gain change between the first three (6.8 ± 4.3%) and last three (13.3 ± 3.3%) days of HFS-B treatment (t2 = 0.01, P > 0.05) (Fig. 4A, No DBS). The 16-Hz STN DBS that also failed to allow HFS-B short-term gain modification (Fig. 3, 16 Hz) had no significant effect on long-term gain changes (t2 = 1.40, P > 0.05, Fig. 4A, 16 Hz). Although normal short-term blink plasticity occurred when rats received 130-Hz STN DBS throughout the HFS-B paradigm (130 Hz) or just during HFS-B treatment (130-D), long-term modifications might not occur because of the abnormal basal ganglia activity transpiring throughout the period between experiments. Nevertheless, the gain decrease caused by HFS-B treatment in rats receiving 130-Hz and 130-D STN DBS was significantly larger during the last three days (52.8 ± 10.9%), than during the first three days (22.4 ± 12.6%; t2 = 4.23, P > 0.05) of HFS-B treatment (Fig. 4A, 130 Hz). Unlike the absence of a significant increase in gain modification for rats receiving 16-Hz DBS (r2 = 0.34, P > 0.05; Fig. 4B, ▲) or No DBS (r2 = 0.005, P > 0.05; Fig. 4B, ◇), there was a significant, negatively sloped line relating the amount of blink depression produced by HFS-B treatment each day, as a function of days of HFS-B treatment when receiving 130-Hz STN DBS (r2 = 0.42, P < 0.05; Fig. 4B, ●).

Fig. 4.

Fig. 4.

Open in a new tab

Long-term changes in reflex blink plasticity with 16-Hz, 130-Hz, or no STN DBS. A: mean gain change over the first three and last three days for 6-OHDA lesioned rats receiving consecutive days of No DBS, 130, or 16 Hz STN DBS. B: mean change for 6-OHDA lesioned rats receiving consecutive days of No DBS (◇), 130-Hz STN DBS (●), or 16 Hz (▲) as a function of days of HFS-B treatment. Lines are linear best fits. C: average pre-HFS blink amplitude relative to median pre-HFS blink amplitude on day 1 for 6-OHDA lesioned rats receiving consecutive days of No DBS (◇),130-Hz STN DBS (●), or 16 Hz (▲) as a function of days of HFS-B treatment. Lines are logarithmic best fits. Error bars are SE.

Our study in normal rats demonstrated that the trigeminal system became less effective in evoking reflex blinks across days of HFS-B treatment, because blink amplitude before HFS-B treatment decreased across days, while blink threshold remained constant (Ryan et al. 2014). The 6-OHDA lesioned rats in the present study also did not exhibit a change in threshold across days of HFS-B treatment, while receiving either No DBS (r2 = 0.12, P > 0.05, not illustrated), 130-Hz STN DBS (r2 = 0.01, P > 0.05, not illustrated), or 16-Hz STN DBS (r2 = 0.05, P > 0.05, not illustrated). As with normal rats (Ryan et al. 2014), 6-OHDA lesioned rats undergoing 130-Hz STN DBS exhibited a logarithmic decrease in Pre HFS R1 amplitude across days of HFS-B treatment (r2 = 0.56, P < 0.01, Fig. 4C, ●). This long-term decrease did not occur in rats receiving 16-Hz STN DBS (r2 = 0.09, P > 0.05; Fig. 4C, ▲). Rats that did not receive DBS exhibited a small but significant increase in pre HFS R1 blink amplitude across days (r2 = 0.65, P < 0.01; Fig. 4C, ◇).

Spontaneous blinking.

As with PD (Agostino et al. 2008; Bologna et al. 2012; Deuschl and Goddemeier 1998; Korosec et al. 2006), the 6-OHDA rat lesion model of PD exhibited a significantly lower spontaneous blink rate (3.2 ± 0.3 blinks/min) than normal (Kaminer et al. 2011) (5.30 ± 0.03 blinks/min; t50 = 2.46, P < 0.02; Fig. 5A). Also similar to PD patients (Bologna et al. 2012), 130-Hz STN DBS, did not restore a normal blink rate in 6-OHDA lesioned rats. The blink rate with 130-Hz STN DBS, 2.9 ± 0.3 blinks/min, was not significantly different from the No DBS condition (t4 = 1.8, P > 0.05; Fig. 5A).

