Design of a novel stimulation system with time-varying paradigms for investigating new modes of high frequency stimulation in brain

Abstract

Background: Deep brain stimulation (DBS) has shown wide clinical applications for treating various disorders of central nervous system. High frequency stimulation (HFS) of pulses with a constant intensity and a constant frequency is typically used in DBS. However, new stimulation paradigms with time-varying parameters provide a prospective direction for DBS developments. To meet the research demands for time-varying stimulations, we designed a new stimulation system with a technique of LabVIEW-based virtual instrument.

Methods: The system included a LabVIEW program, a NI data acquisition card, and an analog stimulus isolator. The output waveforms of the system were measured to verify the time-varying parameters. Preliminary animal experiments were run by delivering the HFS sequences with time-varying parameters to the hippocampal CA1 region of anesthetized rats.

Results: Verification results showed that the stimulation system was able to generate pulse sequences with ramped intensity and hyperbolic frequency accurately. Application of the time-varying HFS sequences to the axons of pyramidal cells in the hippocampal CA1 region resulted in neuronal responses different from those induced by HFS with constant parameters. The results indicated important modulations of time-varying stimulations to the neuronal activity that could prevent the stimulation from inducing over-synchronized firing of population neurons.

Conclusions: The stimulation system provides a useful technique for investigating diverse stimulation paradigms for the development of new DBS treatments.

Keywords: Axonal block; High frequency stimulation; LabVIEW software; Time-varying frequency; Time-varying intensity.

Fig. 1

Schematic diagram of the stimulation system (left), test connections or experiment connections (middle), and the recording device (right)

Fig. 2

Biphasic pulse generated by a LabVIEW sub-VI that multiplied two monophasic pulses

Fig. 3

User interface of the stimulation system

Fig. 4

Test results for pulse sequences with time-varying intensity and with time-varying frequency. a Comparison between the theoretical intensity and measured intensity for a pulse sequence with time-varying intensity 0.3–3.0 V, pulse frequency 400 Hz and duration 5 s. b Comparison between the theoretical frequency and measured frequency for a pulse sequence with time-varying frequency 400–100 Hz, intensity 3 V and duration 5 s

Fig. 5

Neuronal responses to stimulation paradigms with various pulse frequencies. a Schematic diagram of a recording electrode (RE) in the CA1 pyramidal cell layer and an antidromic stimulation electrode (ASE) in the alveus of rat hippocampus. b Example of CAl neurons’ responses to 1-min A-HFS with constant parameters of an intensity 0.3 mA and a frequency 100, 200 and 400 Hz, respectively. Large APS events were always evoked by pulses at the initial phase of A-HFS with constant parameters. Red bars indicate the periods of A-HFS. c Scatter diagrams of the amplitudes of APS evoked by each pulse (normalized by the baseline APS evoked by a single pulse) during the whole 1-min A-HFS (left) and during the initial 2 s period (right)

Fig. 6

Neuronal responses to a time-varying stimulation paradigm. a A-HFS with a ramped-intensity and 400 Hz frequency suppressed the initial APS events, but large APS reappeared when the pulse frequency dropped directly from 400 to 100 Hz. Top: schematic diagrams of the changes of pulse frequency and intensity; middle: recording signal with stimulation artifacts removed; bottom: expanded plots of APS waveforms. b Scatter diagrams of the normalized amplitudes of APS evoked by each pulse during the 100-s stimulation

Fig. 7

Neuronal responses to another time-varying stimulation paradigm. a Similar to the paradigm in Fig. 6 but decreasing the frequency smoothly and gradually to 100 Hz after the initial 10 s stimulation, no large APS appeared. b Scatter diagrams of the normalized amplitudes of APS evoked by each pulse during the 100-s stimulation