Microelectrode locations, unit counts, and experimental design.

(A) Behnke Fried-style macro/micro depth electrode (left) and microelectrode bundle locations projected in MNI space (right). (B) The proportion of units recorded from each brain area (left) and the proportion of units that met the criteria for inclusion in analyses (average pre-trial baseline firing rate ≥ 0.1 Hz) (right). (C) Counts of total (grey) and included (colored) units within each region. (D) Intracranial recording and stimulation took place in the context of a two-phase (encoding, retrieval) visual recognition memory task. A series of neutral valence images were shown (3 s), half of which were followed by direct electrical stimulation (1 s). Retrieval memory was tested during a self-paced task ∼24 hours later. (E) Simulated theta-burst stimulation trace (left) and individual stimulation pulse (right); charge-balanced, bipolar, biphasic rectangular pulses were delivered over a 1 s period. HIP = hippocampus (coral), OFC = orbitofrontal cortex (yellow), AMY = amygdala (blue), ACC = anterior cingulate cortex (purple).

Example raster plots depicting heterogeneous responses to stimulation.

(A) Representative example of modulation during stimulation. The highpass-filtered, trial-averaged LFP from the corresponding microwire is shown (top) above the spike raster for an example unit located in the hippocampus (middle); the grey shaded region depicts the duration of stimulation with onset at t = 0. The average firing rate across trials was estimated by convolving the binned spike counts (100 ms bins) with a Gaussian kernel (bottom). (B) The difference in the number of spikes in the 1 s peri-stimulation epochs for each trial is shown (top). We subsequently performed a Wilcoxon signed-rank test on the during- and post-stimulation spike counts for each trial vs. the pre-trial baseline and compared the empirical test statistic against a null distribution generated by shuffling the epoch labels 1,000 times (bottom); the grey-shaded region represents the distribution containing 95% of observed values. (C) Some units (left, left-middle) exhibited increased firing rates, whereas others (right-middle, right) had their firing suppressed. The temporal dynamics of the firing rate modulation (e.g., onset, duration) were highly variable across units. The averaged waveform for each of the visualized units is shown below its corresponding peri-stimulation raster plot (WFs = waveforms); the shaded region represents standard deviation across waveforms.

Characterization of modulation in neuronal firing rate.

(A) Percent of modulated units observed across trials separated by stim (purple) vs. no-stim conditions (orange). (B) Percent of modulated units as a function of recording region. (C) Comparison of baseline firing rate in units separated by condition (stim vs. no-stim) and outcome (NS = not significant, Mod = modulated). (D) Venn diagram depicting the shared and independent proportions of units modulated by image onset (Image) and the two experimental conditions (stim vs. no-stim). (E) Scatterplot of pre-stimulation firing rate relative to the firing rate during the two contrast windows (during, post) for the stim (left) and no-stim (right) conditions. Modulated units are highlighted in purple (stim) or orange (no-stim). (F) Temporal dynamics of pseudo-population coactivity within each condition, represented by the first three principal components of the trial-averaged firing rates. The grey-shaded region depicts the duration of stimulation with onset at t = 0. Images were presented on screen for 3 s, with onset at t = -3. * p < 0.05, *** p < 0.001, NS = not significant.

Summary of behavioral performance during memory task.

(A) Memory performance for each session is quantified using d’ (left); grey lines connect d’ scores across conditions for an individual session. Boxplot of the observed difference in d’ scores across conditions (right). (B) Hit rate (percent of old images correctly recognized) and false alarm rate (percent of new images incorrectly labeled as old) across conditions.

Unit quality metrics.

(A) Number of units detected per implanted microelectrode bundle. (B) Mean firing rate (Hz) across recording session. (C) Percent of interspike intervals < 3 ms. (D) Interspike interval coefficient of variation. (E) Mean presence ratio of firing within units (1 s bins). (F) Signal-to-noise ratio of unit waveform peak. (G) Mean signal-to-noise ratio across the entire unit waveform. (H) Representative example of stereotyped, high-amplitude stimulation-artifact waveform; non-physiological waveforms were excluded from analysis.

Characterization of units based on laterality relative to stimulation.

(A) Unit counts on the contralateral (Contra) or ipsilateral (Ipsi) side of stimulation. (B) Unit counts separated by laterality and region. (C) Stacked histograms of Euclidean distance between microelectrode bundle location and stimulation contacts, separated by laterality (bin size = 5 mm).

Analysis of pseudo-population activity within regions, separated by laterality relative to stimulation.

Pseudo-population activity was characterized within each region via a linear dimensionality reduction on the trial-averaged firing rates. The temporal dynamics of each region’s first three principal components are shown for (A) units ipsilateral to stimulation and (B) units contralateral to stimulation. HIP = hippocampus (coral), OFC = orbitofrontal cortex (yellow), AMY = amygdala (blue), ACC = anterior cingulate cortex (purple).

Sub-analysis of stimulation parameters used across experiments.

Comparison of the proportion of stimulation-modulated units across sessions with 1 mA (n = 23) vs. 0.5 mA (n = 7). (B) Comparison of the proportion of stimulation-modulated units across sessions testing distinct pulse frequencies: 33 Hz vs. 80 Hz (n = 1) and 50 Hz vs. 80 Hz (n = 6). The values above individual bars represent the number of sessions using that stimulation parameter. NS = not significant.

Control analyses for the detection of modulated units.

The same permutation-based analyses reported in the manuscript were repeated under different control conditions. The percent of units (total n = 203) that met the firing rate threshold for inclusion (pink), the percent of included units modulated in the stim condition (purple), and the percent of included units modulated in the no-stim condition are shown. (A) The threshold for inclusion of units was varied from 0–3 Hz (0.1 step size); the black dashed line represents the ≥ 0.1 Hz threshold used in the manuscript. (B) To control for the possibility that non-physiological stimulation artifacts may preclude the detection of temporally adjacent spiking, we removed segments of data beginning at the onset of each burst of pulses (0–60 ms, 5 ms step size). Identical temporal windows were removed from the corresponding pre- and post-stimulation epochs to mitigate effects resulting solely from summation over different epoch sizes (reduced spike counts with shorter windows).