As with dopamine receptor blockade (Kaminer et al. 2011), the 6-OHDA lesioned rat model of PD exhibited increased variability in the temporal organization of spontaneous blinking relative to normal rats. The positive slope of the counting interval-Fano factor relationship revealed underlying periodicity of spontaneous blinking (Middleton et al. 2003) and demonstrated that occurrences of spontaneous blinks were not independent processes. Although the spontaneous blinks of both control (Kaminer et al. 2011) (Fig. 5, B and C) and 6-OHDA lesioned rats (Fig. 5, C and D) exhibited a positive slope of the counting interval-Fano factor relationship, the mean slope of the Fano factor for control rats (0.42 ± 0.03) was significantly larger than that of 6-OHDA lesioned rats (0.29 ± 0.04; t31 = 2.2, P < 0.05; Fig. 5B). The steeper slope indicated that the periodicity was stronger in control than in 6-OHDA lesioned rats. If the periodicity was real, then shuffling the order of the interblink intervals to disrupt temporal patterns should diminish the slope of counting interval-Fano factor relationship. Shuffling significantly reduced the slope of the Fano factor for control rats (t27 = 6.7, P < 0.001, 5, B and C), but not for 6-OHDA lesioned rats with (t4 = 0.22, P > 0.05) or without 130-Hz STN DBS (t4 = 0.36, P > 0.05; Fig. 5, B and D).

An autocorrelation of the occurrence of spontaneous blinks provided a second measure of spontaneous blink periodicity (Fig. 5, E and F). For control rats, the autocorrelation revealed a repeating pattern of frequent blinks interspersed with a period of few blinks. Shuffling interblink interval order significantly reduced the autocorrelation periodicity (Fig. 5E). Consistent with the shallow slope of the counting interval-Fano factor relationship for 6-OHDA lesioned rats, autocorrelation demonstrated weak periodicity, and shuffling the order of interblink intervals did not appear to affect this periodicity significantly (Fig. 5F). We quantified autocorrelation periodicity by performing a fast Fourier transform on normal and shuffled data. For control rats, shuffling the order of interblink intervals significantly reduced the power at the peak frequency relative to the normal data (t27 = 5.25 P < 0.001; Fig. 5G, Control). In addition, shuffling significantly shifted the dominant frequency relative to normal data (t27 = −3.15, P < 0.01; Fig. 5H). In contrast, there was no significant difference in the peak frequency power between normal and shuffled data for 6-OHDA rats without DBS (t4 = 1.26, P > 0.05) or when receiving 130-Hz STN DBS (t4 = 0.18, P > 0.05; Fig. 5G). Moreover, there was no significant difference in the dominant frequency between normal and shuffled data with (t4 = 0.51, P > 0.05) or without 130-Hz STN DBS (t4 = −0.24, P > 0.05; Fig. 5H). Therefore, 6-OHDA lesions disrupted the normal periodicity of spontaneous blinking and 130-Hz STN DBS failed to restore a normal blink rate or temporal organization to spontaneous blinking.

DISCUSSION

The shared blink abnormalities in PD and the 6-OHDA lesion rat model of PD indicate that it is possible to identify circuits in rodents through which the aberrant basal ganglia activity of PD disrupts blinking. For example, neurons in the substantia nigra pars reticulata, superior colliculus, nucleus raphe magnus, and spinal trigeminal complex comprise a trisynaptic circuit through which the basal ganglia can modulate trigeminal reflex blink excitability (Basso and Evinger 1996; Basso et al. 1996; Gnadt et al. 1997). In the paired stimulus paradigm, the condition stimulus activates trigeminal blink circuits to evoke the condition blink, and trigeminal complex neurons send an excitatory drive to intermediate/deep layer collicular neurons (Huerta et al. 1983; Nagata and Kruger 1979; Ndiaye et al. 2000; Redgrave et al. 1996; Rhoades et al. 1989). Trigeminal activation of these collicular neurons provides a transient excitatory drive onto nucleus raphe magnus neurons, which inhibit spinal trigeminal blink circuits (Basso and Evinger 1996; de Tommaso et al. 2000). Reduction in test blink amplitude takes place because the test stimulus occurs during nucleus raphe magnus inhibition of trigeminal blink circuits. The hyperexcitability of the R2 component of the trigeminal reflex blink in both PD and the rat 6-OHDA model of PD (Agostino et al. 1987; Basso et al. 1993; Deuschl and Goddemeier 1998; Kimura 1973; Peshori et al. 2001) (Fig. 2) could result from changes in the substantia nigra input that reduce the collicular response to trigeminal input from the condition stimulus. Our demonstration that 16-Hz STN DBS creates R2 trigeminal reflex blink hyperexcitability in normal rats (Kaminer et al. 2014) supports the hypothesis that hypersynchronized beta oscillations associated with PD (Brown and Eusebio 2008; Gatev et al. 2006; Jenkinson and Brown 2011) and the 6-OHDA rat model (Lehmkuhle et al. 2009; Li et al. 2007; Mallet et al. 2008; McConnell et al. 2012; Sharott et al. 2005) can reduce the responsiveness of collicular neurons to trigeminal inputs in PD. The suppression of beta oscillations by 130-Hz STN DBS (Dorval et al. 2010; McConnell et al. 2012; Ray et al. 2008; Wingeier et al. 2006) and its restoration of normal blink reflex excitability (Fig. 2) further support the interpretation that exaggerated beta oscillations reduce collicular excitation by trigeminal inputs from the condition stimulus. This circuit organization also explains why 130-Hz STN DBS affects the test, but not the condition blink.

