Modulation of hippocampal activity with fornix Deep Brain Stimulation Paul H. Stypulkowski, Scott R. Stanslaski, Jonathon E. Giftakis  Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation  DOI: 10.1016/j.brs.2017.09.002 Copyright © 2017 The Authors Terms and Conditions

Fig. 1 DBS lead locations. Representative examples of the position of the contact arrays of the leads located adjacent to the fornix (A–D) and within the hippocampus (E–F) derived from post-operative CT and merged with pre-operative MRI. Coronal image (A) is at the AP level of the lead tip; panel (B) shows an atlas section at the same approximate AP position illustrating ascending columns and body of fornix (arrows); coronal image (C) is at the AP level of the last electrode of the array; and panel (D) shows mid-sagittal view. In this subject the most distal contact pair (0–1+) produced the largest evoked potentials in the hippocampus. For reference, AC-PC length is 15.5 mm. Panel (E) shows a coronal image at the AP level of the tip of the hippocampal lead traversing the dentate gyrus (arrow), with a corresponding atlas image in panel (F). Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 2 Hippocampal evoked potentials. EPs recorded from three subjects illustrating input-output relationship with increasing amplitude of fornix stimulation. Stimulation and recording configurations for each were: (top) FX 1–2+, HC 8–11; (middle) FX 0–1+, HC 9–11; (bottom) FX 0–1+, HC 8–11. Stimulus amplitude legend applies to all three panels. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 3 Network evoked potentials. EPs recorded within the network in response to stimulation at different sites. Bidirectional EPs recorded in one subject in response to hippocampal stimulation (top) (HC 10–11+, record FX 0–3) and fornix stimulation (middle) (FX 0–1+, record HC 8–11). Bottom panel is from Stypulkowski et al. (2014) showing hippocampal EPs in response to anterior thalamic (ANT) stimulation, illustrating similarity to longer latency response in middle panel (arrows). Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 4 Fornix Stimulation – amplitude effects. Hippocampal LFPs (top), derived theta band (4–9 Hz) power (middle), and corresponding spectrogram (40 dB scale) recorded during fornix stimulation with bursts of increasing stimulus amplitude (120 us, 40 Hz, 0.1 mA/s ramp, 10 s burst). Inset (arrow) shows LP filtered trace illustrating theta burst at end of stimulus. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 5 Fornix Stimulation - frequency effects. Hippocampal LFPs (top), derived theta band (4–9 Hz) power (middle), and corresponding spectrogram (40 dB scale) recorded during fornix stimulation with bursts of increasing stimulus frequency (120 us, 4 mA, 0.1 mA/s ramp, 10 s burst). Inset (arrow) shows LP filtered trace illustrating theta burst at end of stimulus. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 6 Change in network state following fornix stimulation. Spectrogram (40 dB scale), power spectra, and phase-amplitude coupling for periods before and after stimulation induced hippocampal theta burst. Stimulation (FX 1–2+) was slowly ramped to 4 mA (120 us, 40 Hz, 0.1 mA/s ramp, 10 s burst) which generated a theta burst and long-lasting state change in hippocampal activity. DBS was on only during the period indicated at the top of the figure. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions

Fig. 7 Closed-loop fornix stimulation. Example of closed-loop DBS controlled by theta band power level. Records show hippocampal LFP signal (top, LP filtered to remove stimulus artifact), low theta band (3–5 Hz) power level (2nd trace), higher frequency (22–38 Hz) power level (3rd trace), DBS amplitude (4th trace) and LFP spectrogram (bottom, 40 dB scale). The closed loop DBS algorithm was active for the period indicated. Dotted lines in the theta power band record identify threshold levels to initiate/ramp up stimulation (lower threshold) and stop ramp/turn off stimulation (upper threshold) when the theta power crossed these levels for a duration of 10 s. During the period of closed-loop operation, three slow ramps of DBS, lasting approximately one minute, were delivered (0.1 mA/s ramp, 120 us, 40 Hz) as indicated. DBS was off at all other times. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation DOI: (10.1016/j.brs.2017.09.002) Copyright © 2017 The Authors Terms and Conditions