Temporal patterns of deep brain stimulation generated with a true random number generator and the logistic equation: effects on CNS arousal in mice

Abstract

Deep brain stimulation (DBS) has shown promise in the treatment of many neurological and psychiatric disorders as well as a disorder of consciousness, the minimally conscious state (MCS). In the clinic, DBS is always monotonic standard pulses; however, we have hypothesized that temporally patterned pulses might be more efficient in achieving desired behavioral responses. Here we present two experiments on DBS of the central thalamus to increase arousal, as measured by motor activity, and to affect the electroencephalogram (EEG). In the first, we optimized amplitude and frequency in standard stimulation of the central thalamus in intact mice. In the second, the optimized fixed frequency was compared to two alternative temporal patterns, chaotic and random, which were physically identical to each other and fixed frequency in all ways except temporal pattern. In both experiments and with all types of stimulation, DBS of the central thalamus increased arousal as measured by motor activity. These data also revealed that temporal patterning of pulses can modulate response to stimulation. That temporal patterns in DBS of the central thalamus were found to alter motor activity response implies possible usefulness of temporal patterns in DBS of other contexts. More investigation into exactly how temporally patterned stimulation may affect neuronal circuit dynamics is necessary.

Figure 1. Parametric Experiment: Behavior

Behavioral response to amplitude (A. B. and C.), frequency (D. E. and F.), and light phase (G. H. and I.) of CT/DBS. Three behavioral measures are shown: activity counts (whole body movement), horizontal activity (fidgeting), and total distance (ambulation). ANOVA analyses revealed an overall effect of CT/DBS in activity counts (p<0.001), horizontal activity (p<0.001), and total distance (p<0.01). ANOVA also showed an effect of amplitude in activity counts (A. p<0.001), horizontal activity (B. p<0.001), and total distance (C. p<0.01). An overall effect of frequency was found in horizontal activity (E. p<0.05) and total distance (F. p<0.001). Light phase of CT/DBS was found to be significant in horizontal activity (H. p<0.001) and total distance (I. p<0.001). Panels include 10 minutes of data during and 10 minutes of data after CT/DBS, all normalized to before stimulation. Data are presented as mean ± s.e.m. * p<0.05 compared to before, ° p<0.05 compared to 75 μA, ^ p<0.05 compared to 100 μA, # p<0.05 compared to dark phase.

Figure 2. Parametric Experiment: EEG

EEG response to amplitude (A. B. C. D. and E.), frequency (F. G. H. I. and J.), and light phase (K. L. M. N. and P.) of CT/DBS. EEG waves are defined by the following frequency bins: delta (0.5–4 hz), theta (4.5–8 hz), alpha (8.5–12 hz), beta (12.5–20 hz), and gamma (35–45 hz). ANOVA analyses revealed an overall effect of CT/DBS in theta (p<0.001), alpha (p<0.001), beta (p<0.001), and gamma (p<0.001) waves. ANOVA also showed an effect of amplitude in theta (B. p<0.05) and alpha (C. p<0.01) waves. An effect of frequency was found in alpha (H. p<0.05) waves. Light phase of CT/DBS was found to be significant in theta (L. p<0.05), alpha (M. p<0.01), beta (N. p<0.01), and gamma (P. p<0.001) waves. Panels include 10 minutes of data after CT/DBS, normalized to before stimulation. Data are presented as mean ± s.e.m. * p<0.05 compared to before, # p<0.05 compared to dark phase.

Figure 3. Parametric Experiment - example of behavior at high temporal resolution

Motor activity behavior of one mouse at 4 frequencies of stimulation, 100 μA, in the light phase. A. 50 hz, B. 125 hz, C. 175 hz, D. 225 hz. Activity counts ('counts') shown at 1 sample every 10 seconds, Horizontal activity ('Hactv') and Total distance ('Totdist') shown at 1 sample every 1 second. Grey boxes mark epochs of stimulation.

Figure 4. Temporal Pattern Experiment: Behavior

Behavioral response to temporal pattern (A. B. and C.) and light phase (D. E. and F.) of CT/DBS. Three behavioral measures are shown: activity counts (whole body movement), horizontal activity (fidgeting), and total distance (ambulation). ANOVA analyses revealed an overall effect of temporal pattern in activity counts (A. p<0.001) and horizontal activity (B. p<0.01). Panels include 10 minutes of data during and 10 minutes of data after CT/DBS, all normalized to before stimulation. Data are presented as mean ± s.e.m. * p<0.05 compared to before, # p<0.05 compared to chaotic.

Figure 5. Temporal Pattern Experiment: EEG

EEG response to temporal pattern (A. B. C. D. and E.) and light phase (F. G. H. I. and J.) of CT/DBS. EEG waves are defined by the following frequency bins: delta (0.5–4 hz), theta (4.5–8 hz), alpha (8.5–12 hz), beta (12.5–20 hz), and gamma (35–45 hz). ANOVA analyses revealed an effect of CT/DBS in activity counts (p<0.001), horizontal activity (p<0.001), and total distance (p<0.001) Light phase of CT/DBS also had a significant effect in delta (F. p<0.05) and theta (G. p<0.05) waves. Panels include 10 minutes of data after CT/DBS, normalized to before stimulation. Data are presented as mean ± s.e.m. * p<0.05 compared to before, # p<0.05 compared to dark phase.

Figure 6. Temporal Pattern Experiment - example of behavior at high temporal resolution

Motor activity behavior of one mouse at 3 temporal patterns of stimulation, 100 μA, in the light phase. A. Fixed, B. Random, and C. Chaotic. Activity counts ('counts') shown at 1 sample every 10 seconds, Horizontal activity ('Hactv') and Total distance ('Totdist') shown at 1 sample every 1 second. Grey boxes mark epochs of stimulation.