Although our data (Figs. 3 and 4) (Kaminer et al. 2014) and patient studies (Battaglia et al. 2006; Crupi et al. 2008; Suppa et al. 2011) highlight a critical role of the basal ganglia in normal blink reflex plasticity, the circuits through which the basal ganglia modulate this behavior are uncertain. The cerebellum plays an essential role in HFS-induced blink reflex plasticity (Ryan et al. 2014). It is likely that the disruption of normal basal ganglia-cerebellar interactions (Bostan et al. 2010; Bostan and Strick 2010; Hoshi et al. 2005; Jinnah and Hess 2006) by PD's pathological basal ganglia activity impairs blink reflex plasticity. Given that 16-Hz STN DBS impairs blink reflex plasticity in normal rats (Kaminer et al. 2014), the hypersynchronized beta oscillations found in PD (Brown et al. 2001; Kuhn et al. 2005) and 6-OHDA lesioned rats (Lehmkuhle et al. 2009; Li et al. 2007; Mallet et al. 2008; McConnell et al. 2012; Sharott et al. 2005) are probably responsible for impairing blink plasticity in PD. The frequency of hypersynchronized basal ganglia oscillatory activity may be critical in how basal ganglia disorders affect plasticity. Dystonia, a basal ganglia disorder characterized by a lower frequency of oscillatory activity than PD (Chen et al. 2006; Liu et al. 2008; Silberstein et al. 2003; Starr et al. 2005; Weinberger et al. 2012) exaggerates blink plasticity (Quartarone et al. 2006). Consistent with this interpretation, 7-Hz STN DBS in normal rats exaggerates blink reflex plasticity (Kaminer et al. 2014).

At 130 Hz, but not 16 Hz, STN DBS restores normal blink reflex plasticity in 6-OHDA lesioned rats (Figs. 3 and 4). Given the apparent importance of hypersynchronized beta oscillations in impairing blink plasticity (Kaminer et al. 2014), 130-Hz STN DBS may restore plasticity by suppressing exaggerated beta oscillations in 6-OHDA lesioned rats (Lehmkuhle et al. 2009; Li et al. 2007; McConnell et al. 2012). Our experiment showing that delivering 130-Hz STN DBS only during the HFS-B treatment (130-D) restores blink reflex plasticity (Fig. 3) indicates that the hypersynchronized beta oscillations of PD only affect the induction of plasticity. Indeed, 130-Hz STN DBS only during the HFS-B treatment (130-D) was sufficient to restore long- as well as short-term plasticity of the blink reflex in 6-OHDA lesioned rats. Thus exaggerated beta oscillations present in the absence of 130-Hz STN DBS in 6-OHDA lesioned rats do not affect the long-term enhanced effectiveness of HFS-B treatment in depressing reflex blink gain and the progressive weakening of the trigeminal system's drive on reflex blinks caused by repeated HFS-B treatments (Fig. 4).

Although 130-Hz STN DBS restores normal reflex blink excitability (Fig. 2) and plasticity (Figs. 3 and 4), it fails to reinstate a normal blink rate or temporal organization to spontaneous blinking (Fig. 5). Spontaneous blinking is remarkably insensitive to PD treatments. With dopamine therapy, the spontaneous blink rate of PD patients is between 50 and 60% of normal (Bologna et al. 2012; Deuschl and Goddemeier 1998; Karson et al. 1982; Kimber and Thompson 2000), and combining STN DBS and dopamine therapy does not significantly improve the blink rate over drug treatment alone (Bologna et al. 2012). The limited effects of STN DBS on restoring normal behavior of the spontaneous blink central pattern generator are consistent with the unreliable effects of STN DBS on restoring normal gait in PD patients (Lozano and Snyder 2008; Moreau et al. 2008; St George et al. 2010).

The study of the blink reflex makes the relationship between exaggerated beta oscillations in PD and reflex movement clearer. Although PD increases the average power of beta oscillations, moment-to-moment oscillation strength varies with voluntary movement and movement cues (Brucke et al. 2012; Doyle et al. 2005; Kuhn et al. 2004; Kuhn et al. 2006; Leventhal et al. 2012; Levy et al. 2002; Liu et al. 2008; Priori et al. 2002; Williams et al. 2003). Over the long term, however, reflex blinks are uncorrelated with the temporal variations in oscillation strength associated with voluntary movement. Because of the hypersynchronized beta oscillations of PD, reflex blink circuits experience higher than normal beta oscillations on average. Our previous data demonstrate that beta frequency STN DBS is sufficient to induce Parkinsonian-like blink reflex abnormalities in normal rats (Kaminer et al. 2014), and the current data show that 130-Hz STN DBS, which suppresses hypersynchronous beta oscillations (Lehmkuhle et al. 2009; Li et al. 2007; McConnell et al. 2012), restores normal behavior of this brain stem reflex in the 6-OHDA lesion model of PD. Nevertheless, 130-Hz STN DBS does not affect the rate or temporal organization of spontaneous blinking in 6-OHDA lesion animals. This result highlights the complexity of Parkinson's disease, as dopamine depletion does not affect all blink systems via the same neural mechanisms.

GRANTS

This work was supported by grants from the National Institutes of Health (EY-07391) and the Thomas Hartman Center for Parkinson Research to C. Evinger and National Institute of Neurological Disorders and Stroke Grant F31-NS-078838 to J. Kaminer.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

Author contributions: J.K. and C.E. conception and design of research; J.K. and P.T. performed experiments; J.K., P.T., and C.E. analyzed data; J.K., P.T., and C.E. interpreted results of experiments; J.K. and C.E. prepared figures; J.K. and C.E. drafted manuscript; J.K., P.T., and C.E. edited and revised manuscript; J.K., P.T., and C.E. approved final version of manuscript.

ACKNOWLEDGMENTS

We thank D. Schmidt for technical assistance and Dr. A. S. Powers and P. Enmore for helpful comments on earlier versions of this manuscript.

Present address for J. Kaminer: Center for Molecular and Behavioral Neuroscience, Rutgers Univ., Newark, NJ 07102-1811.

REFERENCES

  1. Agostino R, Berardelli A, Cruccu G, Stocchi F, Manfredi M. Corneal and blink reflexes in Parkinson's disease with “on-off” fluctuations. Mov Disord 2: 227–235, 1987. [DOI] [PubMed] [Google Scholar]
  2. Agostino R, Bologna M, Dinapoli L, Gregori B, Fabbrini G, Accornero N, Berardelli A. Voluntary, spontaneous, and reflex blinking in Parkinson's disease. Mov Disord 23: 669–675, 2008. [DOI] [PubMed] [Google Scholar]
  3. Basso MA, Evinger C. An explanation for reflex blink hyperexcitability in Parkinson's disease. II. Nucleus raphe magnus. J Neurosci 16: 7318–7330, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Basso MA, Powers AS, Evinger C. An explanation for reflex blink hyperexcitability in Parkinson's disease. I. Superior colliculus. J Neurosci 16: 7308–7317, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Basso MA, Strecker RE, Evinger C. Midbrain 6-hydroxydopamine lesions modulate blink reflex excitability. Exp Brain Res 94: 88–96, 1993. [DOI] [PubMed] [Google Scholar]
  6. Battaglia F, Ghilardi MF, Quartarone A, Bagnato S, Girlanda P, Hallett M. Impaired long-term potentiation-like plasticity of the trigeminal blink reflex circuit in Parkinson's disease. Mov Disord 21: 2230–2233, 2006. [DOI] [PubMed] [Google Scholar]
  7. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 8: 67–81, 2009. [DOI] [PubMed] [Google Scholar]
  8. Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson's disease. Brain 124: 2131–2146, 2001. [DOI] [PubMed] [Google Scholar]
  9. Bologna M, Fasano A, Modugno N, Fabbrini G, Berardelli A. Effects of subthalamic nucleus deep brain stimulation and l-DOPA on blinking in Parkinson's disease. Exp Neurol 235: 265–272, 2012. [DOI] [PubMed] [Google Scholar]
  10. Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci USA 107: 8452–8456, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bostan AC, Strick PL. The cerebellum and basal ganglia are interconnected. Neuropsychol Rev 20: 261–270, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bove J, Prou D, Perier C, Przedborski S. Toxin-induced models of Parkinson's disease. NeuroRx 2: 484–494, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, Horak FB, Okun MS, Foote KD, Krack P, Pahwa R, Henderson JM, Hariz MI, Bakay RA, Rezai A, Marks WJ Jr, Moro E, Vitek JL, Weaver FM, Gross RE, DeLong MR. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 68: 165, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Brown P, Eusebio A. Paradoxes of functional neurosurgery: clues from basal ganglia recordings. Mov Disord 23: 12–20; quiz 158, 2008. [DOI] [PubMed] [Google Scholar]
  15. Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, Di Lazzaro V. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease. J Neurosci 21: 1033–1038, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Brucke C, Huebl J, Schonecker T, Neumann WJ, Yarrow K, Kupsch A, Blahak C, Lutjens G, Brown P, Krauss JK, Schneider GH, Kuhn AA. Scaling of movement is related to pallidal gamma oscillations in patients with dystonia. J Neurosci 32: 1008–1019, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci 3: 574–579, 2002. [DOI] [PubMed] [Google Scholar]
  18. Chen CC, Kuhn AA, Trottenberg T, Kupsch A, Schneider GH, Brown P. Neuronal activity in globus pallidus interna can be synchronized to local field potential activity over 3–12 Hz in patients with dystonia. Exp Neurol 202: 480–486, 2006. [DOI] [PubMed] [Google Scholar]
  19. Chong RK, Horak FB, Woollacott MH. Parkinson's disease impairs the ability to change set quickly. J Neurol Sci 175: 57–70, 2000. [DOI] [PubMed] [Google Scholar]
  20. Cody FW, MacDermott N, Matthews PB, Richardson HC. Observations on the genesis of the stretch reflex in Parkinson's disease. Brain 109: 229–249, 1986. [DOI] [PubMed] [Google Scholar]
  21. Crupi D, Ghilardi MF, Mosiello C, Di Rocco A, Quartarone A, Battaglia F. Cortical and brainstem LTP-like plasticity in Huntington's disease. Brain Res Bull 75: 107–114, 2008. [DOI] [PubMed] [Google Scholar]
  22. Dauvergne C, Evinger C. Experiential modification of the trigeminal reflex blink circuit. J Neurosci 27: 10414–10422, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. de Tommaso M, Guido M, Libro G, Sciruicchio V, Puca F. Zolmitriptan reverses blink reflex changes induced during the migraine attack in humans. Neurosci Lett 289: 57–60, 2000. [DOI] [PubMed] [Google Scholar]
  24. Deuschl G, Goddemeier C. Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects. J Neurol Neurosurg Psychiatry 64: 320–324, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Dorval AD, Kuncel AM, Birdno MJ, Turner DA, Grill WM. Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity. J Neurophysiol 104: 911–921, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Doyle LM, Kuhn AA, Hariz M, Kupsch A, Schneider GH, Brown P. Levodopa-induced modulation of subthalamic beta oscillations during self-paced movements in patients with Parkinson's disease. Eur J Neurosci 21: 1403–1412, 2005. [DOI] [PubMed] [Google Scholar]
  27. Duysens J, Van Wezel BM, Smits-Engelsman B. Modulation of cutaneous reflexes from the foot during gait in Parkinson's disease. J Neurophysiol 104: 230–238, 2010. [DOI] [PubMed] [Google Scholar]
  28. Eden UT, Kramer MA. Drawing inferences from Fano factor calculations. J Neurosci Methods 190: 149–152, 2010. [DOI] [PubMed] [Google Scholar]
  29. Evinger C, Basso MA, Manning KA, Sibony PA, Pellegrini JJ, Horn AK. A role for the basal ganglia in nicotinic modulation of the blink reflex. Exp Brain Res 92: 507–515, 1993. [DOI] [PubMed] [Google Scholar]
  30. Gatev P, Darbin O, Wichmann T. Oscillations in the basal ganglia under normal conditions and in movement disorders. Mov Disord 21: 1566–1577, 2006. [DOI] [PubMed] [Google Scholar]
  31. Gnadt JW, Lu SM, Breznen B, Basso MA, Henriquez VM, Evinger C. Influence of the superior colliculus on the primate blink reflex. Exp Brain Res 116: 389–398, 1997. [DOI] [PubMed] [Google Scholar]
  32. Horak FB, Nutt JG, Nashner LM. Postural inflexibility in parkinsonian subjects. J Neurol Sci 111: 46–58, 1992. [DOI] [PubMed] [Google Scholar]
  33. Hoshi E, Tremblay L, Feger J, Carras PL, Strick PL. The cerebellum communicates with the basal ganglia. Nat Neurosci 8: 1491–1493, 2005. [DOI] [PubMed] [Google Scholar]
  34. Huerta MF, Frankfurter A, Harting JK. Studies of the principal sensory and spinal trigeminal nuclei of the rat: projections to the superior colliculus, inferior olive, and cerebellum. J Comp Neurol 220: 147–167, 1983. [DOI] [PubMed] [Google Scholar]
  35. Jenkinson N, Brown P. New insights into the relationship between dopamine, beta oscillations and motor function. Trends Neurosci 34: 611–618, 2011. [DOI] [PubMed] [Google Scholar]
  36. Jinnah HA, Hess EJ. A new twist on the anatomy of dystonia: the basal ganglia and the cerebellum? Neurology 67: 1740–1741, 2006. [DOI] [PubMed] [Google Scholar]
  37. Kaminer J, Powers AS, Horn KG, Hui C, Evinger C. Characterizing the spontaneous blink generator: an animal model. J Neurosci 31: 11256–11267, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kaminer J, Thakur P, Evinger C. Frequency matters: beta-band subthalamic nucleus deep-brain stimulation induces Parkinsonian-like blink abnormalities in normal rats. Eur J Neurosci 40: 3237–3242, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Karson CN, LeWitt PA, Calne DB, Wyatt RJ. Blink rates in parkinsonism. Ann Neurol 12: 580–583, 1982. [DOI] [PubMed] [Google Scholar]
  40. Kimber TE, Thompson PD. Increased blink rate in advanced Parkinson's disease: a form of “off”-period dystonia? Mov Disord 15: 982–985, 2000. [DOI] [PubMed] [Google Scholar]
  41. Kimura J. Disorder of interneurons in Parkinsonism. The orbicularis oculi reflex to paired stimuli. Brain 96: 87–96, 1973. [DOI] [PubMed] [Google Scholar]
  42. Korosec M, Zidar I, Reits D, Evinger C, Vanderwerf F. Eyelid movements during blinking in patients with Parkinson's disease. Mov Disord 21: 1248–1251, 2006. [DOI] [PubMed] [Google Scholar]
  43. Kuhn AA, Brandt SA, Kupsch A, Trottenberg T, Brocke J, Irlbacher K, Schneider GH, Meyer BU. Comparison of motor effects following subcortical electrical stimulation through electrodes in the globus pallidus internus and cortical transcranial magnetic stimulation. Exp Brain Res 155: 48–55, 2004. [DOI] [PubMed] [Google Scholar]
  44. Kuhn AA, Kupsch A, Schneider GH, Brown P. Reduction in subthalamic 8–35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease. Eur J Neurosci 23: 1956–1960, 2006. [DOI] [PubMed] [Google Scholar]
  45. Kuhn AA, Trottenberg T, Kivi A, Kupsch A, Schneider GH, Brown P. The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease. Exp Neurol 194: 212–220, 2005. [DOI] [PubMed] [Google Scholar]
  46. Lawrence MS, Redmond DE Jr. MPTP lesions and dopaminergic drugs alter eye blink rate in African green monkeys. Pharmacol Biochem Behav 38: 869–874, 1991. [DOI] [PubMed] [Google Scholar]
  47. Lehmkuhle MJ, Bhangoo SS, Kipke DR. The electrocorticogram signal can be modulated with deep brain stimulation of the subthalamic nucleus in the hemiparkinsonian rat. J Neurophysiol 102: 1811–1820, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Leventhal DK, Gage GJ, Schmidt R, Pettibone JR, Case AC, Berke JD. Basal ganglia beta oscillations accompany cue utilization. Neuron 73: 523–536, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain 125: 1196–1209, 2002. [DOI] [PubMed] [Google Scholar]
  50. Li S, Arbuthnott GW, Jutras MJ, Goldberg JA, Jaeger D. Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation. J Neurophysiol 98: 3525–3537, 2007. [DOI] [PubMed] [Google Scholar]
  51. Liu X, Wang S, Yianni J, Nandi D, Bain PG, Gregory R, Stein JF, Aziz TZ. The sensory and motor representation of synchronized oscillations in the globus pallidus in patients with primary dystonia. Brain 131: 1562–1573, 2008. [DOI] [PubMed] [Google Scholar]
  52. Lozano AM, Snyder BJ. Deep brain stimulation for parkinsonian gait disorders. J Neurol 255, Suppl 4: 30–31, 2008. [DOI] [PubMed] [Google Scholar]
  53. MacAskill MR, Anderson TJ, Jones RD. Adaptive modification of saccade amplitude in Parkinson's disease. Brain 125: 1570–1582, 2002. [DOI] [PubMed] [Google Scholar]
  54. Mallet N, Pogosyan A, Sharott A, Csicsvari J, Bolam JP, Brown P, Magill PJ. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci 28: 4795–4806, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Mao JB, Evinger C. Long-term potentiation of the human blink reflex. J Neurosci 21: RC151, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. McConnell GC, So RQ, Hilliard JD, Lopomo P, Grill WM. Effective deep brain stimulation suppresses low-frequency network oscillations in the basal ganglia by regularizing neural firing patterns. J Neurosci 32: 15657–15668, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Middleton JW, Chacron MJ, Lindner B, Longtin A. Firing statistics of a neuron model driven by long-range correlated noise. Phys Rev E Stat Nonlin Soft Matter Phys 68: 021920, 2003. [DOI] [PubMed] [Google Scholar]
  58. Moreau C, Defebvre L, Destee A, Bleuse S, Clement F, Blatt JL, Krystkowiak P, Devos D. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 71: 80–84, 2008. [DOI] [PubMed] [Google Scholar]
  59. Nagata T, Kruger L. Tactile neurons of the superior colliculus of the cat: input and physiological properties. Brain Res 174: 19–37, 1979. [DOI] [PubMed] [Google Scholar]
  60. Ndiaye A, Pinganaud G, VanderWerf F, Buisseret-Delmas C, Buisseret P. Connections between the trigeminal mesencephalic nucleus and the superior colliculus in the rat. Neurosci Lett 294: 17–20, 2000. [DOI] [PubMed] [Google Scholar]
  61. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego, CA: Academic, 1998. [Google Scholar]
  62. Peshori KR, Schicatano EJ, Gopalaswamy R, Sahay E, Evinger C. Aging of the trigeminal blink system. Exp Brain Res 136: 351–363, 2001. [DOI] [PubMed] [Google Scholar]
  63. Priori A, Foffani G, Pesenti A, Bianchi A, Chiesa V, Baselli G, Caputo E, Tamma F, Rampini P, Egidi M, Locatelli M, Barbieri S, Scarlato G. Movement-related modulation of neural activity in human basal ganglia and its l-DOPA dependency: recordings from deep brain stimulation electrodes in patients with Parkinson's disease. Neurol Sci 23, Suppl 2: S101–S102, 2002. [DOI] [PubMed] [Google Scholar]
  64. Quartarone A, Sant'Angelo A, Battaglia F, Bagnato S, Rizzo V, Morgante F, Rothwell JC, Siebner HR, Girlanda P. Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm. J Neurosci 26: 716–721, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Ray NJ, Jenkinson N, Wang S, Holland P, Brittain JS, Joint C, Stein JF, Aziz T. Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation. Exp Neurol 213: 108–113, 2008. [DOI] [PubMed] [Google Scholar]
  66. Redgrave P, McHaffie JG, Stein BE. Nociceptive neurones in rat superior colliculus. I. Antidromic activation from the contralateral predorsal bundle. Exp Brain Res 109: 185–196, 1996. [DOI] [PubMed] [Google Scholar]
  67. Rhoades RW, Fish SE, Chiaia NL, Bennett-Clarke C, Mooney RD. Organization of the projections from the trigeminal brainstem complex to the superior colliculus in the rat and hamster: anterograde tracing with Phaseolus vulgaris leucoagglutinin and intra-axonal injection. J Comp Neurol 289: 641–656, 1989. [DOI] [PubMed] [Google Scholar]
  68. Rothwell JC, Obeso JA, Traub MM, Marsden CD. The behaviour of the long-latency stretch reflex in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 46: 35–44, 1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Ryan M, Kaminer J, Enmore P, Evinger C. Trigeminal high-frequency stimulation produces short- and long-term modification of reflex blink gain. J Neurophysiol 111: 888–895, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Sharott A, Magill PJ, Harnack D, Kupsch A, Meissner W, Brown P. Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat. Eur J Neurosci 21: 1413–1422, 2005. [DOI] [PubMed] [Google Scholar]
  71. Silberstein P, Kuhn AA, Kupsch A, Trottenberg T, Krauss JK, Wohrle JC, Mazzone P, Insola A, Di Lazzaro V, Oliviero A, Aziz T, Brown P. Patterning of globus pallidus local field potentials differs between Parkinson's disease and dystonia. Brain 126: 2597–2608, 2003. [DOI] [PubMed] [Google Scholar]
  72. St George RJ, Nutt JG, Burchiel KJ, Horak FB. A meta-regression of the long-term effects of deep brain stimulation on balance and gait in PD. Neurology 75: 1292–1299, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Starr PA, Rau GM, Davis V, Marks WJ Jr, Ostrem JL, Simmons D, Lindsey N, Turner RS. Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. J Neurophysiol 93: 3165–3176, 2005. [DOI] [PubMed] [Google Scholar]
  74. Sunohara N, Tomi H, Satoyoshi E, Tachibana S. Glabella tap sign. Is it due to a lack of R2-habituation? J Neurol Sci 70: 257–267, 1985. [DOI] [PubMed] [Google Scholar]
  75. Suppa A, Belvisi D, Bologna M, Marsili L, Berardelli I, Moretti G, Pasquini M, Fabbrini G, Berardelli A. Abnormal cortical and brain stem plasticity in Gilles de la Tourette syndrome. Mov Disord 26: 1703–1710, 2011. [DOI] [PubMed] [Google Scholar]
  76. Tatton WG, Lee RG. Evidence for abnormal long-loop reflexes in rigid Parkinsonian patients. Brain Res 100: 671–676, 1975. [DOI] [PubMed] [Google Scholar]
  77. Taylor JR, Elsworth JD, Lawrence MS, Sladek JR Jr, Roth RH, Redmond DE Jr. Spontaneous blink rates correlate with dopamine levels in the caudate nucleus of MPTP-treated monkeys. Exp Neurol 158: 214–220, 1999. [DOI] [PubMed] [Google Scholar]
  78. Weinberger M, Hutchison WD, Alavi M, Hodaie M, Lozano AM, Moro E, Dostrovsky JO. Oscillatory activity in the globus pallidus internus: comparison between Parkinson's disease and dystonia. Clin Neurophysiol 123: 358–368, 2012. [DOI] [PubMed] [Google Scholar]
  79. Weiss C, Disterhoft JF. Evoking blinks with natural stimulation and detecting them with a noninvasive optical device: a simple, inexpensive method for use with freely moving animals. J Neurosci Methods 173: 108–113, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. White OB, Saint-Cyr JA, Sharpe JA. Ocular motor deficits in Parkinson's disease. I. The horizontal vestibulo-ocular reflex and its regulation. Brain 106: 555–570, 1983. [DOI] [PubMed] [Google Scholar]
  81. Williams D, Kuhn A, Kupsch A, Tijssen M, van Bruggen G, Speelman H, Hotton G, Yarrow K, Brown P. Behavioural cues are associated with modulations of synchronous oscillations in the human subthalamic nucleus. Brain 126: 1975–1985, 2003. [DOI] [PubMed] [Google Scholar]
  82. Wingeier B, Tcheng T, Koop MM, Hill BC, Heit G, Bronte-Stewart HM. Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease. Exp Neurol 197: 244–251, 2006. [DOI] [PubMed] [Google Scholar]
  83. Wolfarth S, Konieczny J, Smialowska M, Schulze G, Ossowska K. Influence of 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway on the muscle tone and electromyographic activity measured during passive movements. Neuroscience 74: 985–996, 1996. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurophysiology are provided here courtesy of American Physiological Society

RESOURCES